A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule

A recently characterized class of compounds, dopamine partial agonists, have been suggested as potential therapeutic candidates for pharmacological intervention in psychostimulant addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are thought to behave as functional antagonists in conditions of high dopaminergic tone, and as agonists in conditions of low receptor occupancy by dopamine. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the D2 receptor subtype, on intravenous self-administration of amphetamine in a progressive ratio schedule and to compare it with the effects produced by the dopamine D2 antagonist eticlopride and the dopamine D2 full agonist quinpirole. Terguride at the doses of 0.2 and 0.4 mg/kg i.p. significantly decreased the maximum number of responses delivered for a single injection of amphetamine ("breaking point"), an effect similar to that produced by the antagonist eticlopride (0.01-0.1 mg/kg s.c.). In contrast, administration of quinpirole (0.1-1 mg/kg s.c.) did not significantly modify the breaking point for amphetamine responding. Also, terguride dose-dependently increased responding for amphetamine self-administration on a continuous reinforcement schedule. These data further confirm the effects of terguride on psychostimulant self-administration and indicate that under these conditions partial dopamine agonists act as functional dopamine receptor antagonists.