Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens.
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 intraacumbens infusion saline, 8-bromo-cAMP (2 micrograms/side; a membrane permanent analogue of cAMP which activates PKA), or RP-CPT-cAMP (20 nmol/side; which inhibits PKA). In a separate experiment, control animals received total 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 ona 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.
Miserendino
M J
MJ
Department of Psychiatry and Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508, USA.
Nestler
E J
EJ
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine