Sensitization of Psychomotor Stimulation and Conditioned Reward in Mice: Differential Modulation by Contextual Learning

Abstract

Incentive motivation theory ascribes a critical role to reward-associated stimuli in the generation and maintenance of goal-directed behavior. Repeated psychomotor stimulant treatment, in addition to producing sensitization to the psychomotor-activating effects, can enhance the incentive salience of reward-associated cues and increase their ability to influence behavior. In the present study, we sought to investigate this incentive sensitization effect further by developing a model of conditioned reinforcement (CR) in the mouse and investigating the effects of a sensitizing treatment regimen of amphetamine on CR. Furthermore, we assessed the role of contextual stimuli in amphetamine-induced potentiation of CR. We found that mice responded selectively on a lever resulting in the presentation of a cue previously associated with 30% condensed milk solution, indicating that the cue had attained rewarding properties. Prior treatment with amphetamine (4 Â 0.5 mg/kg i.p.) resulted in psychomotor sensitization and enhanced subsequent responding for the CR. Furthermore, this enhancement of responding for the cue occurred independent of the drug-paired context, whereas the sensitized locomotor response was only observed when mice were tested in the same environment as that in which they had received previous amphetamine. These results demonstrate that the CR paradigm previously developed in the rat can be successfully adapted for use in the mouse, and suggest that behavioral sensitization to amphetamine increases the rewarding properties (incentive salience) of rewardpaired cues, independent of the drug-paired context.

Continuous, but not Intermittent, Antipsychotic Drug Delivery Intensifies the Pursuit of Reward Cues

“…This effect of continuous antipsychotic treatment was observed using a clinically relevant dose and mode of administration, was behaviorally specific (responding on an inactive lever was unaffected), and was persistentFlasting for at least 1 week following the cessation of antipsychotic administration. Consistent with previous work (Mead et al, 2004;Robbins, 1978;Robbins et al, 1983), the dose of amphetamine used here (0.5 mg/kg) had no effect on operant responding for conditioned reward in vehicle-treated control animals. However, this dose potentiated responding for a conditioned reward in rats with a history of continuous exposure to antipsychotic medication.…”

Modeling Sensitization to Stimulants in Humans

“…Indeed, evidence of dopamine release in anticipation of reward has been observed in humans during placebo administration and in primates faced with cues that predict reward. 61,62 Nonetheless, although the expression of sensitization can be modulated by context, 60,63,64 neuroadaptive changes thought to underlie neurochemical sensitization are (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 63, DEC 2006 known to occur in vitro 65,66 and independent of the drugpaired context. 67,68 Until further experiments designed to test for conditioning are completed, the possibility that this effect may have contributed to an enhanced response to stimulant cannot be discarded.…”

A single administration of methamphetamine to mice early in the light period decreases running wheel activity observed during the dark period

“…It has long been known that repeated administration of amphetamines induces a progressive augmentation of motor activity in response to the same drug, termed behavioral sensitization (Ellinwood and Kilbey, 1977; Nishikawa et al, 1983; Robinson and Becker, 1986; Wise and Leeb, 1993; Pierce and Kalivas, 1997). This well-known phenomenon may be part of a broader enhancement of incentive motivation that affects a variety of other circumstances, including non-drug reward-related behavior (Fiorino and Phillips, 1999; Serwatkiewicz et al, 2000; Taylor and Jentsch, 2001; Mead et al, 2004; Mendez et al, 2009). The processes mediating sensitization may involve not just the enhancement of behavior when the drug is initially taken, but also adaptations to drug withdrawal.…”