Who I am and how I discovered this information

We haven't got time to mince words in any way. Who am I? I've been a typical high IQ software engineer(Nerd) of 10 years who's truly internalized that the brain is another kind of computer. I had serious health issues such as sleep apnea, scoliosis, fibromyalgia and others slowly consuming more and more of my life since I was a teenager. My lack of physical abilities was destroying my already waning self-worth. As such, when my wife left me for someone more exciting you can understand the blow was enough to basically finish me off. Fibromyalgia is stress modulated so I was physically and mentally crippled.

At 32 years old I had lost all that I worked for all those years, house cars etc; was nearly homeless and in excruciating pain at all times. I knew that pain perception was in the brain and there must be a way to fix it other than continuing to just take medication as I had for the past 8 years. Taking more would simply complicate the problem eventually. So I became obsessed with the brain and then met my current fiancee who is about to get her bachelor's in Neuroscience.

I've learned all about the brain through her and self study so while I have the abilities I don't have the credentials. I learned everything they taught her and much more. A law passed that caused the pain doctor I had gone to for 5ish years to suddenly stop prescribing any medication and so did everyone else in my area. Doctors I spoke to said they were full up and getting 30-40ish calls a day from people sudeenly cut off. I had to live without medication suddenly on top of everything else. I was being tortured daily into trying to cure myself so you can understand that I've had a lot of incentive. Daily torture does that for you.

While looking at drugs that fix dysfuntions like addiction I discovered that there was one called ibogaine being used all over the world except in the US to CURE heroin addiction. This eventually led to my understanding of Salvia.

I can only tell you the super ultra short story(and even that is long) to help you understand how and why Salvia has changed my life So here it is:

How it all Works

Drugs in general can push buttons in your brain called receptors. Push them too hard and they break. Cocaine presses your satisfaction buttons(dopamine receptors) with a sledge hammer. These button are how you work and even when you just wipe a counter you squirt a little dopamine and hit your own satisfaction buttons.

Pushing the button is called agonism
Blocking up the button so it can't be pressed is called antagonism

When the buttons go away from being pushed too hard it's called downregulation When your body determines you need more of that button and make more it's called upregulation

So you can see that when you take a pain reliever that hits the pain relief button a lot (and all the time) you wear out those buttons and need more of the same chemical to get the same effect. This is why you become dependant. IE when you're a chronic pain sufferer and they give you something to make you feel better, they make the problem worse eventually. (pain relievers are mu opioid agonists)

It is well known in neuroscience that agonism causes downregulation and antagonism causes upregulation.

In the brain, some buttons cause different chemicals to be released to push other buttons etc. Like when the pain relief button is hit(mu opioid), it releases a chimical to hit the satisfaction button(dopamine) Your brain is a homeostasis machine that has lots of loops that make it so that the first thing it did gets turned off. Like the mu gets pushed and releases the chemical that pushes dopamine which releases the chemical that hits a button to turn off the mu pusher chemical. It is always trying to balance to circumstances. That is why antagonism results in upregulation. When you blocked up the button and your body tried to push it, it determined that it couldn't do it well (it pushes millions of the same button at the same time to kinda vote on something) and that it needed more of that sort of buttons.

These buttons can even get a little worn and sticky but get greased to work well again. This is called desensitization and resensitization. It's the frequency of being pushed and the hardness of each push.

At this point let me ask you to keep in mind that most every neurological disorder relates back to dopamine and the addiction system in some way.

Your brain always has small amounts of most chemicals being released all the time so when you increase the number of buttons you make it more likely a lot of buttons will be gettinng pushed at any one time. It's like setting up voting stations in old folks homes. More accessibility gets more votes. And the kappa button is a vote of fear.

How Salvia Works

Studies have shown that increases of the kappa-opioid button in different areas of the brain can result from child abuse and drug use. Kappa buttons are found in high numbers in the amygdala, the fear center, especially following abuse or trauma. Simultaneously we know that drug abuse of nearly every kind reduces dopamine(satisfaction) buttons in a certain area of the brain.

Kappa agonism(button pushing) results in avoidance behaviors, can temporarily increase pain perception in males and cause general dysphoria unless mu is also present. IE an addict or abused child is more likely to experience these negative thoughts and feelings, but excersize can release both simultaneously (mu and kappa) without the same dysphoria.

Strong and sustained kappa agonism(button pushing) results in a huge increase in dopamine(satisfaction) buttons in the area of the brain where needed after they are destroyed by cocaine etc. It also causes resensitization of mu buttons as well. And it downregulates Kappa.

What I'm saying is that

Salvia undoes the negative effects of Drug abuse as well as all the other neurological disorders. It does so on the long term.

It can be a horrific and frightning experience for a short period but can bring new life to the suffering. A single dose can make a gigantic difference in pain and depression for at least two weeks. I know this with number of years experience.

Unfortunataly most normal medication works by fixing the symptoms instead of effecting a cure. Like SSRIs lock serotonin so that it builds up to higher levels. Thereby causing more button pushing more often. Guess what? ...it temporarily feels better and causes dependance.(downregulation of serotonin buttons)

Salvia simply kicks the machine in the place it needs to get going on its own.


I was lead to this discovery intially by researching Ibogaine, a root from africa that cures heroine addicts in a single dose. It's legal in most civilized countries except the US. Addicts in the US have to travel to canada or mexico for it. It's effects are that it hits 5ht2a(serotonin), Mu, and Kappa. I already knew what the first two did... (5ht2a agonism heals as well but that's a different discussion) Kappa is responsible for eliminating the withdrawel and drug craving. Unfortunately ibogaine can be overdosed on fairly easily. There have been no Salvia Overdose deaths.

It is my hypothesis that Kappa is the "negative" or "bad" or "avoid" button. It is closely linked with fear. When in danger frequently your brain needs to be very fearful and therefore careful to avoid death. It will grow more this button so it becomes more likely you'll avoid "bad" things. For instance, when your body is hurt badly it releases mu to reduce your suffering temporarily, that activates dopamine, which creates more kappa buttons

Below is a small sample of some of the research I've put together. There is so much more I'm not even touching on in the hope to get the message across to as wide of an audience as possible. I'm doing all I can but I've got a lot on my plate. This is the most I can do right now to help this cause. Please spread this information. Apparently some nursery organizations are fighting this, I hope you guys can use this as ammo.

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BRAIN REGION TERMS: The Hypothalamus regulates certain metabolic processes and other autonomic activities. It synthesizes and secretes neurohormones, often called hypothalamic-releasing hormones, and these in turn stimulate or inhibit the secretion of pituitary hormones. The hypothalamus controls body temperature, hunger, thirst,[1] and circadian cycles.

Rostral=front
Caudal=rear

The basal ganglia (or basal nuclei) are a group of nuclei in the brain interconnected with the cerebral cortex, thalamus and brainstem. Mammalian basal ganglia are associated with a variety of functions: motor control, cognition, emotions and learning.

The Rostral basal ganglia include:
patumen
caudate nucleus
nucleus accumbens
The Striatum is a subcortical part of the telencephalon. It is the major input station of the basal ganglia system. Anatomically, the striatum is the caudate and the putamen.
The putamen is a structure in the middle of the brain, which, together with the caudate nucleus forms the dorsal striatum.
The putamen is a portion of the basal ganglia that forms the outermost part of the lenticular nucleus. It appears to play a role in reinforcement learning. It is coextensive with the insula, which has been found to contain mirror neurons.

The Caudate Nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate, originally thought to primarily be involved with control of voluntary movement, is now known to be an important part of the brain's learning and memory system.

The Nucleus Accumbens (NAcc), is a collection of neurons located where the head of the caudate and the anterior portion of the putamen meet just lateral to the septum pellucidum. This nucleus is thought to play an important role in reward, laughter, pleasure, and addiction

Images:
http://en.wikipedia.org/wiki/Image:Constudoverbrain.gif
http://en.wikipedia.org/wiki/Image:Telencephalon-Horiconatal.jpg
http://en.wikipedia.org/wiki/Image:Brain_structure.gif
CHEMICALS
Messenger Ribonucleic Acid (mRNA): is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes.


Fluoxetine hydrochloride (Prozac) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.

Quinpirole: is a synthetic compound that acts as a dopamine D2/D3 receptor agonist
U-69593: Kappa opioid agonist
U50,488: a selective kappa opioid receptor agonist
nor-binaltorphimine dihydrochloride: a selective kappa receptor antagonist
Dynorphin: endogenous kappa opioid agonist.

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http://www.iscid.org/encyclopedia/Prodynorphin

Prodynorphin is an opioid polypeptide or protein that is a basic building block of endorphins, the chemical messengers in the brain that appear most heavily involved in the anticipation and experience of pain (and possibly pleasure – the two pathways are closely interrelated chemically) as well as the formation of deep emotional bonds. Endorphins are also critical in learning and memory. Additionally, prodynorphin is a precursor to the neurotransmitters dynorphin A and dynorphin B, both additional opioids.

Prodynorphin levels also seem to be highly correlated with variations in human perception. Studies have shown a positive correlation between low levels of prodynorphin and susceptibility to cocaine addiction. Additional studies have revealed a significant link between certain variations in prodynorphin and the development of epilepsy and schizophrenia. It is likely, as more attention is paid to this previously obscure neural chemical, that more effects will be found.

Recently, interesting discoveries centered around prodynorphin have led researchers to wonder if it is may contribute to the distinctions between humans from other primates. Though all primates possess a nearly identical set of prodynorphin proteins, in humans a gene causes prodynorphins to produce more prolifically than they do in non-human primates. In addition, with 98-99% of genetic base material in humans and other primates being close to identical, the section related to prodynorphins differs by as much as 10%, and there are striking differences in the production of prodynorphins from one population of humans to the next.

Experimental introduction of human and chimpanzee prodynorphin gene segments into human neural cells saw a dramatic difference in prodynorphin expression; the human version expressed 20% more than the chimpanzee version.

Scientists hypothesize that the extra production of prodynorphin encouraged emotional bonding as well as the development of human intelligence and maybe even language. Many are speculating that prodynorphin may be one of the first genetic markers that truly demonstrates what makes us human.

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D2 receptor binding in left caudate nucleus low in OCD patients.

http://cat.inist.fr/?aModele=afficheN&cpsidt=15753612

Low level of dopaminergic D[2] receptor binding in obsessive-compulsive disorder

Auteur(s) / Author(s)

DENYS Damiaan (1) ; VAN DER WEE Nic (1) ; JANSSEN Joost (1) ; DE GEUS Femke (1) ; WESTENBERG Herman G. M. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, PAYS-BAS

Résumé / Abstract

Background: Despite growing evidence for involvement of the dopaminergic system in obssessive-compulsive disorder (OCD), the functional anatomy of the dopaminergic system in the basal ganglia has been investigated sparsely. Methods: Dopamine D[2] receptor binding was assessed in 10 medication-free OCD patients and 10 healthy control subjects, matched forage, gender, and handedness. The binding potential was measured with single photon emission computerized tomography (SPECT) and infusion of the D[2] receptor radiotracer [[123]I] iodobenzamide. With magnetic resonance imaging as reference, regions of interest (caudate and putamen) were delineated for each hemisphere and coregistered with the corresponding SPELT scans Results: Dopamine D[2] receptor binding in the left caudate nucleus was significantly lower in the patients with OCD than in healthy control subjects [F(1,18) = 7.0, p = .016]. In addition, an interbemispheric difference was observed in the patient sample. Both the D[2] receptor binding potential (df = 9, p = .012), and the volume (df = 9, p = .029) of the left caudate nucleus were statistically significantly reduced relative to the right caudate nucleus. Conclusions: This study provides in vivo evidence for abnormalities in the binding potential of the dopamine D[2] receptor, which suggest the direct involvement of the dopaminergic system in the pathophysiology of OCD.

