Dose-Dependent Effects of Psychostimulants on Affect Following Repeated Administration to Laboratory Rats

Psychostimulants produce strong pleasurable effects in users which are thought to play a role in the development of drug addiction. Two highly rewarding and abused psychostimulant drugs are methamphetamine and d-amphetamine. Although there has been extensive investigation of the rewarding effects of these drugs, we used a relatively new approach, drug-induced ultrasonic vocalizations (USVs), to examine the dose-dependent rewarding and aversive effects of these drugs following a single and repeated administration. The inverted-U shaped dose-response curve is seen across many drugs of abuse and behaviors, however this phenomenon has not been reported with USVs. Broadly, it was hypothesized that animals treated with methamphetamine or d-amphetamine would show inverted U dose-dependent responses with ambulations and 50 kHz USVs and that repeated administration of methamphetamine or d-amphetamine would lead to complex changes across doses and behaviors. We conducted two experiments, identical in methodology, with the only difference being the drug (methamphetamine and d-amphetamine). The four major results obtained from the present thesis were: 1) acute administration of methamphetamine and d-amphetamine produced an inverted U dose-response with locomotor activity and reward-related ultrasonic vocalizations (FM 50 kHz USVs); 2) acute administration of the highest dose of methamphetamine or d-amphetamine produced aversive effects and an interplay of reward (FM 50 kHz USVs) and aversion (22 kHz USVs) that helps to explain the inverted U shaped dose response; 3) repeated administration of methamphetamine and d- amphetamine produced sensitization to locomotor effects and USVs at low and moderate doses; and 4) sensitization persisted following a period without drug administration. These data provide a revealing picture of the complex relationship between dose and response, with particular attention to the affective component in drug addiction and abuse.