Repeated cocaine enhances ventral hippocampal-stimulated dopamine efflux in the nucleus accumbens and alters ventral hippocampal NMDA receptor subunit expression

Abstract

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.

Keywords: NMDA; cocaine; mesolimbic; microdialysis; sensitization.

Figure 1

Representative photomicrographs of coronal brain coronal sections of (A) microdialysis probe membrane placement in the nucleus accumbens and (B) infusion cannula placement in the ventral hippocampus.

Figure 2. Cocaine administration increased motoric activity and produced locomotor sensitization

Cumulative activity counts for 60 minutes post-cocaine (20 mg/kg ip) and saline injection are shown. Rats administered cocaine had greater activity than rats administered saline on both day one and day seven (^# significantly different from saline on the same day, P<0.05). On the seventh day of administration, rats injected with cocaine showed a greater increase in activity than on the first day of cocaine administration (*significantly different between day one and seven within cocaine administered rats, P < 0.05). Data are expressed as mean ± SEM beam breaks/60 minute period. (N=9–10/group)

Figure 3. Cocaine pretreatment enhanced ventral hippocampal NMDA-stimulated motor activity and extracellular dopamine in the nucleus accumbens

Effects of ventral hippocampal NMDA infusion on (A) motoric activity and (B) extracellular DA in the nucleus accumbens of saline (N=9) and cocaine (N=10) pre-treated rats, expressed as percentage of baseline. Arrow indicates time of NMDA infusion. Data represent mean ± SEM. ^# significantly different from pre-infusion levels in both saline- and cocaine-pre-treated rats. * Significant difference between saline- and cocaine-pretreated groups (P < 0.05).

Figure 4. Effect of repeated cocaine on NMDA receptor subunit expression in the ventral hippocampus

(A) Representative protein bands on immunoblots for NR1 (120 kD), NR2A (180 kD), and NR2B (190 kD) in the ventral hippocampus (examples are from single animals in each treatment group). (B) NMDA subunit protein levels in ventral hippocampal tissue of saline- and cocaine-administered rats. (C) Calculated NR2A:NR2B ratios of rats injected with saline or cocaine for seven days. Repeated cocaine resulted in a reduced NR2A:NR2B ratio in the ventral hippocampus compared with repeated saline (*significant difference between saline and cocaine groups, P < 0.05). Means + SEM are shown. (N=9–10/group)