D2 binding low in caudate and patumen (striatum)in antisocial patients.

http://ajp.psychiatryonline.org/cgi/content/abstract/157/3/457

Low Dopamine D2 Receptor Binding Potential in Social Phobia

Franklin R. Schneier, M.D., Michael R. Liebowitz, M.D., Anissa Abi-Dargham, M.D., Yolanda Zea-Ponce, Ph.D., Shu-Hsing Lin, Ph.D. and Marc Laruelle, M.D.

OBJECTIVE: This study compared dopamine D2 receptor binding potential in patients with social phobia and healthy comparison subjects. METHOD: Dopamine D2 receptor binding potential was assessed in 10 unmedicated subjects with generalized social phobia and no significant lifetime psychiatric comorbidity and 10 healthy comparison subjects matched for age and sex. Binding potential was measured in the striatum by using single photon emission computerized tomography and constant infusion of the D2 receptor radiotracer [123I]iodobenzamide ([123I]IBZM). RESULTS: Mean D2 receptor binding potential was significantly lower in the subjects with social phobia than in the comparison subjects. Within the social phobia group, there was a nonsignificant correlation of binding potential with the Liebowitz Social Anxiety Scale score. CONCLUSIONS: Generalized social phobia may be associated with low binding of [123I]IBZM to D2 receptors in the striatum.

Cocaine increases prodynorphin in caudate patumen(striatum) and decreases in hypothalamus. Kappa opioids do opposite plus reduce it in hippocampus. However if Serotonin is low, there is no effect but cocaine then increased dynorphin in the hippocampus.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17055175&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Role of serotonin in the regulation of the dynorphinergic system by a kappa-opioid agonist and cocaine treatment in rat CNS.D'Addario C, Di Benedetto M, Izenwasser S, Candeletti S, Romualdi P.

Department of Pharmacology, University of Bologna, Irnerio 48, Bologna, 40126 Italy.

It has been shown that chronic cocaine increases prodynorphin mRNA in the caudate putamen and decreases it in the hypothalamus. In addition, treatment with a kappa-opioid receptor agonist produced the opposite effect on prodynorphin gene expression in these brain regions and also evoked a decrease in the hippocampus. It is already known that kappa-opioid receptor agonists decrease the development of sensitization to some of the behavioral effects of cocaine. The serotonin system has also been shown to regulate dynorphin gene expression and a continuous infusion of fluoxetine induced prodynorphin gene expression in the same pattern as the kappa-opioid agonist (+)(5a,7a,8b)-N-methyl-N-[7-(1-pyrrolidinyl)-1 oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U-69593) in the brain regions investigated. It is interesting to note that treatment with a continuous infusion of cocaine produced different effects on this parameter. To determine whether serotonin plays a role in the regulation of prodynorphin mRNA by kappa-opioid agonists or cocaine, rats were treated with the serotonin depleter parachloroamphetamine (PCA). Beginning 24 h later, rats were treated with the selective kappa-opioid agonist U-69593 for 5 days or continuously with cocaine for 7 days and prodynorphin mRNA was measured. Prodynorphin mRNA was decreased significantly in the hypothalamus, caudate putamen, and hippocampus of rats treated with a single injection of PCA. Subsequent to PCA administration the effects of U-69593 or cocaine on prodynorphin mRNA were differentially affected across brain regions. Prodynorphin gene expression was still increased by U-69593 treatment in the hypothalamus and decreased in the caudate putamen. Cocaine treatment still produced a decrease in this parameter in the hypothalamus and an increase in the caudate putamen. In contrast, in the hippocampus, the decrease in prodynorphin mRNA produced by U-69593 was no longer evident after PCA and cocaine, which previously had no effect, now increased it in the serotonin-depleted group. These findings suggest that serotonin is necessary to maintain normal levels of dynorphin mRNA in all of the investigated brain areas and that the regulation of prodynorphin mRNA expression by chronic treatment with a kappa-opioid receptor agonist or cocaine requires serotonin in the hippocampus, but not in the hypothalamus or caudate putamen.

PMID: 17055175 [PubMed - indexed for MEDLINE]

Kappa opiods decrease cocaine use and block sensitization that normally occurs. Slows re-instatement of drug use.

http://www.springerlink.com/content/ucnnay3py6v5jydb/

U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking

Authors

S. Schenk1, Brian Partridge1, Toni S. Shippenberg2

1Texas A&M University, Department of Psychology, College Station, TX 77843, USA e-mail: sxs@psyc.tamu.edu Fax: +1-409-845-4727

2National Institute on Drug Abuse, Integrative Neuroscience Unit, Behavioral Neuroscience Lab, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA

Abstract

Rationale: Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. Objectives: This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. Methods: During daily test sessions, the dose-effect curve (0.015- 1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. Results: U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. Conclusions: These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine.

D2 receptors reduced in caudate patumen 40% but returned after 10 days. D2 increase in nucleus accumbens 65% after 10 days.

http://www.ncbi.nlm.nih.gov/pubmed/9776131?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www3.interscience.wiley.com/cgi-bin/abstract/77883/ABSTRACT?CRETRY=1&SRETRY=0

Repeated treatment with the selective kappa opioid agonist U-69593 produces a marked depletion of dopamine D2 receptors

Sari Izenwasser 1 *, Jane B. Acri 2, Paul M. Kunko 1, Toni Shippenberg 2

1Psychobiology Section, National Institute on Drug Abuse, Divison of Intramural Research, National Institutes of Health, Baltimore, Maryland

2Integrative Neuroscience Unit, National Institute on Drug Abuse, Division of Intramural Research, National Institutes of Health, Baltimore, Maryland

email: Sari Izenwasser (sizenwas@newssun.med.miami.edu)

*Correspondence to Sari Izenwasser, Department of Neurology, University of Miami Medical School, 1501 NW 9th Ave., Rm. 4061, Miami, FL 33136

