title: Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice.
abstract: The abuse of substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) can result in neurotoxicity, manifested as the depletion of dopamine (DA) and 5-hydroxytriptamine (5-HT; serotonin) axon terminal markers in humans and animal models. Human METH and MDMA users exhibit impairments in memory and executive functions, which may be a direct consequence of the neurotoxic potential of amphetamines. The objective of this study was to investigate the influence of amphetamines-induced neurotoxicity on Pavlovian learning. Using mouse models of selective DA neurotoxicity (METH; 5 mg/kg x 3), selective 5-HT neurotoxicity (fenfluramine /FEN; 25 mg/kg x 4) and dual DA and 5-HT neurotoxicity (MDMA; 15 mg/kg x 4), appetitive and aversive conditioning were investigated. Dopaminergic neurotoxicity significantly impaired METH and cocaine conditioned place preference (CPP), but had no effect on LiCl-induced conditioned place aversion (CPA). In contrast, serotonergic neurotoxicity significantly enhanced CPP, and had no effect on CPA. Dual dopaminergic/serotonergic neurotoxicity had no apparent effect on CPP; however, CPA was significantly attenuated. Postmortem analysis revealed that significantly diminished levels of DA and 5-HT markers persisted in the striatum, frontal cortex, hippocampus, and amygdala. These findings suggest that amphetamines-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on the affective state produced by subsequent drug reward, while dual dopaminergic/serotonergic neurotoxicity impairs associative learning of aversive conditioning. Furthermore, results revealed that amphetamines-induced DA and 5-HT neurotoxicity modulates appetitive Pavlovian conditioning similar to other DA and 5-HT neurotoxins. Modulation of Pavlovian conditioning by amphetamines-induced neurotoxicity may be relevant to compulsive drug-seeking behavior in METH and MDMA abusers.
authors.affiliation: Neuroscience Program and Department of Psychiatry & Behavioral Sciences (R-629), University of Miami School of Medicine, Miami, FL 33136, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Achat-Mendes
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Yossef
authors.initials: Y
authors.lastname: Itzhak
mesh_terms: D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001070:Appetitive Behavior / Q000187:drug effects*; D001362:Avoidance Learning / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003214:Conditioning, Classical / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D005277:Fenfluramine / Q000633:toxicity; D006213:Hallucinogens / Q000633:toxicity; D018021:Lithium Chloride; D008297:Male; D008694:Methamphetamine / Q000633:toxicity; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity; D009411:Nerve Endings / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000523:psychology*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012054:Reinforcement, Psychology; D012201:Reward; D012701:Serotonin / Q000378:metabolism / Q000502:physiology
chemical_list: D000662:Amphetamines; D018692:Antimanic Agents; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D011985:Receptors, Serotonin; D005277:Fenfluramine; D012701:Serotonin; D008694:Methamphetamine; D018021:Lithium Chloride; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine