Modulation of behavioral sensitization to cocaine by NAALADase inhibition

Sensitization to cocaine has been attributed to alterations in excitatory a mino acid and dopamine neurotransmission in the mesolimbic system. The pres ent study sought to determine whether inhibition of NAALADase, an enzyme th at cleaves glutamate from the endogenous neuropeptide, N-acetyl-aspartyl-gl utamate (NAAG), attenuates sensitization to the psychomotor stimulant effec ts of cocaine. Rats received daily injections of cocaine (20.0 mg/kg/day; i .p.) or saline for 5 days. Fifteen minutes prior to these injections they r eceived an i.p. injection of the NAALADase inhibitor, 2-PMPA (50.0-100 mg/k g), or vehicle. Locomotor activity and stereotypy produced by a challenge d ose of cocaine (15.0 mg/kg) were assessed 3 days later. Acute cocaine admin istration increased locomotor activity in control animals. In animals with a prior history of cocaine administration, the behavioral response to cocai ne was significantly enhanced. In animals that had received 8-PMPA in combi nation with cocaine, the enhancement of cocaine-induced locomotor activity was attenuated. No alteration in cocaine-evoked activity was observed in an imals that had received once daily injections of 8-PMPA, alone. Acute admin istration of 2-PMPA also did not modify saline-induced locomotor activity o r activity produced by an acute cocaine challenge. These data demonstrate t hat NAALADase inhibition attenuates the development of sensitization to the locomotor-activating effects of cocaine. Furthermore, this action cannot b e attributed to an antagonism of the acute effects of cocaine. (C) 2000 Wil ey-Liss, Inc.