PM288. Preclinical Evaluation of Neutral Cannabinoid CB1 Receptor Antagonists and Cannabinoid CB1 Receptor Negative Allosteric Modulators for Treating Drug Addiction

s | 3 of adverse effects that currently limit the use of opioids in the clinic. Supported by USPHS Grant K05DA017918 PM288 Preclinical Evaluation of Neutral Cannabinoid CB1 Receptor Antagonists and Cannabinoid CB1 Receptor Negative Allosteric Modulators for Treating Drug Addiction Eliot L. Gardner1, Guo-Hua Bi1, Ganesh Thakur2, Alexandros Makriyannis2, Herbert H. Seltzman3, Xiang-Hu He4, Zheng-Xiong Xi1 1National Institute on Drug Abuse, Baltimore, Maryland, USA 2Northeastern University, Boston, Massachusetts, USA 3Research Triangle Institute, Research Triangle Park, North Carolina, USA 4Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China Abstract Objective: Preclinical animal studies show that cannabinoid CB1 receptor (CB1R) orthosteric antagonists/inverse agonists have strong anti-addiction effects against many addictive drugs. However, development of CB1R orthosteric antagonists/inverse agonists was terminated in 2008 due to significant side-effects (anxiety, depression, suicidal ideation) in clinical trials and use in Europe of the lead CB1R orthosteric antagonist/inverse agonist SR141716 (rimonabant). We propose that neutral CB1R antagonists (lacking inverse agonism) or CB1R negative allosteric modulators (binding to transmembrane allosteric sites rather than extracellular orthosteric sites) may have therapeutic anti-addiction potential without unwanted effects. Methods: We evaluated the effects of these three types of CB1R ligand in animal models relating to drug addiction – including intravenous drug self-administration and drug-enhanced electrical brain-stimulation reward (BSR). Results: We found that 1) the inverse CB1R agonist SR141716 (3, 10 mg/kg, i.p.) significantly inhibited cocaine, heroin, or nicotine self-administration and cocaine-enhanced BSR in laboratory rats; but SR141716 itself produced dysphoric effects in the BSR model; 2) the CB1R neutral antagonists AM4113 and PIMSR1 (3, 10 mg/kg) significantly attenuated cocaine, nicotine, or heroin self-administration and cocaine-enhanced brain-stimulation reward; by themselves, the two compounds had no effect on basal BSR functions; 3) the CB1R negative allosteric modulators (NAMs) GAT358 and GAT369 (10, 20 mg/kg) altered neither nicotine-enhanced BSR nor basal BSR functions. Conclusions: Neutral CB1R antagonists appear more promising than CB1R orthosteric antagonists/inverse agonists or CB1R NAMs in medication development for treatment of drug abuse and addiction.Objective: Preclinical animal studies show that cannabinoid CB1 receptor (CB1R) orthosteric antagonists/inverse agonists have strong anti-addiction effects against many addictive drugs. However, development of CB1R orthosteric antagonists/inverse agonists was terminated in 2008 due to significant side-effects (anxiety, depression, suicidal ideation) in clinical trials and use in Europe of the lead CB1R orthosteric antagonist/inverse agonist SR141716 (rimonabant). We propose that neutral CB1R antagonists (lacking inverse agonism) or CB1R negative allosteric modulators (binding to transmembrane allosteric sites rather than extracellular orthosteric sites) may have therapeutic anti-addiction potential without unwanted effects. Methods: We evaluated the effects of these three types of CB1R ligand in animal models relating to drug addiction – including intravenous drug self-administration and drug-enhanced electrical brain-stimulation reward (BSR). Results: We found that 1) the inverse CB1R agonist SR141716 (3, 10 mg/kg, i.p.) significantly inhibited cocaine, heroin, or nicotine self-administration and cocaine-enhanced BSR in laboratory rats; but SR141716 itself produced dysphoric effects in the BSR model; 2) the CB1R neutral antagonists AM4113 and PIMSR1 (3, 10 mg/kg) significantly attenuated cocaine, nicotine, or heroin self-administration and cocaine-enhanced brain-stimulation reward; by themselves, the two compounds had no effect on basal BSR functions; 3) the CB1R negative allosteric modulators (NAMs) GAT358 and GAT369 (10, 20 mg/kg) altered neither nicotine-enhanced BSR nor basal BSR functions. Conclusions: Neutral CB1R antagonists appear more promising than CB1R orthosteric antagonists/inverse agonists or CB1R NAMs in medication development for treatment of drug abuse and addiction. PM289 Reduction of sensitivity to nicotine aversion in repeated nicotine-injected rats Hyunchan Lee, Jihyun Noh Dankook University, Republic of Korea Abstract Nicotine not only stimulates brain reward circuits to establish and maintain the tobacco smoking habit, but also produces aversive reactions to nicotine after initial exposure, due to its noxious properties. To determine the effects of repeatedly exposed nicotine on the sensitivity to nicotine aversive behavior in rats, we performed the two-bottle free choice test for nicotine-injected rats in a nicotine concentration difference. At first test day, saline-injected rats showed nicotine indifference, but nicotine-injected rats more preferred nicotine water. Whereas saline-injected rats presented increased nicotine preference during two days against a preferable low dose of nicotine, nicotine-injected rats showed no significant alteration of nicotine preference. This result implies that the repeated nicotine preexposure mitigates the nicotine aversive behaviors against the new nicotine choice. In a high concentration of nicotine preference test, both salineand nicotine-injected rats showed nicotine aversive behavior but the nicotine consumption in nicotine-injected rats more increased than that of saline-injected rats. Importantly, whereas nicotine preference in saline-injected rats reduced when the dose of nicotine water increased, there was no significant difference in nicotine-injected rats. There was similar to sweet saccharine preference for positive reward and bitter quinine preference for negative avoided reward in both salineand nicotine-injected rats, suggesting that the alteration of nicotine preference is nicotine specific, possibly via nicotine specific regulating system. Taken together, we demonstrate that repeated nicotine exposure reduce the sensitivity to nicotine aversive behaviors in rats. This phenomenon would provide a new insight to the feasibility of developing novel therapeutic agents for nicotine addiction that act by enhancing nicotine avoidance. (supported by NRF-2013R1A1A1057712 and NRF-2014R1A2A2A04007391)Nicotine not only stimulates brain reward circuits to establish and maintain the tobacco smoking habit, but also produces aversive reactions to nicotine after initial exposure, due to its noxious properties. To determine the effects of repeatedly exposed nicotine on the sensitivity to nicotine aversive behavior in rats, we performed the two-bottle free choice test for nicotine-injected rats in a nicotine concentration difference. At first test day, saline-injected rats showed nicotine indifference, but nicotine-injected rats more preferred nicotine water. Whereas saline-injected rats presented increased nicotine preference during two days against a preferable low dose of nicotine, nicotine-injected rats showed no significant alteration of nicotine preference. This result implies that the repeated nicotine preexposure mitigates the nicotine aversive behaviors against the new nicotine choice. In a high concentration of nicotine preference test, both salineand nicotine-injected rats showed nicotine aversive behavior but the nicotine consumption in nicotine-injected rats more increased than that of saline-injected rats. Importantly, whereas nicotine preference in saline-injected rats reduced when the dose of nicotine water increased, there was no significant difference in nicotine-injected rats. There was similar to sweet saccharine preference for positive reward and bitter quinine preference for negative avoided reward in both salineand nicotine-injected rats, suggesting that the alteration of nicotine preference is nicotine specific, possibly via nicotine specific regulating system. Taken together, we demonstrate that repeated nicotine exposure reduce the sensitivity to nicotine aversive behaviors in rats. This phenomenon would provide a new insight to the feasibility of developing novel therapeutic agents for nicotine addiction that act by enhancing nicotine avoidance. (supported by NRF-2013R1A1A1057712 and NRF-2014R1A2A2A04007391) PM290 Involvement of dorsohippocampal orexin-2 receptors in drug-dependency: A psychopharmacological study