Keywords

cocaine • sensitization • tolerance

Abstract

U-69593, the selective k-opioid agonist, was repeatedly administered in single daily injections (0.32 mg/kg) to male, Sprague-Dawley rats. Two or ten days later, the rats were euthanized and dopamine D1 and D2 receptors were measured using (3H]SCH 23390 or [3H]sulpiride, respectively, in caudate putamen and nucleus accumbens. Two days after the last of three injections, dopamine D2 receptors in the caudate putamen were decreased by approximately 40%, with no change in D1 receptors. Dopamine D2 receptor number had returned to normal by 10 days posttreatment. In contrast, in the nucleus accumbens there was a small, nonsignificant decrease in dopamine D2 receptors 2 days after treatment, but a large increase (65%) after 10 days. In agreement with the changes in D2 receptors, there was a significant downward shift in the locomotor activity curve for the D2 agonist quinpirole after a 2-day withdrawal. There were no differences in either the total amount of dopamine taken up or in the IC50 for cocaine to inhibit dopamine uptake following this treatment, suggesting that the dopamine transporter and presynaptic terminals were intact. The results of these studies demonstrate that repeated administration of a selective k-opioid agonist induces long-term alterations in dopamine D2 receptors. Furthermore, the finding that these changes in receptor number require both repeated injections and a withdrawal time greater than 1 day suggests that these alterations are compensatory in nature. Synapse 30:275-283, 1998. © 1998 Wiley-Liss, Inc.

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Shows that low d2 receptors in Nacc is causal of addiction

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11280926&ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJ, Comings DE.

Department of Biological Sciences, University of North Texas, Denton, Texas, USA.

The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces "reward" when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. "The reward cascade" involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or "reward site." It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the "pleasure molecule" and/or the "antistress molecule." When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor A1 allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette's Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome.

PMID: 11280926 [PubMed - indexed for MEDLINE]

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Shows that chronic cocaine reduces d2 receptor desities/availability in striatum and NAcc

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17544385&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Active versus passive cocaine administration: differences in the neuroadaptive changes in the brain dopaminergic system.Stefanski R, Ziólkowska B, Kusmider M, Mierzejewski P, Wyszogrodzka E, Kolomanska P, Dziedzicka-Wasylewska M, Przewlocki R, Kostowski W.

Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Sobieskiego 9, 02-957 Warsaw, Poland.

There is considerable evidence that chronic exposure to cocaine is associated with low striatal dopamine D2 receptor availability. In the present study we wished to determine whether neuroadaptive changes in densities of D2 receptors were due to direct pharmacological actions of cocaine or they reflected motivational states that were present when cocaine injection depended on active drug-seeking behavior and whether these changes were related to the actual expression of D2 mRNA. To achieve this goal we utilized a "yoked" procedure in which rats were tested simultaneously in groups of three, with only one rat actively self-administering cocaine while the other two received yoked injections of either cocaine or saline. Only passively administered cocaine produced a decrease in dopamine D2 receptor levels in the anterior and central regions of caudate/putamen, and both the shell and core of the nucleus accumbens, as measured by in vitro quantitative autoradiography. In contrast, examination of D2 receptor gene expression using in situ hybridization analysis revealed that there was an increase in D2 receptor mRNA levels in the ventral tegmental area of rats actively self-administered cocaine. We conclude that the reductions in striatal D2 receptor densities may be related to the chronic administration of cocaine per se and not to the motivated process of reinforced responding. Our results also suggest that increases in D2 receptor mRNA levels in limbic regions do not necessarily result in increased receptor densities and these changes likely reflect motivational states that were present when cocaine injection dependent on active drug self-administration.

PMID: 17544385 [PubMed - indexed for MEDLINE]

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Additionally shows reduction of D2 in NAcc from chronic cocaine admin

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9704885&ordinalpos=16&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys.Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP.

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083, USA.

The present study used autoradiography to examine the effects of PThe dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces chronic self-administration of cocaine on the density of dopamine D2 receptors in nonhuman primates. Three rhesus monkeys intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months until they were euthanized immediately after a self-administration session. Binding site density of the D2 ligand [3H]raclopride (2 nM) was assessed in these monkeys as well as three untreated controls, using quantitative in vitro receptor autoradiography. As compared to untreated controls, D2 binding site density was significantly lower in the animals that self-administered cocaine in all regions of the striatum rostral to the anterior commissure. These regions include the anterior and central regions of the caudate nucleus, putamen, olfactory tubercle, and both the shell and core of the nucleus accumbens. Within the substantia nigra and ventral tegmental area, by contrast, no differences were found in the density of D2 binding sites. These findings suggest a pervasive effect of cocaine on the regulation of D2 receptors in the striatum. The lack of change within the ventral midbrain, however, suggests a differential regulation of D2 receptors in the striatum and ventral midbrain. This study confirms and extends our knowledge of the neurobiological changes in the mesolimbic dopamine system that result from chronic exposure to cocaine.

PMID: 9704885 [PubMed - indexed for MEDLINE]

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Shows that dopamine in NAcc causes decrease in PFC ACh

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17681559&ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

D2-like receptors in nucleus accumbens negatively modulate acetylcholine release in prefrontal cortex.Brooks JM, Sarter M, Bruno JP.

Department of Psychology, The Ohio State University, Columbus, OH 43210, USA.

Glutamatergic and dopaminergic inputs converge on medium spiny neurons in nucleus accumbens and regulate the excitability of these projections to target areas including the cholinergic basal forebrain. NMDA receptors situated on these projections are locally modulated by D1- and D2-like receptors. We previously reported that the D1-like positive modulation of NMDA receptor activity is expressed trans-synaptically in the control of basal forebrain cholinergic projections to prefrontal cortex. The present experiments tested the hypothesis that D2-like receptors in accumbens negatively modulate cortical ACh release. Perfusion of NMDA (150 microM) into the shell region of the accumbens produced a sustained increase (150-200%) in ACh release in prefrontal cortex. This increase was completely blocked by co-perfusion with the D2-like agonist quinpirole (100 microM). Perfusion of quinpirole also reduced basal ACh release (approximately 50%) in prefrontal cortex. The contribution of D2 receptors to the quinpirole effect was assessed in two additional studies. The first study revealed that co-perfusion of the D2 antagonist haloperidol (100 microM) blocked the quinpirole-induced attenuation of NMDA mediated ACh release. The second experiment demonstrated that intra-accumbens perfusion of quinelorane (100 microM), a more selective D2 agonist than quinpirole, also attenuated the NMDA mediated ACh release. Collectively, these studies demonstrate that D2 receptors in accumbens negatively modulate basal and NMDA mediated increases in ACh release in prefrontal cortex. This negative modulation may contribute to the integration of normal attentional processing and goal directed behavior and to the therapeutic effects of antipsychotic medication on cognition in psychopathologies such as schizophrenia.

