Relationship Between Nicotine Intake and Reward Function in Rats With Intermittent Short Versus Long Access to Nicotine.

INTRODUCTION: Tobacco use improves mood states and smoking cessation leads to anhedonia, which contributes to relapse. Animal studies have shown that noncontingent nicotine administration enhances brain reward function and leads to dependence. However, little is known about the effects of nicotine self-administration on the state of the reward system. METHODS: To investigate the relationship between nicotine self-administration and reward function, rats were prepared with intracranial self-stimulation electrodes and intravenous catheters. The rats were trained on the intracranial self-stimulation procedure and allowed to self-administer 0.03 mg/kg/infusion of nicotine. All rats self-administered nicotine daily for 10 days (1 hour/day) and were then switched to an intermittent short access (ShA, 1 hour/day) or long access (LgA, 23 hour/day) schedule (2 days/week, 5 weeks). RESULTS: During the first 10 daily, 1-hour sessions, nicotine self-administration decreased the reward thresholds, which indicates that nicotine potentiates reward function. After switching to the intermittent LgA or ShA schedule, nicotine intake was lower in the ShA rats than the LgA rats. The LgA rats increased their nicotine intake over time and they gradually consumed a higher percentage of their nicotine during the light phase. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine induced a larger increase in reward thresholds (ie, anhedonia) in the LgA rats than the ShA rats. In the LgA rats, nAChR blockade with mecamylamine decreased nicotine intake for 2 hours and this was followed by a rebound increase in nicotine intake. CONCLUSIONS: A brief period of nicotine self-administration enhances reward function and a high level of nicotine intake leads to dependence. IMPLICATIONS: These animal studies indicate that there is a strong relationship between the level of nicotine intake and brain reward function. A high level of nicotine intake was more rewarding than a low level of nicotine intake and nicotine dependence was observed after long, but not short, access to nicotine. This powerful combination of nicotine reward and withdrawal makes it difficult to quit smoking. Blockade of nAChRs temporarily decreased nicotine intake, but this was followed by a large rebound increase in nicotine intake. Therefore, nAChR blockade might not decrease the use of combustible cigarettes or electronic cigarettes.

Self-administration of the synthetic cathinone MDPV enhances reward function via a nicotinic receptor dependent mechanism.

Methylenedioxypyrovalerone (MDPV) is an addictive synthetic drug with severe side effects. Previous studies have shown that MDPV has positive reinforcing properties. However, little is known about the effect of MDPV self-administration on the state of the brain reward system and the neuronal mechanisms by which MDPV mediates its effects. The goal of the present studies was to determine the effect of MDPV self-administration on reward function and the role of cholinergic neurotransmission in the reinforcing effects of MDPV. To study the effect of MDPV self-administration on the brain reward system, rats were prepared with intravenous catheters and intracranial self-stimulation electrodes (ICSS). For 10 days, the reward thresholds were assessed immediately before (23 h post prior session) and after 1 h of MDPV self-administration. The reward thresholds were decreased immediately after MDPV self-administration, which is indicative of a potentiation of brain reward function. The reward thresholds 23 h after MDPV intake gradually increased over time, which is indicative of anhedonia. Pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased the self-administration of MDPV and completely prevented the decrease in reward thresholds. A control study with palatable chocolate pellets showed that responding for a natural reinforcer does not affect the state of the brain reward system. Furthermore, mecamylamine did not affect responding for food pellets. In conclusion, the self-administration of MDPV potentiates reward function and nAChR blockade prevents the reward enhancing effects of MDPV self-administration. Preventing the MDPV-induced increase in cholinergic neurotransmission might be a safe approach to diminish MDPV abuse.

Functional connectivity, behavioral and dopaminergic alterations 24 hours following acute exposure to synthetic bath salt drug methylenedioxypyrovalerone.

Among cathinone drugs known as bath salts, methylenedioxypyrovalerone (MDPV) exerts its potent actions via the dopamine (DA) system, and at intoxicating doses may produce adverse behavioral effects. Previous work by our group suggests that prolonged alterations in correlated neural activity between cortical and striatal areas could underlie, at least in part, the adverse reactions to this bath salt drug. In the present study, we assessed the effect of acute MDPV administration on brain functional connectivity at 1 and 24 h in rats. Using graph theory metrics to assess in vivo brain functional network organization we observed that 24 h after MDPV administration there was an increased clustering coefficient, rich club index, and average path length. Increases in these metrics suggests that MDPV produces a prolonged pattern of correlated activity characterized by greater interactions between subsets of high degree nodes but a reduced interaction with regions outside this core subset. Further analysis revealed that the core set of nodes include prefrontal cortical, amygdala, hypothalamic, somatosensory and striatal areas. At the molecular level, MDPV downregulated the dopamine transporter (DAT) in striatum and produced a shift in its subcellular distribution, an effect likely to involve rapid internalization at the membrane. These new findings suggest that potent binding of MDPV to DAT may trigger internalization and a prolonged alteration in homeostatic regulation of DA and functional brain network reorganization. We propose that the observed MDPV-induced network reorganization and DAergic changes may contribute to previously reported adverse behavioral responses to MDPV.