The proposed research will characterize behavioral and in vivo neurochemical interactions between serotonin and cocaine in the context of self-administration behavior in nonhuman primates. It is well recognized that dopamine plays a fundamental role in the behavioral pharmacology of cocaine associated with its addictive properties. However, a substantial literature has documented that serotonergic function also plays a significant role in the abuse-related effects of cocaine and other psychomotor stimulants. Specifically, selective serotonin transporter (SERT) inhibitors can effectively attenuate cocaine self-administration and cocaine-induced increases in extracellular dopamine, suggesting that drug interactions on behavior are mediated through neurochemical interactions between serotonin and dopamine. However, the mechanistic basis for these drug interactions on behavior and neurochemistry has not been adequately established. The proposed studiesin squirrel monkeys will investigate the involvement of specific receptor mediated mechanisms, and extend drug interactions on self-administration to other abuse-related effects including drug-induced reinstatement and cue-mediated behavior. Pharmacological targets for the manipulation of serotonergic activity will include the SERT and the 5HT2C and 5HT2A receptor subtypes.
The Specific Aims are: 1) to establish the effectiveness of SERT inhibitors to attenuate the abuse-related effects of cocaine across multiple behavioral paradigms including i.v. drug self-administration, drug-induced reinstatement and, cue-induced behavior;2) to correlate the behavioral effects of SERT inhibitors with in vivo neurochemistry including SERT occupancy with PET neuroimaging, and extracellular serotonin and dopamine with in vivo microdialysis;and 3) to define the role of 5HT2C and 5HT2A receptor subtypes in the interactions observed between SERT inhibitors and cocaine. The innovative design employed effectively integrates behavioral pharmacology and sophisticated in vivo neurochemistry in a nonhuman primate model. The results obtained will evaluate the effectiveness of serotonergic systems as potential targets for cocaine medications development. Moreover, serotonin has significant therapeutic potential in the treatment of a variety of psychiatric disorders. Accordingly, the elucidation of basic neurochemical interactions between serotonin and dopamine in vivo in nonhuman primates should have significant impact on the development of therapeutics outside the field of drug addiction.
The objective of the present proposal is to identify potential therapeutic targets for the treatment of cocaine abuse and dependence. These translational studies in nonhuman primates will determine the effectiveness of the serotonin system to modulate the behavioral and neurochemical effects cocaine. Moreover, the documentation of basic neurochemical interactions between serotonin and dopamine in vivo in nonhuman primates should have significant impact on the development of therapeutics outside the field of drug addiction.
|Cooper, Debra A; Kimmel, Heather L; Manvich, Daniel F et al. (2014) Effects of pharmacologic dopamine Î²-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther 350:144-52|
|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|
|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|
|Kimmel, Heather L; Nye, Jonathon A; Voll, Ronald et al. (2012) Simultaneous measurement of extracellular dopamine and dopamine transporter occupancy by cocaine analogs in squirrel monkeys. Synapse 66:501-8|
|Manvich, Daniel F; Kimmel, Heather L; Cooper, Debra A et al. (2012) The serotonin 2C receptor antagonist SB 242084 exhibits abuse-related effects typical of stimulants in squirrel monkeys. J Pharmacol Exp Ther 342:761-9|
|Bauzo, Rayna M; Kimmel, Heather L; Howell, Leonard L (2012) The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys. Pharmacol Biochem Behav 101:288-96|
|Manvich, Daniel F; Kimmel, Heather L; Howell, Leonard L (2012) Effects of serotonin 2C receptor agonists on the behavioral and neurochemical effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 341:424-34|
|Andersen, Monica L; Sawyer, Eileen K; Howell, Leonard L (2012) Contributions of neuroimaging to understanding sex differences in cocaine abuse. Exp Clin Psychopharmacol 20:2-15|
|Sawyer, E K; Howell, L L (2011) Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration. Pharmacology 88:44-9|
|Murnane, Kevin S; Howell, Leonard L (2011) Neuroimaging and drug taking in primates. Psychopharmacology (Berl) 216:153-71|
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