The abuse of phenethylamine and tryptamine based hallucinogenic drugs continues to be a serious problem that is now rivaled by the appearance of numerous cannabinoid agonists and cathinones (bath salts). We have begun a program to synthesize and evaluate a number of these hallucinogenic agents and their antagonists. We recently developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is providing this important research tool. MDMA (racemic 3,4-methylenedioxymethamphetamine) also known as Ecstasy is a widely abused street drug. We studied the effects of racemic and R-(-)-MDMA on plasma prolactin secretion by plasma analysis and extracellular serotonin in the monkey striatum by in vivo microdialysis. Pretreatment with fluoxetine attenuated serotonin release by racemic or R-(-)-MDMA. Neither fluoxetine nor MDL100907 alone suppressed prolactin secretion by (-)-MDMA. However, coadministration of both of these drugs attenuated prolactin release suggesting that both serotonin release and 5HT2A agonism is required for prolactin secretion. Our results provide insight into the complex pharmacology of racemic MDMA. Sigma receptors are high affinity binding sites widely distributed in the mammalian central nervous system and periphery. Two subtypes, sigma-1 and sigma-2, have been characterized and shown to be involved in numerous physiologic functions and in some aspects of drug abuse. Earlier, we introduced BD-1063 as a selective sigma-1 antagonist that attenuates drug reinforcement in some assays. Binge eating is a disorder that resembles drug self-administration as a compulsive behavior regardless of predictable negative consequences. We examined the question of whether BD1063 can block binge eating in a rat model. BD1063 reduced food-seeking behavior, the quantity food consumed and the rate of eating vs. a control group. Furthermore, sigma-1 mRNA was altered in several brain regions in the binge group compared to the control group. Our findings indicate the involvement of the sigma-1 receptor in binge eating in the rat and in related neurobiological adaptations.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$117,183
Indirect Cost
Name
National Institute on Drug Abuse
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Type
DUNS #
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