Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens

Abstract

We have previously observed that chronic cocaine administration increases levels of adenylyl cyclase and cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc). In the present work we directly examined the involvement of the cAMP system at the level of the NAc in cocaine-induced locomotor activity and sensitization. Groups of rats were pretreated on 3 consecutive days with cocaine (10 mg/kg, i.p.) concurrently with intraaccumbens infusion of saline, 8-bromo-cAMP (2 μg/side; a membrane permeant analogue of cAMP which activates PKA), or RP-CPT-cAMP (20 nmol/side; which inhibits PKA). In a separate experiment, control animals received local infusion of either 8-bromo-cAMP or saline plus i.p. saline. All animals were tested for locomotor activity on pretreatment days, and following an additional cocaine challenge on a subsequent day. Over pretreatment days, animals given 8-bromo-cAMP showed greater cocaine-induced activity, while animals given RP-CPT-cAMP tended to be less active, compared to saline infused animals. When subsequently challenged with cocaine, animals pretreated with intraaccumbens 8-bromo-cAMP showed greater locomotor activity during the last 30 min of the 60 min test session than animals pretreated with saline or RP-CRT-cAMP. No differences in locomotor activity were evident between the two control groups on pretreatment or challenge days. These data suggest that PKA activation at the level of the NAc may have a facilitative role with respect to acute and long-term stimulant-induced locomotor activity.