PMID: 17681559 [PubMed - in process]

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Shows that schizo rats have high ach in PFC. They are overly responsive to Ach.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15056275&ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Alterations in dopaminergic modulation of prefrontal cortical acetylcholine release in post-pubertal rats with neonatal ventral hippocampal lesions.Laplante F, Srivastava LK, Quirion R.

Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montréal, Québec, Canada.

Excitotoxic lesion of the ventral hippocampus in neonatal rats is a putative animal model of schizophrenia with characteristic developmental abnormalities in dopaminergic neurotransmission and prefrontal cortical functions. Converging evidence also points to the involvement of the central cholinergic system in neuropsychiatric disorders. These two neurotransmitter systems are interlinked in the prefrontal cortex (PFC) where dopamine stimulates acetylcholine (ACh) release. In the present study, we investigated the role of dopamine in the developmental regulation of prefrontal cortical ACh release and the expression of nicotinic and muscarinic receptors in pre- and post-pubertal rats with neonatal ibotenic acid-induced lesions of the ventral hippocampus (NVH). In vivo microdialysis in the PFC revealed that systemic injections of the D(1)-like receptor agonist (+/-)-6-chloro-7,8-dihydroxy-1-phenyl2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) (2.5 and 5.0 mg/kg i.p.) caused significantly higher ACh release in post-pubertal NVH-lesioned animals (250 and 300% baseline for 2.5 and 5.0 mg/kg, respectively) compared with post-pubertal shams (150 and 220% baseline for 2.5 and 5.0 mg/kg, respectively). Most interestingly, while prefrontal cortical perfusion of SKF 81297 (100 and 250 microM) had no significant effect on ACh release in post-pubertal sham-operated animals, it significantly stimulated ACh release to approximately 250% baseline at both doses in post-pubertal NVH-lesioned animals. Receptor autoradiography demonstrated a significant and selective increase in M(1)-like receptor binding sites in the infralimbic area of the PFC in the post-pubertal NVH-lesioned animals. For all experiments, significant differences between sham and NVH-lesioned animals were observed only in post-pubertal rats. These results suggest a developmentally specific reorganization of the prefrontal cortical cholinergic system involving D(1)-like receptors in the NVH model.

PMID: 15056275 [PubMed - indexed for MEDLINE]

Cocaine caused big upshift(3x) of D3 sites in nucleus accumbens. D3 mRNA increased 6x. -- Doubled kappa receptors. (suggests natural corrective system in light of other studies)

http://www.annalsnyas.org/cgi/content/abstract/877/1/507

D3 Dopamine and Kappa Opioid Receptor Alterations in Human Brain of Cocaine-overdose Victims

DEBORAH C. MASHa AND JULIE K. STALEY

Departments of Neurology, and Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33136, USA

aAddress correspondence to Deborah C. Mash, Ph.D., Department of Neurology (D4-5), University of Miami School of Medicine, P.O. Box 016960, Miami, Florida 33101. Voice: 305-243-5888; fax: 305-243-4678; dmash@mednet.med.miami.edu

Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine-overdose victims. The number of D3 binding sites was increased one- to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine-overdose victims, as compared to age-matched and drug-free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine-overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine-overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.

Kappa opioid agonist caused 50% reduction in cocaine induced dopamine release in nucleus accumbens

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=7898771&dopt=Citation

U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats.

Maisonneuve IM, Archer S, Glick SD.

Department of Pharmacology and Toxicology, Albany Medical College, NY 12208.

Because an increase in extracellular levels of dopamine in the nucleus accumbens has been associated with the reinforcing effects of addictive drugs, we investigated whether U50,488, a selective kappa opioid receptor agonist, would alter cocaine-induced increases in extracellular dopamine in the nucleus accumbens using in vivo microdialysis in awake and freely moving rats. Cocaine (20 mg/kg i.p.) produced a 10-fold increase in extracellular dopamine levels. Pretreatment (20 min beforehand) with U50,488 (10 mg/kg i.p.), which alone caused a modest decrease in dopamine levels, produced a 50% decrease in the effect of cocaine on dopamine levels. This attenuation was completely reversed by administration of a kappa opioid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), 20 min before the agonist challenge. Treatment with nor-binaltorphimine alone induced a brief increase in dopamine levels. These findings indicate that activation of kappa receptors attenuates cocaine's effects and that kappa opioid receptor agonists may, therefore, be useful as functional cocaine antagonists.

Kappa opioid agonist decreased herioine induced dopamine release in NAcc and decreased self-admin. Suggests natural system against addiction. Mu and Kappa seem opposing.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9435173&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Dopamine release in the nucleus accumbens during heroin self-administration is modulated by kappa opioid receptors: an in vivo fast-cyclic voltammetry study.Xi ZX, Fuller SA, Stein EA.

Department of Psychiatry, Medical College of Wisconsin, Milwaukee, USA.

Mu and kappa opioid agonists are known to produce different, and sometimes opposite, effects on several pharmacological and behavioral measures. However, whether kappa agonists can be used to antagonize the reinforcing and putative dopamine (DA)-releasing properties of a mu agonist such as heroin is unclear. With the use of the high temporal and spatial resolution of in vivo fast-cyclic voltammetry to measure changes in extracellular DA in the nucleus accumbens (NAcc), we observed (1) dose-dependent increases in DA in the NAcc during heroin self-administration (SA), (2) that coadministration of the kappa agonist U50,488H with heroin or intracerebroventricular dynorphin A pretreatment significantly depressed the heroin-stimulated DA release during SA, where U50,488H alone inhibited the basal DA release in the NAcc, (3) that coadministration of low-dose U50,488H or dynorphin A significantly increased heroin SA behavior, whereas high-dose U50,488H, which alone did not support SA behavior, reduced or completely blocked heroin SA and (4) that nor-binaltorphimine dihydrochloride (a selective kappa receptor antagonist) potentiated DA release in the NAcc and modestly decreased heroin SA. Taken together, these data suggest that endogenous kappa receptor activation can inhibit mu agonist-induced activation of the mesolimbic DA pathway, which may in turn depress heroin-induced reinforcement.

Kappa opioid system reduces voluntary ethenol intake.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11182162&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

The selective kappa-opioid receptor agonist U50,488H attenuates voluntary ethanol intake in the rat.Lindholm S, Werme M, Brené S, Franck J.

Department of Clinical Neuroscience, Karolinska Institutet, Beroendecentrum Nord, Magnus Huss M4, SE-171 76 Stockholm, Sweden.

Non-selective opioid receptor antagonists are increasingly used in the treatment of alcohol dependence. The clinical effects are significant but the effect size is rather small and unpleasant side effects may limit the benefits of the compounds. Ligands acting at mu- and/or delta- receptors can alter the voluntary intake of ethanol in various animal models. Therefore, the attenuating effects of selective opioid receptor ligands on ethanol intake may be of clinical interest in the treatment of alcoholism. The objective of this study was to examine the effects of a selective kappa-receptor agonist, U50,488H on voluntary ethanol intake in the rat. We used a restricted access model with a free choice between an ethanol solution (10% v/v) and water. During the 3-days baseline period, the rats received a daily saline injection (1 ml/kg, i.p.) 15 min before the 2 h access to ethanol. The animals had free access to water at all times. The control group received a daily saline injection during the 4-days treatment-period, whereas the treatment groups received a daily dose of U50,488H (2.5, 5.0 or 10 mg/kg per day). Animals treated with U50,488H dose-dependently decreased their ethanol intake. The effect of the highest dose of U50,488H was reduced by pre-treatment with the selective kappa-antagonist nor-binaltorphimine (nor-BNI). These results demonstrate that activation of kappa-opioid receptors can attenuate voluntary ethanol intake in the rat, and the data suggest that the brain dynorphin/kappa-receptor systems may represent a novel target for pharmacotherapy in the treatment of alcohol dependence.

PMID: 11182162 [PubMed - indexed for MEDLINE]

Kappa opioid antagonist immediately increased ethenol intake

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16001119&ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats.Mitchell JM, Liang MT, Fields HL.

Department of Neurology, University of California at San Francisco, P. O. Box 0114, San Francisco, CA 94143, USA. juniper@itsa.ucsf.edu

RATIONALE: Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake. OBJECTIVES: To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP. METHODS: Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg(-1)) while ethanol intake was monitored. RESULTS: A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline. CONCLUSIONS: Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.

PMID: 16001119 [PubMed - indexed for MEDLINE]

Salvia is a effective kappa opioid agonist.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14718611&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations.Chavkin C, Sud S, Jin W, Stewart J, Zjawiony JK, Siebert DJ, Toth BA, Hufeisen SJ, Roth BL.

Department of Biochemistry;, University of Washington School of Medicine, Seattle, Washington, USA.

The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective kappa-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. Additional studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective kappa-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for kappa-opioid receptor binding and activation. Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K(+) channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593) (two standard kappa-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for kappa-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.

PMID: 14718611 [PubMed - indexed for MEDLINE]

Prolactin increase shown in kappa opioid treatment. D2/D3 agonist blocked effect.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11448491&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists.Butelman ER, Kreek MJ.

Laboratory on the Biology of Addictive Diseases, The Rockefeller University (Box 171), 1230 York Avenue, New York, NY 10021, USA. butelme@mail.rockefeller.edu

Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine receptor system in vivo in primates. The effectiveness of dopamine D(2)-like receptor agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid receptor agonists to modulate dopamine D(2)-like receptor function, and may also be used to quantify dopamine D(2)-like receptor agonist potency in primates.

PMID: 11448491 [PubMed - indexed for MEDLINE]

Kappa reduces dopamine and reward from cocaine and reduced place preference.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=14712342&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Effect of the kappa opioid agonist R-84760 on cocaine-induced increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice.Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ.

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, Box 171, New York, NY 10021, USA. zhangyo@mail.rockefeller.edu

RATIONALE: While the effects of several kappa opioid receptor agonists on cocaine-induced reward have been studied, such effects of R-84760, a novel non-peptidic, potent and selective kappa opioid agonist that has been studied in humans, are not yet known. OBJECTIVE: To study the effects of R-84760 on basal levels of dopamine, cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and locomotor activity in mice. METHODS: In the first experiment, R-84760 was administered i.p. (0, 0.01, 0.05 or 0.1 mg/kg) to C57BL/6J mice. Its effect on basal dopamine levels in the caudate putamen was measured with in vivo microdialysis. In the second experiment, the effect of pretreatment with 0.1 mg/kg R-84760 on cocaine-induced increases in dopamine levels was studied. The third experiment examined the effect of R-84760 (0.1 mg/kg) on the development of cocaine-induced conditioned place preference and locomotor activity in the conditioning chamber. RESULTS: R-84760 decreased dopamine levels in a dose-dependent manner. The highest dose of R-84760 (0.1 mg/kg, i.p.) significantly decreased dopamine levels relative to vehicle, an effect completely blocked by pre-injection with 10 mg/kg of the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). The same dose of R-84760 blocked cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and attenuated cocaine-induced locomotor response. CONCLUSION: These findings suggest that R-84760 decreases dopamine levels in the caudate putamen through kappa-opioid receptors. The inhibitory effect of R-84760 on striatal dopamine may contribute to its blockade of cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and the associated increases in locomotor activity.

