Substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) are currently major psychostimulants of abuse. Continuous use leads to addiction and can produce severe dopamine (DA) and serotonin (5-HT) neurotoxicity in humans. Clinical testing has revealed that METH and MDMA abusers consistently exhibit impairments in attention, decision-making, learning and memory. It is not clear whether this cognitive disturbance is a direct consequence of the neurotoxic potential of amphetamines or mere amphetamine exposure and the mechanisms by which this could occur are unknown. We generated mouse models of: (1) DA neurotoxicity induced by METH, (2) 5-HT neurotoxicity by fenfluramine (FEN) and (3) dual DA and 5-HT neurotoxicity by MDMA, all of which endured diminished levels of transporter densities and neurotransmitter and metabolite concentrations. These models of amphetamine-induced neurotoxicity were examined using Pavlovian conditioning paradigms that required incentive-based learning. Appetitive conditioning by drug reward was impaired by METH neurotoxicity, and enhanced by FEN neurotoxicity. Aversive conditioning by lithium chloride was impaired by MDMA neurotoxicity. Locomotor activity studies revealed that amphetamine-induced neurotoxicity did not disrupt normal sensitization to exposure to psychostimulants. The involvement of N-methyl-D-aspartate receptor (NMDAR) activation in the impairment of appetitive conditioning by METH neurotoxicity was tested. Pharmacological stimulation of NMDAR by D-cycloserine and N-acetylcysteine restored behavioral deficits after METH neurotoxicity. These data indicate that (a) amphetamines have the potential to injure DA and 5-HT axon terminals; (b) amphetamine-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on appetitive conditioning by drug reward; and (c) amphetamine-induced neurotoxicity impairs Pavlovian conditioning via disruption of glutamate receptor activation. Furthermore, since enhancing NMDAR activity restored deficient appetitive conditioning, it is likely that cognitive impairments as a result of amphetamine-induced neurotoxicity may be amenable to pharmacological intervention
