INVOLVEMENT OF N-METHYL-D-ASPARTATE RECEPTOR STIMULATION IN THE VENTRAL TEGMENTAL AREA AND AMYGDALA IN BEHAVIORAL SENSITIZATION TO COCAINE

Systemic administration of N-methyl-D-aspartate (NMDA) antagonists pre vents the development of behavioral sensitization to amphetamine-like psychostimulants. Pretreatment with the non-competitive NMDA antagonis t, MK-801, resulted in a dose-dependent blockade of behavioral sensiti zation to cocaine. However, pretreatment with the highest dose of MK-8 01 (0.25 mg/kg i.p.) alone inhibited the behavioral response to a subs equent cocaine challenge 24 hr later. The induction of behavioral sens itization is known to result, at least partly, from an action by psych ostimulants in the ventral tegmental area (VTA). To determine wheter t he dose-dependent inhibition of behavioral sensitization to cocaine by NMDA antagonists resulted from receptor blockade in the VTA, rats wer e pretreated in the VTA with the MK-801 or the competitive NMDA antago nist, 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid, before sys temically administered cocaine (30 mg/kg i.p.). Two to 3 days later ra ts were challenged with cocaine alone (1 5 mg/kg i. p.). Pretreatment with either NMDA antagonist into the VTA prevented the manifestation o f behavioral sensitization. Intracranial pretreatment with MK-801 was also made into the nucleus accumbens and amygdala which have been impl icated in psychostimulant-induced sensitization. Whereas MK-801 was wi thout effect in the nucleus accumbens, when microinjected into the ven tral amygdala it prevented the manifestation of behavioral sensitizati on to a cocaine challenge. The blockade of sensitization by MK-801 in the VTA was produced with a minimum effective dose of 0.01 nmol, where as the minimum effective dose in the amygdala was 1.0 nmol. These data demonstrate that stimulation of NMDA receptors in the VTA and amygdal a is necessary in the development of behavioral sensitization to cocai ne.