Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations

Behavioral sensitization to psychomotor stimulants is accompanied by a numb er of alterations in the mesoaccumbens dopamine (DA) system, including DA a utoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 re ceptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocai ne sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA recep tor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg) . Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine se nsitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. A ll three antagonists prevented the induction of cocaine sensitization. Extr acellular single cell recordings revealed that these antagonists also preve nted the induction of DA autoreceptor subsensitivity in the VTA and DAD1 re ceptor supersensitivity in the NAc. To determine whether the relevant gluta mate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at lea st 7 days before repeated cocaine treatment began. These lesions also preve nted the induction of cocaine sensitization and the associated neuroadaptat ions. Our findings indicate that glutamate transmission from mPFC to the me soaccumbens DA system is critical for the induction of cocaine sensitizatio n and its cellular correlates. Synapse 34:169-180, 1999. (C) 1999 Wiley-Lis s, Inc.