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 and nicotine, to disrupt or modulate food-maintained behavior, to alter emotional responses such as anxiety and to modulate attention learning and memory processes. Currently, studies are focusing on constituents of psychoactive bath salts products, on coacaine, nicotine and methamphetramine, and on a series of inhibitors of endocannabinoid uptake and metabolic breakdown. The abuse of psychoactive 'bath salts'containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. We have evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods (Baumann et al., 2013). In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of (3)Hdopamine (IC(50)=4.1 nM) and (3)Hnorepinephrine (IC(50)=26 nM) with high potency but has weak effects on uptake of (3)Hserotonin (IC(50)=3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts'preparations. Coping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress-related disorders, but the neural control of coping is poorly understood. Based on earlier findings, we hypothesized that coping styles are influenced by endocannabinoids. We have now tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e., we studied the impact of URB597 on the two main attributes of coping styles (Haller et al., 2013). Rats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions. Under the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail-pinch test, i.e., they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both "wariness" induced by aversive conditions and "carelessness" resulting from favorable conditions.Thus, URB597 treatment-induced behavioral changes indicated a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Although further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g., anxiety and depression) and in physical diseases where active coping is therapeutically desirable. Binge eating disorder (BED) is characterized by excessive food intake during short periods of time. Recent evidence suggests that alterations in endocannabinoid signalling could be involved in the pathophysiology of BED. We have investigated whether pharmacological manipulation of endocannabinoid transmission may be effective in modulating the aberrant eating behaviour present in a validated rat model of BED (Scherma et al., 2013). Binge-type eating was induced in female rats by providing limited access to an optional source of dietary fat (margarine). Rats were divided into three groups, all with ad libitum access to chow and water: control (C), with no access to margarine;low restriction (LR), with 2 h margarine access 7 days a week;high restriction (HR), with 2 h margarine access 3 days a week. Compared with the LR group, the HR group consumed more margarine and this was accompanied by an increase in body weight. The cannabinoid CB1 /CB2 receptor agonist delta-9-tetrahydrocannabinol significantly increased margarine intake selectively in LR rats, while the fatty acid amide hydrolase inhibitor URB597 showed no effect. The CB1 receptor inverse agonist/antagonist rimonabant dose-dependently reduced margarine intake in HR rats. Notably, in HR rats, chronic treatment with a low dose of rimonabant induced a selective long-lasting reduction in margarine intake that did not develop tolerance, and a significant and persistent reduction in body weight. Chronic pharmacological blockade of CB1 receptors reduces binge eating behavior in female rats and may prove effective in treating BED, with an associated significant reduction in body weight. Substantial research has focused on developing pharmacological treatments for cocaine abuse but no effective medications have been developed. Enzymes that metabolize cocaine in the periphery and prevent its entry into the brain can prevent cocaine toxicity and its behavioral effects in rodents. We assessed the effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys (Schindler et al., 2013). 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. Pretreatment with 5 mg/kg Albu-CocH also reduced cocaine self-administration and the discriminative stimulus effects of cocaine which suggests 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
28
Fiscal Year
2013
Total Cost
$808,120
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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