HCN2 in cholinergic interneurons of the nucleus accumbens mediates reward response

Cholinergic interneurons (ChIs) of the nucleus accumbens (NAc) are important for mediating the behavioral response to rewarding stimuli. A major role for these cells is to regulate dopamine (DA) transmission by activating cholinergic receptors at local DAergic nerve terminals. However, the mechanisms that enable cholinergic neurons to enhance DA release in response to reward remain unknown. Here we report that the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) in NAc ChIs mediates an enhancement in DA signaling in response to rewarding stimuli. The HCN current in NAc ChIs and its modulation by DA, as well as the increase in cholinergic efflux by local cocaine infusion were impaired in mice with deletion of HCN2 in cholinergic cells. Enhancement in the DA efflux and signaling in the NAc in response to rewarding stimuli, as well as cocaine conditioning were also dependent on HCN2 in ChIs. These results provide a mechanistic link between the activity of NAc ChIs and reward encoding.

Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior

Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific.

Dexmedetomidine Increases the Cocaine Seizure Threshold in Rats

Background Central alpha adrenoceptors have been demonstrated to play an important role in the control of seizure activity; moreover, alpha adrenoceptors have been linked to electroencephalogram changes associated with cocaine. The purpose of this study was to determine if dexmedetomidine, a highly selective alpha -adrenoceptor agonist, alters the threshold for cocaine-induced seizure activity in rats. Methods Sprague-Dawley rats received a cocaine infusion (1.25 mg x kg(-1) x min(-1)) followed 15 min later by the coinfusion of either dexmedetomidine (20-microg/kg intravenous bolus followed by an infusion of 1 microg x kg(-1) x min(-1), CD group, n = 8) or an equal volume of saline (CS group, n = 8). Dexmedetomidine or saline were coinfused with cocaine until the onset of cocaine-induced seizures. Dopamine concentrations in the nucleus accumbens were measured by microdialysis paired with chromatography. To determine if changes in extracellular dopamine were related to the seizures, dopamine (1 microm) was continuously delivered to the nucleus accumbens in a separate group (DACD group, n = 6) retrograde microdialysis. These rats then received an intravenous cocaine infusion followed by dexmedetomidine in the same manner as the CD group. Results Dexmedetomidine significantly increased the dose of cocaine necessary to produce seizures. Seizures occurred at 25.0 +/- 7.7 and 49.3 +/- 14.8 min in CS and CD, respectively (P < 0.001). The ratio of the percent increase in accumbal dopamine to the cocaine dose at the onset of seizure activity was significantly lower in CD, 39.9 +/- 16.5, compared to CS, 82.2 +/- 46.5 (P = 0.04). Intraaccumbal administration of dopamine prevented the effects of dexmedetomidine on the cocaine seizure threshold. Conclusions These data suggest that dexmedetomidine increases the cocaine-induced seizure threshold possibly a mechanism related to the attenuation of the extracellular dopaminergic neurotransmitter response to cocaine.