The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem worldwide for which there is no accepted medication. Numerous lines of investigation indicate that elevation of dopamine (DA) in the nucleus accumbens (NAC) is largely responsible for the reinforcing (rewarding) effects of many classes of drugs including cocaine and methamphetamine. Although the precise mechanism of DA elevation in the NAC differs among drug classes, medications that suppress or deplete such elevation of DA may thus be useful in the treatment and prevention of diverse, destructive self-administration behaviors including excessive eating. We have pursued the chemical synthesis and identification of biogenic amine agonists and their antagonists as research tools and potential medications. In one example, we developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is enabling numerous studies requiring this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. In another study, we showed that MDL 100,907 significantly attenuated drug- and cue-induced reinstatement of cocaine but had no significant effects on cocaine self-administration in rhesus macaques. MDL 100,907 attenuated cocaine-induced dopamine overflow in the caudate nucleus but not in the nucleus accumbens as measured by in vivo microdialysis. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways.

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National Institute on Drug Abuse
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Carbonaro, Theresa M; Eshleman, Amy J; Forster, Michael J et al. (2015) The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice. Psychopharmacology (Berl) 232:275-84
Leitl, Michael D; Onvani, Sara; Bowers, M Scott et al. (2014) Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous *-opioids. Neuropsychopharmacology 39:614-24
Kupchik, Yonatan M; Scofield, Michael D; Rice, Kenner C et al. (2014) Cocaine dysregulates opioid gating of GABA neurotransmission in the ventral pallidum. J Neurosci 34:1057-66
Dong, Hongxin; Wang, Shirlene; Zeng, Ziling et al. (2014) Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-? and behavior in Tg2576 mice. Psychopharmacology (Berl) 231:4711-22
Li, Jun-Xu; Shah, Aparna P; Patel, Sunny K et al. (2013) Modification of the behavioral effects of morphine in rats by serotonin 5-HT?A and 5-HT?A receptor agonists: antinociception, drug discrimination, and locomotor activity. Psychopharmacology (Berl) 225:791-801
Murnane, Kevin S; Winschel, Jake; Schmidt, Karl T et al. (2013) Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates. J Neurosci 33:13367-74
Jutkiewicz, Emily M; Rice, Kenner C; Carroll, F Ivy et al. (2013) Patterns of nicotinic receptor antagonism II: cardiovascular effects in rats. Drug Alcohol Depend 131:284-97
Murnane, Kevin S; Andersen, Monica L; Rice, Kenner C et al. (2013) Selective serotonin 2A receptor antagonism attenuates the effects of amphetamine on arousal and dopamine overflow in non-human primates. J Sleep Res 22:581-8
Briscione, Maria A; Serafine, Katherine M; Merluzzi, Andrew P et al. (2013) The effects of the 5-HT3 receptor antagonist tropisetron on cocaine-induced conditioned taste aversions. Pharmacol Biochem Behav 105:112-7
Jones, Jermaine D; Hall, F Scott; Uhl, George R et al. (2009) Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion. Pharmacol Biochem Behav 93:75-81

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