Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression.
Dopaminergic neurotransmission in the nucleus accumbens is important for various reward-related cognitive processes including reinforcement learning. Repeated cocaine enhances hippocampal synaptic plasticity, and phasic elevations of accumbal dopamine evoked by unconditioned stimuli are dependent on impulse flow from the ventral hippocampus. Therefore, sensitized hippocampal activity may be one mechanism by which drugs of abuse enhance limbic dopaminergic activity. In this study, in vivo microdialysis in freely moving adult male Sprague-Dawley rats was used to investigate the effect of repeated cocaine on ventral hippocampus-mediated dopaminergic transmission within the medial shell of the nucleus accumbens. Following seven daily injections of saline or cocaine (20 mg/kg, ip), unilateral infusion of N-methyl-d-aspartate (NMDA, 0.5 μg) into the ventral hippocampus transiently increased both motoric activity and ipsilateral dopamine efflux in the medial shell of the nucleus accumbens, and this effect was greater in rats that received repeated cocaine compared to controls that received repeated saline. In addition, repeated cocaine altered NMDA receptor subunit expression in the ventral hippocampus, reducing the NR2A : NR2B subunit ratio. Together, these results suggest that repeated exposure to cocaine produces maladaptive ventral hippocampal-nucleus accumbens communication, in part through changes in glutamate receptor composition. A behaviorally sensitizing regimen of cocaine (20 mg/kg, ip 7 days) also sensitized ventral hippocampus (hipp)-mediated dopaminergic transmission within the nucleus accumbens (Nac) to NMDA stimulation (bolts). This was associated with reduced ventral hippocampal NR2A:NR2B subunit ratio, suggesting that repeated exposure to cocaine produces changes in hippocampal NMDA receptor composition that lead to enhanced ventral hippocampus-nucleus accumbens communication.
Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Jeffrey L
JL
Barr
Gina L
GL
Forster
Ellen M
EM
Unterwald
D000818:Animals; D015153:Blotting, Western; D002404:Catheterization; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000187:drug effects
D018765:Dopamine Uptake Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine; D004298:Dopamine
NMDA; cocaine; mesolimbic; microdialysis; sensitization