The dopamine D-2/D-3 antagonist DS121 potentiates the effect of cocaine onlocomotion and reduces tolerance in cocaine tolerant rats

To explore the significance of dopamine (DA) autoreceptors in cocaine toler ance and cocaine induced locomotor activity rats were treated with saline a nd cocaine (40 mg/kg per day via osmotic minipump; normal and cocaine toler ant rats, respectively). Injections of DS121 (0-7 mg/kg, i.p.; S(-)-3-(3-(c yanophenyl)-N-n-propylpiperidine), a DA D-2/3 and autoreceptor preferring a ntagonist, either alone (i.e. DS121 + saline injection) or in combination w ith cocaine (7.5 mg/kg, i.p.) were also given. DS121 (+ saline) increased l ocomotor activity in both saline and cocaine pump (CP) treated animals. DS1 21 also potentiated the effect of cocaine on locomotor activity; this effec t was greatest in CP (tolerant) animals. It is concluded that DS121 can inc rease locomotor activity and that this effect is greatest when the DA tone is high, that is when cocaine is present, suggestive of a presynaptic mecha nism. Furthermore, because DS121 potentiation of cocaine induced locomotor activity is greatest in tolerant animals it is concluded that supersensitiv e DA autoreceptors underlie this effect. These data further support our pre vious data, which show that DA autoreceptors are sensitized after continuou s cocaine (minipump) treatment. (C) 2000 Elsevier Science B.V. All rights r eserved.