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Taylor JR, Jentsch D. 
“Repeated intermittent administration of psychomotor stimulant drugs alters the acquisition of Pavlovian approach behavior in rats: differential effects of cocaine, d-amphetamine and 3,4-methylenedioxymethamphetamine ('Ecstasy')”. 
Bilogical Psychiatry. 2001;50:137-143.

BACKGROUND: Psychomotor stimulant drugs can produce long-lasting changes in neurochemistry and behavior after multiple doses. In particular, neuroadaptations within corticolimbic brain structures that mediate incentive learning and motivated behavior have been demonstrated after chronic exposure to cocaine, d-amphetamine, and 3,4- methylenedioxymethamphetamine (MDMA). As stimulus-reward learning is likely relevant to addictive behavior (i.e., augmented conditioned reward and stimulus control of behavior), we have investigated whether prior repeated administration of psychomotor stimulant drugs (of abuse, including cocaine, d-amphetamine, or MDMA, would affect the acquisition of Pavlovian approach behavior.

METHODS: Water-deprived rats were tested for the acquisition of Pavlovian approach behavior after 5 days treatment with cocaine (15-20 mg/kg once or twice daily), d-amphetamine (2.5 mg/kg once or twice daily), or MDMA (2.5 mg/kg twice daily) followed by a 7-day, drug-free period.

RESULTS: Prior repeated treatment with cocaine or d-amphetamine produced a significant enhancement of acquisition of Pavlovian approach behavior, indicating accelerated stimulus-reward learning, whereas MDMA administration produced increased inappropriate responding, indicating impulsivity. Abnormal drug-induced approach behavior was found to persist throughout the testing period. CONCLUSIONS: These studies demonstrate that psychomotor stimulant-induced sensitization can produce long-term alterations in stimulus-reward learning and impulse control that may contribute to the compulsive drug taking that typifies addiction.

Summary by Ilsa Jerome

This study investigated the effects that apparently non-neurotoxic regiments of psychostimulants have on acquisition of reward-related behavior. Prior to conditioning, rats either received saline, cocaine (15-20 mg/kg), d-amphetamine (2.5 mg/kg) or MDMA (2.5 mg/kg) via intra-peritoneal injection for 5 days. Amphetamine and cocaine were further divided into 1 or 2 daily administrations but combined due to lack of differences; MDMA administered twice daily. Seven days after drug or saline treatment, water-restricted rats first exposed to time-dependent appearance of water reward, and then exposed to conditioning where inappropriate head entries reset time elapsed for reward. Finally, a tone and light were followed immediately by water reward. Duration and number of head entries for water during appropriate period and inappropriate head entries both counted, and learning of reward-cue analyzed across days. Pre-treatment with either amphetamine or cocaine increased head entries during appropriate time and increased acquisition of Pavlovian approach behavior (approach toward reward-associated cue). Pre-treatment with MDMA did not enhance approach toward reward cue, but did increase head entries at “inappropriate” times, which the authors considered “impulsive.” The authors conclude that amphetamine and cocaine produce neuroadaptation of the corticolimbic circuit that results in greater sensitivity to and control over reward-related behavior, but that MDMA produced inefficient regulation of reward-related behavior. No information is provided on effects of drug treatments on monoamines or monoaminergic neurons in brain.
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