David L. Wolgin - US grants

The proposed research is designed to evaluate the hypothesis that contingent tolerance to the "anorexigenic" effect of amphetamine and related drugs involves learning to suppress incompatible responses. This hypothesis derives from the observation that such tolerance is accompanied by the suppression of stereotyped head scanning movements in bottle-fed, but not in cannula-fed, rats. To determine whether the suppression of stereotypy is under operant control, amphetamine-treated rats will be required to hold their heads stationary for intraoral mild infusions. Stimulus control will be assessed by making milk delivery contingent on suppression of stereotypy in the presence of a discriminiative cue. To determine whether prior sensitization of stereotypy retards tolerance development, rats will be given noncontingent injections of amphetamine prior to the tolerance phase. The generality of the hypothesis will be assessed by analyzing the effects of chronic injections of cocaine, methylphenidate, and apomorphine of the intake and activity of cannula- and bottle-fed rats. To determine whether tolerance occurs when motoric effects do not contribute to the suppression of intake, the effects of chronic pre- and post-test injections of amphetamine in cannula-fed rates will be compared. Finally, to determine whether contingent tolerance is suppressed when drug treatment blunts reinforcement, the effects of chronic pre- and post-test injections of haloperidol will be assessed. Taken together, the results of the proposed research will clarify the role of instrumental learning in drug tolerance and provide new insights into the relationship between tolerance and sensitization to stimulant drugs. This, in turn, may lead to new treatment strategies for extinguishing conditioned behaviors that contribute to stimulant drug abuse in humans.

biomedical equipment purchase;

This proposal addresses the hypothesis that behavioral tolerance to stimulant drugs is mediated by instrumental learning. Previous research has shown that amphetamine initially suppresses the ingestion of sweetened milk primarily by inducing stereotyped head movements, which interfere with feeding (Wolgin et al., 1987). We propose that tolerance to this effect involves learning to channel such movements into a more adaptive stereotyped response, namely, licking a drinking tube. One aim of the proposed research is to determine whether tolerance develops when licking is precluded. Rats implanted with oral cannulas and given chronic injections of amphetamine will be reinforced with milk directly into their mouths for holding their heads stationary with or without the opportunity to lick an empty drinking tube. A second aim is to determine whether individual differences in motor activity evoked by an acute injection of amphetamine are correlated with the rate and/or level of tolerance that subsequently develops to the hypophagic effect of the drug. A third aim is to assess the generality of the theory by determining whether tolerance to the hypophagic effect of apomorphine, cocaine, and methylphenidate also involves learning to channel stereotyped movements into licking. This will be accomplished by comparing the effect of each of these drugs on the milk intake and movement patterns of cannula- and bottle-fed rats. A final aim of this proposal is to determine whether tolerance develops to the hypophagic effect of amphetamine when stereotyped movements do not contribute to hypophagia, i.e., in "free feeding" cannula-fed rats. The relatively rapid development of tolerance to the behaviorally disruptive effects of stimulant drugs may contribute to their widespread abuse. To the extent that behavioral tolerance involves instrumental learning, the proposed research will provide a rationale for understanding how people adapt to the behaviorally disruptive effects of stimulant drugs of abuse.