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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

National Institute on Drug Abuse

1 Z01 DA000001-23 BNRB
Control Of Behavior By Drug Injection

Principal Investigator: Steven R Goldberg, PhD (PP, NIDA)
Lab staff: Leigh V. Panlilio, PhD (PP, NIDA)
Sergi Ferre, M.D., Ph.D (PP, NIDA)
Maria Scherma, PhD (PP, NIDA)
Godfrey Redhi (PP, NIDA)
Charles W. Schindler, PhD (PP, NIDA)
Carrie Wertheim (PP, NIDA)
Chanel Barnes (PP, NIDA)
Joanne Gilman (PP, NIDA)
Julie B Medalie (PP, NIDA)
Jessica A Stroik (PP, NIDA)
Eric B Thorndike (PP, NIDA)
NIH Collaborators: Jean Lud Cadet, MD (MNB, NIDA)
Svetlana Chefer, PhD (NB, NIDA)
Gianfrancesco Cormaci, M.D. (DP, NIDA)
Teruo Hayashi, MD, PhD (CNRB, NIDA)
Alane S. Kimes, PhD (NB, NIDA)
Elliot A Stein, PhD (NB, NIDA)
Tsung Ping Su, PhD (MN, NIDA)
Gianluigi Tanda, PhD (NIDA)
Extramural Collaborators: Marcello Solinas, PhD (CNRS, University of Poitiers)
Daniele Piomelli, PhD (Department of Pharmacology, University of California-Irvine)
Marco Bortolato, PhD (Department of Pharmacology, University of California-Irvine)
Alexandros Makriyannis, PhD (Center for Drug Discovery, Northeastern University)
Jack Bergman, PhD (ADARC/McLean Hospital, Harvard Medical School)
Sevil Yasar, MD (Johns Hopkins Univ Sch Med)
P Fadda (University of Cagliari)
W Fratta (University of Cagliari)
J Haller (Institute of Experimental Medicine, Budapest)
Z Justinova (University o;f Maryland)
B Le Foll (University of Toronto)
E Mikics (Institute of Experimental Medicine, Budapest)
K Vadivel (Northeastern University, Boston)
 from October 01, 2006 to September 30, 2007
Human subject research: Neither Human Subjects nor Human Tissues
Total Staff Years:4
Keywords:drug abuse; cannabinoids; methamphetamine; nicotine; cocaine; heroin; drug-discrimination; self-administration; stimulus control; rats; monkeys; tobacco; marijuana; drug dependence; dopamine; brainreward pathways
Goals and Objectives:Our overall goal is to understand the neuropharmacological and behavioral mechanisms underlying the self-administration of abused drugs. Our research is conducted in rats and monkeys and our research emphasis is on cannabioids(marijuana), nicotine (tobacco), cocaine and methamphetamine. We are particularly interested in how different drus are discriminated by subjects (subjective effects) and how drug-associted environmental stimuli control the lpersistence of drug-seeking behavior and relapse to drug-seeking behavior in abstinent indivililduals. A main goal is to evaluate the ability of pharmacological treatments (medications)or behavioral manipulations to modify drug addictio;n and dependence and to assess potential new medications for freedom from abuse liability.
Summary:Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior.

Cannabinoid CB1 receptors mediate most central effects of THC, the main psychoactive ingredient in marijuana, particularly effects contributing to abuse liability. Pharmacological manipulation of endocannabinoid system activity by drugs that inhibit transport of endogenous ligands for cannabinoid CB1 receptors into cells where they are degraded or inhibit enzymes responsible for intracellular degradation of endogenous CB1-receptor ligands has been suggested as a safer approach for the treatment of pain and neuropsychiatric disorders than the use of directly-acting cannabinoid CB1-receptor agonists.

We have been investigating behavioral and neurochemical effects of the endogenous CB1-receptor ligand anandamide, of inhibitors of fatty acid amide hydrolase (FAAH), the main enzyme responsible for rapid inactivation of anandamide, and of inhibitors of endocannabinoid transport. We previously demonstrated that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys. We also showed that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, we previously demonstrated that the reinforcing effects of both anandamide and methanandamide were blocked by pretreatment with the cannabinoid CB1 receptor antagonist rimonabant (SR141716). Thus, converging evidence from our labs suggests the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. We have now evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1 receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward), depending on dose and procedural details. Anandamide (0.03 to 3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamides metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50 to 300 g/kg, intravenous) produced dose-related conditioned place aversions. Development of place aversions with URB597 plus anandamide and with WIN 55,212-2 were prevented by pretreatment with the CB1-receptor antagonist AM251 (3 mg/kg intraperitoneal). When anxiety-related effects of anandamide and URB597 were evaluated in a light-dark box, both anandamide (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. The high 3 mg/kg dose of anandamide produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Thus, additive interactions between the effects of endocannabinoid system activation on brain reward processes and anxiety may account for the aversive effects of high levels of endocannabinoid system activation.

Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here we show that homomeric 7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective 7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine (DHBE), 1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, 2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 and 3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens (NAc). Altogether our results indicate that blockade of 7 nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannnabinoids at doses that did not produce depressant or toxic effects, further pointing to 7 nicotinic Ach antagonists as potentially useful agents in the treatment of cannabis abuse in humans.

The development of new efficacious medications for the treatment of tobacco dependence is of critical importance and suitable animal models for testing potential medications are needed. Nicotine is the main psychoactive ingredient in tobacco. We previously demonstrated robust reinforcing effects of nicotine in squirrel monkeys under fixed-ratio, fixed-interval and second-order schedules were shown to be mediated by nicotinic receptors, since they could be blocked by pretreatment with the nicotinic antagonist mecamylamine. We have now replicated and extended these findings to progressive-ratio schedules of nicotine self-administration in squirrel monkeys, without the use of any setting conditions such as previous experimental or drug exposure history, and this procedure now allows a clear measure of reinforcing efficacy of nicotine in a non-human primate model that is optimal for preclinical assessment of new anti-smoking medications. These findings provide the clearest demonstration to date that nicotine, by itself and in the absence of other ingredients in tobacco smoke or non-pharmacological stimuli associated with tobacco smoking, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. In these studies, the squirrel monkeys behavior was clearly directed toward self-administration of nicotine and nicotine-seeking was persistent and robust, supporting the use of nicotinic ligands as efficacious approaches to the treatment of tobacco dependence.

In recent experiments we have studied the potential of topiramate, a novel anticonvulsant that is approved by the Food and Drug Administration for the treatment of childhood epilepsy, as a medication for nicotine and cocaine abuse. Preliminary clinical trial findings from human studies concerning the potential use of topiramate for the treatment of cocaine and nicotine dependence are encouraging. We have now studied the effects of topiramate in rats trained to discriminate administration of either 0.4 mg/kg nicotine or 10 mg/kg cocaine from administration of saline under a fixed-ratio 10 schedule of food delivery. Topiramate (1-60 mg/kg) did not produce any nicotine- or cocaine-like discriminative effects by itself and did not produce any shift in the dose-response curves for nicotine or cocaine discrimination. Thus, the ability to discriminate nicotines or cocaines effects does not appear to be altered by topiramate administration. Also, topiramate, given either alone or in combination with nicotine or cocaine, did not depress rates of responding. These experiments indicate that topiramate does not enhance or reduce the ability of rats to discriminate the effects of nicotine or cocaine.
Publications generated by this research:
  1. Ferre S, Diamond I, Goldberg SR, Yao L, Hourani SM, Huang ZL, Urade Y, Kitchen I (2007) Adenosine A(2A) receptors in ventral striatum, hypothalamus and nociceptive circuitry Implications for drug addiction, sleep and pain. Prog Neurobiol, in press (e-pub ahead of print). PubMed
  2. Le Foll B, Wertheim C, Goldberg SR (2007) High reinforcing efficacy of nicotine in non-human primates. PLoS ONE 2:e230. PubMed -- Full Text (PubMed Central)
  3. LeFoll B, Chefer SI, Kimes AS, Shumway D, Goldberg SR, Stein EA, Mukhim AG (2007) Validation of an extra-cerebral reference region approach for quantification of brain nicotinic acetylcholine receptors in squirrel monkeys with PET and 2-[18F]FA. J Nucl Med 48:1492-1500. PubMed
  4. LeFoll B, Goldberg SR (2007) Contribution of the endogenous cannabinoid system to nicotine addiction: Therapeutic implications. Addict Biol, in press.
  5. LeFoll B, Goldberg SR (2007) Blocking cannabinoid CB1 receptors for the treatment of nicotine dependence: insights from clinical and preclinical and clinical studies. Addict Biol, in press.
  6. LeFoll B, Goldberg SR, Sokoloff P (2007) Dopamine D3 receptor ligands for the treatment of tobacco dependence. Expert Opin Investig Drugs 16:45-57.
  7. LeFoll B, Justinova Z, Tanda G, Solinas M, Selby P, Goldberg SR (2007) Potential use of opioid antagonists in the treatment of marijuana abusedependence. , in Opioid Receptors and Antagonists: From Bench to Clinic. Negus S, Dean R, eds., Humana Press (Totowa, NJ USA), in press.
  8. LeFoll B, Justinova Z, Wertheim C, Barnes C, Goldberg SR (2007) Topiramate does not alter nicotine or cocaine discrimination in rats. Eur J Pharmacol, in press.
  9. Panlilio LV, Goldberg SR (2007) Self-administration of drugs in animals and humans. Addiction, in press.
  10. Panlilio LV, Solinas M, Matthews SA, Goldberg SR (2007) Previous exposure to THC alters the reinforcing efficacy and anxiety-related effects of cocaine in rats. Neuropsychopharmacology 32:646-57. PubMed
  11. Scherma M, Medalie JB, Fratta W, Makriyannis A, Vadivel SK, Piomelli D, Tanda G, Mikics E, Haller J, Goldberg SR (2007) Motivational anxioloytic and locomotor effects of anandamide alone and after inhibition of fatty acid amide hydrolase (FAAH). Neuropharmacology, in press.
  12. Schindler CW, Graczyk Z, Gilman JP, Negus SS, Bergman J, Mello NK, Goldberg SR (2007) Kappa opioid agonists increase heart rate through kappa opioid receptors in conscious squirrel monkeys. Eur J Pharmacol, in press.
  13. Solinas M, Goldberg SR (2007) Endocannabinoids and drug addiction. Pharmacol Res, in press.
  14. Solinas M, Scherma M, Fattore L, Stroik J, Wertheim C, Tanda G, Fratta W, Goldberg SR (2007) Nicotinic alpha 7 receptors as a new target for treatment of cannabis abuse. J Neurosci 27:5615-20. PubMed
  15. Solinas M, Scherma M, Tanda G, Wertheim CE, Fratta W, Goldberg SR (2007) Nicotinic facilitation of delta9-tetrahydrocannabinol discrimination involves endogenous anandamide. J Pharmacol Exp Ther 321:1127-34. PubMed
  16. Solinas M, Tanda G, Justinova Z, Wertheim CE, Yasar S, Piomelli D, Vadivel SK, Makriyannis A, Goldberg SR (2007) The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J Pharmacol Exp Ther 321:370-80. PubMed

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