The proposed research will evaluate whether dopaminergic mechanisms play a role in the elicitation of symptoms of amphetamine-induced acute withdrawal. This will be done using an animal model approach. Rats will be housed in stations where behavior can be monitored for extended periods of time, they will receive control and drug treatments, and the effects of these treatments on activity and food intake will be monitored. In rats, moderate doses of amphetamine produce hypoactivity and hypophagia 18 to 24 hours later, suggesting that an acute withdrawal is present during that time. The hypoactivity can be produced by moderate doses of the nonselective dopamine agonist apomorphine and by moderate doses of D1 and D2 agonists given together, but not alone. We want to know if these same treatments can produce hypophagia. The results would not only show the degree of dependence of these symptoms on dopaminergic mechanisms, but would also begin to reveal how symptoms of acute withdrawal are organized: If different symptoms are similarly responsive to the same treatments, then mediation of these symptoms by a common mechanism would be indicated. Otherwise, distributed mechanisms would be indicated. In addition to these manipulations, we also want to see to see whether blocking either dopamine receptor subtype prior to amphetamine administration can prevent the hypoactivity. This result would confirm that amphetamine produces hypoactivity by promoting an interaction of D1 and D2 receptors in the short term. Finally we will begin to determine whether the expression of amphetamine-induced hypoactivity and hypophagia are due to a change in dopamine D1 or D2 receptor number. To do this we will see how genes for D1 and D2 receptors are expressed in different brain areas at different times after saline and amphetamine treatment, using real time PCR. Acute withdrawal is associated with personal distress, decreased productivity, and increased risk of drug relapse: Consequently, preventing and ameliorating acute withdrawal is an important objective. Acute withdrawal can be managed only if the factors that give rise to the symptoms can be identified. The proposed research will provide an ethical, well controlled, and efficient means for identifying the brain and body factors that contribute to acute withdrawal and for evaluating potential treatments. ? ? ?
| White, Wesley; White, Ilsun M (2016) Amphetamine and morphine may produce acute-withdrawal related hypoactivity by initially activating a common dopamine pathway. Physiol Behav 165:187-94 |
| White, Wesley; Beyer, Jason D; White, Ilsun M (2015) Acute withdrawal-related hypophagia elicited by amphetamine is attenuated by pretreatment with selective dopamine D1 or D2 receptor antagonists in rats. Physiol Behav 151:345-54 |
| White, Wesley; Hundley, Marcus B; White, Ilsun M (2010) The effects of dose and repeated administration on the longer-term hypophagia produced by amphetamine in rats. Pharmacol Biochem Behav 97:384-91 |
| White, Wesley; Sherrill, Luke K; White, Ilsun M (2007) Time-dependent effects of amphetamine on feeding in rats. Brain Res 1171:75-82 |
| White, Wesley; Feldon, Joram; White, Ilsun M (2004) Development of acute withdrawal during periodic administration of amphetamine in rats. Pharmacol Biochem Behav 79:55-63 |
