Additive effects of intra-accumbens infusion of the cAMP-specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward.
Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaine's reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaine's actions on these pathways.
Knapp
C M
CM
Department of Psychiatry, Boston University School of Medicine, MA 02118, USA. cknapp@bu.edu
Lee
K
K
Foye
M
M
Ciraulo
D A
DA
Kornetsky
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004333:Drug Administration Routes; D004357:Drug Synergism; D009714:Nucleus Accumbens; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D012201:Reward; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D003042:Cocaine; D020889:Rolipram