PMID: 14712342 [PubMed - indexed for MEDLINE]

Another study shows Salvia divinorum a strong kappa opioid agonist

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17060493&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ.

Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York NY 10021, USA. butelme@mail.rockefeller.edu

This study focused on the in vivo effects of the kappa-opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy kappa-agonist U69,593 ((+)-(5alpha,7 alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED50, 0.015 mg/kg; U69,593 ED(50), 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce kappa-antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey kappa-opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

PMID: 17060493 [PubMed - indexed for MEDLINE]

Shows kappa fixes mu via upregulation. (Upregulation of Mu then causes increase in seratonin...)

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12753076&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Heterologous mu-opioid receptor adaptation by repeated stimulation of kappa-opioid receptor: up-regulation of G-protein activation and antinociception.Narita M, Khotib J, Suzuki M, Ozaki S, Yajima Y, Suzuki T.

Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.

The present study was designed to investigate the effect of repeated administration of a selective kappa-opioid receptor agonist (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride [(-)U-50,488H] on antinociception and G-protein activation induced by mu-opioid receptor agonists in mice. A single s.c. injection of (-)U-50,488H produced a dose-dependent antinociception, and this effect was reversed by a selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). Furthermore, a single s.c. pre-treatment with (-)U-50,488H had no effect on the mu-opioid receptor agonist-induced antinociception. In contrast, repeated s.c. administration of (-)U-50,488H resulted in the development of tolerance to (-)U-50,488H-induced antinociception. Under these conditions, we demonstrated here that repeated s.c. injection of (-)U-50,488H significantly enhanced the antinociceptive effect of selective mu-opioid receptor agonists endomorphin-1, endomorphin-2 and [d-Ala2,N-MePhe4,Gly-ol5] enkephalin (DAMGO). Using the guanosine-5'-o-(3-[35S]thio) triphosphate ([35S]GTP gamma S) binding assay, we found that (-)U-50,488H was able to produce a nor-BNI-reversible increase in [35S]GTP gamma S binding to membranes of the mouse thalamus, which has a high level of kappa-opioid receptors. Repeated administration of (-)U-50,488H caused a significant reduction in the (-)U-50,488H-stimulated [35S]GTP gamma S binding in this region, whereas chronic treatment with (-)U-50,488H exhibited the increase in the endomorphin-1-, endomorphin-2- and DAMGO-stimulated [35S]GTP gamma S bindings in membranes of the thalamus and periaqueductal gray. These results suggest that repeated stimulation of kappa-opioid receptors leads to the heterologous up-regulation of mu-opioid receptor functions in the thalamus and periaqueductal gray regions, which may be associated with the supersensitivity of mu-opioid receptor-mediated antinociception.

PMID: 12753076 [PubMed - indexed for MEDLINE]

Shows higher kappa receptors in amygdala of alchohol preferring (when mu goes down, kappa goes up in response) but higher kappa in addiction areas was found in alcohol avoiding mice.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9394118&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Content of dynorphins and kappa-opioid receptors in distinct brain regions of C57BL/6 and DBA/2 mice.Jamensky NT, Gianoulakis C.

Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montréal, Québec, Canada.

Differences in the activity of various components of the endogenous opioid system under basal conditions and after ethanol exposure have been reported between strains and lines of animals showing either high or low ethanol consumption. The objective of the present studies was to investigate the presence of differences in (a) the density of kappa-opioid binding sites, (b) the content of prodynorphin mRNA, and (c) the content of dynorphin peptides in distinct brain regions between the C57BL/6 (ethanol-preferring) and the DBA/2 (ethanol-avoiding) mice. Results indicated that the C57BL/6 mice have a higher content of kappa-opioid binding sites and dynorphin A 1-13 in the amygdala, and dynorphin A 1-8 in the ventral tegmental area, whereas the DBA/2 mice presented a significantly higher content of kappa-opioid binding sites, prodynorphin mRNA, as well as dynorphin A 1-13 and dynorphin A 1-8 peptides in the nucleus accumbens and septum. In addition, the DBA/2 mice presented a higher content of kappa-opioid receptors in the periaqueductal gray and dynorphin A 1-13 and dynorphin A 1-8 in the caudate putamen. Because enhanced stimulation of the kappa-opioid receptors at the level of the nucleus accumbens has been associated with decreased dopamine release and aversive states, the higher content of kappa-opioid receptors, pro-dynorphin mRNA, and dynorphin peptides (the endogenous ligand of k-binding sites) in regions of the limbic system of the DBA/2 mice may play an important role in determining their low alcohol consumption.

PMID: 9394118 [PubMed - indexed for MEDLINE]

Shows that kappa reduced addictive association caused by alcohol via lessening the reward effect.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10096764&ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Different roles of mu-, delta- and kappa-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress.Matsuzawa S, Suzuki T, Misawa M, Nagase H.

Department of Pharmacology, School of Pharmacy, Hoshi University, Ebara, Tokyo, Japan.

The present study was designed to investigate the role of the endogenous opioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previously with electric foot shock), using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated this ethanol-induced place preference. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine (3 and 10 mg/kg, i.p.) and the selective delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) significantly attenuated ethanol-induced place preference. In contrast, the selective kappa-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) significantly enhanced ethanol-induced place preference. Furthermore, 75 mg/kg ethanol (which tended to produce place preference) combined with the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha- octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67; 20 mg/kg, s.c.), at doses which alone did not produce place preference, produced significant place preference. However, co-administration of the selective kappa-opioid receptor agonist trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethanol (300 mg/kg, i.p.) dose dependently attenuated ethanol-induced place preference. Moreover, conditioned fear stress shifted the response curve for the aversive effect of U50,488H to the left. These results suggest that mu- and delta-opioid receptors may play critical roles in the rewarding mechanism of ethanol, and that kappa-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress.

