Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice

Cindy Achat-Mendes, Syed F. Ali, Yossef Itzhak

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1128-1137
Number of pages10
JournalNeuropsychopharmacology
Volume30
Issue number6
DOIs
StatePublished - Jun 1 2005

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Amphetamines
N-Methyl-3,4-methylenedioxyamphetamine
Serotonin
Methamphetamine
Dopamine
Amphetamine-Related Disorders
Drug-Seeking Behavior
Learning
Compulsive Behavior
Fenfluramine
Executive Function
Presynaptic Terminals
Neurotoxins
Frontal Lobe
Conditioning (Psychology)
Amygdala
Reward
Cocaine
Hippocampus
Animal Models

Keywords

  • Associative learning
  • Conditioned place aversion (CPA)
  • Conditioned place preference (CPP)
  • Dopamine
  • Psychostimulants
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice. / Achat-Mendes, Cindy; Ali, Syed F.; Itzhak, Yossef.

In: Neuropsychopharmacology, Vol. 30, No. 6, 01.06.2005, p. 1128-1137.

Research output: Contribution to journalArticle

Achat-Mendes, Cindy ; Ali, Syed F. ; Itzhak, Yossef. / Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice. In: Neuropsychopharmacology. 2005 ; Vol. 30, No. 6. pp. 1128-1137.
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