Experiments are being conducted to assess the different neuropharmacological and behavioral mechanisms underlying behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify discrimination, as well as self-administration, of THC or nicotine, to disrupt ongoing food-maintained behavior to alter emotional responses such as anxiety or to modulate attention learning and memory processes. Currently, studies are focusing on nicotine and a series of cannabinoids, the non-cannabinoid fatty acid amides OEA and PEA, the anandamide uptake inhibitor AM404, and the fatty acid amide hydrolase (FAAH) inhibitor URB597. Natural and synthetic cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes habituation. To investigate the relationship between the affective properties of tastes and the response of NAc shell dopamine we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo dopamine transmission in the NAc shell to intraoral sucrose (DeLuca et al., 2012). Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the cannabinoid CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC made sucrose effective in raising extracellular dopamine levels in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell dopamine under THC underwent one trial habituation. Together these findings demonstrate that stimulation of cannabinoid CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes Delta-9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term working memory. Delayed matching-to-position and nonmatching-to-position procedures are widely used to model working memory in rodents and we have recently been adapting these procedures to dissect some of the behavioral for our studies of the cognitive effects of cannabinoids (Panlilio et al., 2011, 2012). Mediating behavior-which enhances performance but is not explicitly required by the task-is generally considered an obstacle to the measurement of memory, but often occurs despite attempts to prevent it. The ubiquitous nature of mediating behavior suggests it might be analogous to rehearsal, an important component of learning and memory in humans.
Our aim was to study an easily recordable, rehearsal-like mediating response in rats under baseline conditions and after treatment with different doses of amnestic drugs (scopolamine) and THC. Lighted nosepoke holes were used to present position cues and record delayed matching or nonmatching responses. Performance of a distractor task was required to prevent simply waiting at the correct choice, but the nosepoke holes were left accessible during the delay. Each rat trained with the nonmatching task exhibited one of two mediating "strategies" that increased the odds of a correct choice: responding in the to-be-correct hole during the delay or responding in the opposite hole during the delay. Rats trained with the matching task all showed the former strategy. Treatment with scopolamine disrupted performance of the mediating response. Scopolamine and THC both decreased the effectiveness of the mediating response, increasing errors even on trials when the "appropriate" mediating behavior did occur. The procedures and data analysis approach used here provide an objective, automated means of measuring mediating behavior, which might be useful as an animal model of memory rehearsal. Recent studies have demonstrated that exposure to environmental enrichment (EE) during withdrawal periods reduces the risks of relapse to drug-seeking behavior. In one study (Chauvet et al., 2012), we investigated whether EE could prevent the development of time-dependent increases in cocaine-seeking behavior (incubation of craving). In addition, we investigated whether EE could eliminate already developed incubation and whether the effects of EE would last when enrichment was discontinued. For this, we allowed rats to self-administer cocaine for 10 daily 6h sessions and measured cocaine seeking 1, 30 and 60 days after the last self-administration session. In between these tests, rats were kept in forced abstinence and housed either in EE or standard environments (SE). Between day 30 and 60 of withdrawal, half of the rats in each group were maintained in their environmental condition and the other half was switched to the other environmental condition. We found that exposure to EE prevented development of incubation of cocaine craving and eliminated already developed incubation. In addition, contrary to our expectations, when EE was discontinued, its positive effects on incubation of craving disappeared. These results indicate that EE can reduce cocaine seeking but only temporarily and questions the hypothesis that EE can permanently eliminate the neural consequences of exposure to drugs. Therefore, stimulating environments could have positive effects on the treatment of cocaine abuse only if they are maintained for long periods of abstinence that encompass the time-frame during which addicts are most vulnerable to relapse. Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, preventing its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. We have recently assessed the effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys (Schindler et al., 2012). Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a relatively long half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 g/kg/injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also reduced the reinstatement of extinguished cocaine-seeking behavior by an i.v. priming injection of cocaine and, in separate studies, attenuated the discriminative stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in monkeys suggests that it may be effective in reducing cocaine addiction and relapse liability or in reversing acute cocaine toxicity in man.

Project Start
Project End
Budget Start
Budget End
Support Year
27
Fiscal Year
2012
Total Cost
$834,824
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Panlilio, L V; Justinova, Z; Trigo, J M et al. (2016) Screening Medications for the Treatment of Cannabis Use Disorder. Int Rev Neurobiol 126:87-120
Vaupel, D B; Schindler, C W; Chefer, S et al. (2016) Delayed emergence of methamphetamine's enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence. Drug Alcohol Depend 159:181-9
Krasnova, Irina N; Justinova, Zuzana; Cadet, Jean Lud (2016) Methamphetamine addiction: involvement of CREB and neuroinflammatory signaling pathways. Psychopharmacology (Berl) 233:1945-62
Schindler, Charles W; Thorndike, Eric B; Goldberg, Steven R et al. (2016) Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats. Psychopharmacology (Berl) 233:1981-90
Panlilio, Leigh V; Thorndike, Eric B; Nikas, Spyros P et al. (2016) Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats. Psychopharmacology (Berl) 233:1879-88
Justinova, Zuzana; Panlilio, Leigh V; Secci, Maria E et al. (2015) The Novel Metabotropic Glutamate Receptor 2 Positive Allosteric Modulator, AZD8529, Decreases Nicotine Self-Administration and Relapse in Squirrel Monkeys. Biol Psychiatry 78:452-62
Justinova, Zuzana; Panlilio, Leigh V; Moreno-Sanz, Guillermo et al. (2015) Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse. Neuropsychopharmacology 40:2185-97
Gamaleddin, Islam Hany; Trigo, Jose M; Gueye, Aliou B et al. (2015) Role of the endogenous cannabinoid system in nicotine addiction: novel insights. Front Psychiatry 6:41
Astarita, Giuseppe; Avanesian, Agnesa; Grimaldi, Benedetto et al. (2015) Methamphetamine accelerates cellular senescence through stimulation of de novo ceramide biosynthesis. PLoS One 10:e0116961
Panlilio, L V; Goldberg, S R; Justinova, Z (2015) Cannabinoid abuse and addiction: Clinical and preclinical findings. Clin Pharmacol Ther 97:616-27

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