Ž . Brain Research 814 1998 112–119 Research report Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies Kaitlin E. Browman a , Lana Kantor b , Sarah Richardson b , Aldo Badiani a , Terry E. Robinson a , Margaret E. Gnegy b, ) a Department of Psychology, Biopsychology Program, The UniÕersity of Michigan, 2220E MSRB III, Ann Arbor, MI 48109-0632, USA b Department of Pharmacology, The UniÕersity of Michigan Medical School, 2220E MSRB III, Ann Arbor, MI 48109-0632, USA Accepted 29 September 1998 Abstract The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Dopamine; Locomotion; Nucleus accumbens; Amphetamine; Protein kinase C; Dopamine release 1. Introduction Amphetamine appears to enhance locomotor activity Ž . because of its ability to release dopamine DA in the w x nucleus accumbens 11,12 . For example, the local injec- tion of amphetamine directly into the nucleus accumbens of animals is sufficient to produce robust locomotor activ- w x ity 18 , whereas DA depletion in the accumbens inhibits w x the locomotor response to systemic amphetamine 10 . Amphetamine is hypothesized to increase DA in the synap- tic cleft by a non-exocytotic Ca 2q independent mechanism w x requiring the transporter 19 , and specifically through an wx accelerative-exchange diffusion mechanism 4 . This model postulates that extracellular amphetamine binds to the DA ) Corresponding author. Fax: q1-313-763-4450; E-mail: pgnegy@umich.edu transporter and is then transported into the nerve terminal. Upon dissociation of amphetamine, DA is thought to bind to the transporter, whereby it is transported into the synap- Ž w x. tic cleft for a review see Refs. 4,14 . There is accumulat- ing evidence, however, that signal-transduction mecha- nisms may contribute to amphetamine-induced DA release. Phorbol esters and lipids that activate protein kinase C Ž . PKC activity enhance the release of DA from synapto- wx somes in vitro 3 . Conversely, treating striatal synapto- somes or cultured cells containing the DA transporter with w 3 x PKC-activating phorbol esters or lipids decreases H DA w x uptake 2,7 . This suggests that PKC activation may alter the action of amphetamine. Furthermore, non-selective PKC inhibitors are reported to block amphetamine-induced wx DA release from rat striatal synaptoneurosomes 5 . Recently, we found that selective PKC inhibitors from Ž three different chemical classes chelerythrine, calphostin 0006-8993r98r$ - see front matter q 1998 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 98 01040-3