PMID: 10096764 [PubMed - indexed for MEDLINE]

Mice with knocked out CRF system didn't have withdrawel. Kappa agonists cause place aversion. Shows Dynorphin is not increased in NAcc during withdrawel.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16339307&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal.Contarino A, Papaleo F.

Dipartimento di Farmacologia e Anestesiologia, Università degli Studi di Padova, Largo Meneghetti 2, 35131 Padua, Italy.

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF1) and CRF2. Here we report that genetic disruption of CRF1 receptor pathways in mice eliminates the negative affective states of opiate withdrawal. In particular, neither CRF1 receptor heterozygous (CRF1+/-) nor homozygous (CRF1-/-) null mutant mice avoided environmental cues repeatedly paired with the early phase of opiate withdrawal. These results were not due to altered associative learning processes because CRF1+/- and CRF1-/- mice displayed reliable, conditioned place aversions to environmental cues paired with the kappa-opioid receptor agonist U-50,488H. We also examined the impact of CRF1 receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal. Consistent with the behavioral indices, we found that, during the early phase of opiate withdrawal, neither CRF1+/- nor CRF1-/- showed increased dynorphin mRNA levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction.

PMID: 16339307 [PubMed - indexed for MEDLINE]

Withdrawel caused by CRF causes release of dynorphin. Suggests natural corrective system for opioid abuse. (kappa antinociceptive effect replaces mu activation)

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=1361439&ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Stimulation by corticotropin-releasing factor of the release of immunoreactive dynorphin A from mouse spinal cords in vitro.Song ZH, Takemori AE.

Department of Pharmacology, Medical School, University of Minnesota, Minneapolis 55455.

Corticotropin-releasing factor (CRF) has been shown to release endogenous opioid peptides from several rat brain regions. Since we have demonstrated previously that the actions produced by intrathecally administered CRF in mice involve spinal kappa opioid receptors, experiments were conducted in this study to test the possibility that CRF may release dynorphin A, a putative endogenous kappa opioid agonist, from the mouse spinal cord. Using a superfusion system in vitro, mouse spinal cords were superfused with aerated (95% O2, 5% CO2) Krebs-Ringer buffer. Fractions of superfusion were collected and dynorphin A levels in each fraction were monitored by radioimmunoassay. The presence of CRF in the perfusion buffer stimulated significantly the release of immunoreactive dynorphin A. The releasing rate of immunoreactive dynorphin A returned to the basal level after withdrawing CRF from the superfusion buffer. The stimulatory effect of CRF on the release of immunoreactive dynorphin A was abolished by alpha-helical CRF-(9-41), a CRF receptor antagonist, indicating that the dynorphin-releasing effect of CRF was mediated by CRF receptors in the spinal cord. Also the dynorphin-releasing effect of CRF was a concentration-related phenomenon, with an estimated EC50 value of 5.3 nM. The results from this study support the hypothesis that intrathecally administered CRF may produce its effects by releasing endogenous dynorphin from the terminals of dynorphin-containing neurons in the spinal cord. This study also provides evidence to support the notion that there is a close communication between CRF- and opioid peptide-containing neuronal pathways in the central nervous system.

PMID: 1361439 [PubMed - indexed for MEDLINE]

A good example how a study can cause confusion by not understanding all the factors. Wiping out Kappa opioids makes the mice no longer have a re-sensitization system for mu and delta so those two systems may start to deteriorate. Many other factors could be in place when you knock out one link in a complex and connected system.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15897716&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus

Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice.Kovacs KM, Szakall I, O'Brien D, Wang R, Vinod KY, Saito M, Simonin F, Kieffer BL, Vadasz C.

Laboratory of Neurobehavioral GeneticsNathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. kkovacs@nki.rfmh.org

BACKGROUND: Although a large body of evidence suggests a role for the opioid system in alcoholism, the precise role of mu-, delta-, kappa-, and ORL1-opioid receptors and the physiological significance of their natural genetic variation have not been identified. The method of targeted gene disruption by homologous recombination has been used to knock out (KO) genes coding for opioid receptors, and study their effects on alcohol self-administration. Here we examined the effects of targeted disruption of kappa-opioid receptor (KOR) on oral alcohol self-administration and other behaviors. METHODS: Oral alcohol, saccharin and quinine self-administration was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol, or tastant solutions. In preference tests 12% alcohol, 0.033% and 0.066% saccharin, and 0.03 mM and 0.1 mM quinine solutions were used. Open-field activity was determined in an arena equipped with a computer-controlled activity-detection system. Subjects were tested for three consecutive days. Locomotor activity was assessed on days 1 and 2 (after saline injection, i.p.) and on day 3 (after alcohol injection, i.p.). Alcohol-induced locomotor activity was determined as the difference in activity between day 3 and day 2. RESULTS: Male KOR KO mice in preference tests with 12% alcohol consumed about half as much alcohol as wild-type (WT) or heterozygous (HET) mice, showed lower preference for saccharin (0.033% and 0.066%) and higher preference to quinine (0.1 mM) than WT mice. Female KOR KO mice showed similar reduction in alcohol consumption in comparison to WT and HET mice. Partial deletion of KOR in HET mice did not change alcohol consumption in comparison to WT mice. In all genotype-groups females drank significantly more alcohol than males. MANOVA of locomotor activity among KO, WT, and HET mice indicated that strain and sex effects were not significant for alcohol-induced activation (p > 0.05), while strain x sex interaction effects on alcohol-induced activation could be detected (F(1,55) = 6.07, p < 0.05). CONCLUSION: Our results indicating decreased alcohol consumption, lower saccharin preference, and higher quinine preference in KOR KO mice are in line with previous observations of opioid involvement in maintenance of food intake and raise the possibility that the deficient dynorphin/KOR system affects orosensory reward through central mechanisms which reduce alcohol intake and disrupt tastant responses, either as direct effects of absence of kappa-opioid receptors, or as effects of indirect developmental compensatory changes.

PMID: 15897716 [PubMed - indexed for MEDLINE]