The serotonin 2C receptor agonist lorcaserin, alone and in combination with the opioid receptor antagonist naltrexone, attenuates binge-like ethanol drinking.

The serotonin (5-HT) system has been implicated in the pathophysiology of alcohol (ethanol; EtOH) use disorders. Lorcaserin, a 5-HT2C receptor agonist, attenuates drug self-administration in animal models. We investigated the effects of lorcaserin on EtOH intake using the drinking-in-the-dark (DID) procedure, an animal model of binge-like drinking. We compared the effects of lorcaserin to those of the Food and Drug Administration (FDA)-approved drug naltrexone and examined the effects of combining lorcaserin and naltrexone. To examine whether effects were specific for EtOH, we examined the effects of lorcaserin and naltrexone, administered alone and in combination, on saccharin intake. Adult male C57BL/6J mice received EtOH access (20% v/v) for 2 h in the home-cage during the first 3 days of the DID procedure, beginning 3 h into the dark cycle. On day 4, mice were injected with lorcaserin, naltrexone, or a combination of lorcaserin and naltrexone prior to a 4-h EtOH access. Intake was measured at 2 and 4 h. Lorcaserin reduced EtOH intake in a dose-dependent fashion over the 2- and 4-h measurement periods. Naltrexone also reduced EtOH intake when administered alone, with dose-dependent effects being more pronounced over 2 h rather than the full 4-h session. Combining lorcaserin and naltrexone reduced binge-like EtOH drinking to a greater extent than either drug alone. A similar pattern of results was obtained for saccharin intake. These results suggest that lorcaserin and naltrexone can have additive effects on binge-like EtOH drinking. They also support continued research into the therapeutic potential of lorcaserin for alcohol use disorders.

The pharmacological stressor yohimbine, but not U50,488, increases responding for conditioned reinforcers paired with ethanol or sucrose.

RATIONALE: Environmental stimuli paired with alcohol can function as conditioned reinforcers (CRfs) and trigger relapse to alcohol-seeking. In animal models, pharmacological stressors can enhance alcohol consumption and reinstate alcohol-seeking, but it is unknown whether stress can potentiate the conditioned reinforcing properties of alcohol-paired stimuli. OBJECTIVES: We examined whether the pharmacological stressors, the α-2 adrenoreceptor antagonist yohimbine (vehicle, 1.25, 2.5 mg/kg; IP) and the K-opioid receptor agonist U50,488 (vehicle, 1.25, 2.5 mg/kg; SC), increase responding for conditioned reinforcement, and if their effects interact with the nature of the reward (alcohol vs. sucrose). We subsequently examined the effects of yohimbine (vehicle, 1.25, 2.5 mg/kg; IP) on responding for sensory reinforcement. METHODS: Male Long-Evans underwent Pavlovian conditioning, wherein a tone-light conditioned stimulus (CS) was repeatedly paired with 12% EtOH or 21.7% sucrose. Next, tests of responding for a CRf were conducted. Responding on the CRf lever delivered the CS, whereas responding on the other lever had no consequences. In a separate cohort of rats, the effects of yohimbine on responding just for the sensory reinforcer were examined. RESULTS: Both doses of yohimbine, but not U50,488, increased responding for conditioned reinforcement. This enhancement occurred independently of the nature of the reward used during Pavlovian conditioning. Yohimbine-enhanced responding for a CRf was reproducible and stable over five tests; it even persisted when the CS was omitted. Both doses of yohimbine also increased responding for sensory reinforcement. CONCLUSIONS: Yohimbine increases operant responding for a variety of sensory and conditioned reinforcers. This enhancement may be independent of its stress-like effects.

Nicotine enhances responding for conditioned reinforcement via α4ß2 nicotinic acetylcholine receptors in the ventral tegmental area, but not the nucleus accumbens or the prefrontal cortex.

Nicotine enhances the conditioned reinforcing properties of reward-paired cues. We investigated the role of the ventral tegmental area (VTA), nucleus accumbens (NAcc), and prelimbic (PrL) and infralimbic (IL) cortices in mediating this enhancement. Male Long-Evans rats were implanted with bilateral guide cannulae aimed at either the VTA, NAcc, PrL or IL cortex. Next, rats underwent 12 sessions of Pavlovian conditioning. Each session consisted of 30 trials wherein a 5 s conditioned stimulus (CS) was paired with water (0.05 ml). Tests of responding for conditioned reinforcement were conducted during which presentation of the CS, now acting as a conditioned reinforcer (CRf), was contingent upon pressing one of two levers (CRf lever). Pressing the other lever had no consequences (NCRf lever). To determine if nicotinic acetylcholine receptors (nAChRs) in the VTA, NAcc, PrL cortex, or IL cortex mediate nicotine-enhanced responding for a CRf, the α4ß2 nAChR antagonist Dihydro-Beta-Erythroidine (DHßE; 10 nmol/0.5 µL) was infused into the respective areas prior to a systemic nicotine injection (0.2 mg/kg; SC). DHßE infused into the VTA, NAcc, or IL cortex, but not PrL cortex, attenuated nicotine-enhanced responding for a CRf. Next, to confirm that nAChRs in the VTA, NAcc, or IL cortex mediate this enhancement, nicotine (8, 16, or 32 nmol/0.5 µL) was infused into the respective areas. Nicotine infused into the VTA, but not NAcc or IL cortex, enhanced responding for a CRf. These findings suggest that nicotine primarily acts on α4ß2 nAChRs in the VTA to potentiate the conditioned reinforcing properties of reward-related cues.

Effects of sucrose concentration and water deprivation on Pavlovian conditioning and responding for conditioned reinforcement.

An appetitive Pavlovian conditioned stimulus (CS) can predict an unconditioned stimulus (US) and acquire incentive salience. We tested the hypothesis that US intensity and motivational state of the subject would influence Pavlovian learning and impact the attribution of incentive salience to an appetitive Pavlovian CS. To this end, we examined the effects of sucrose concentration and water deprivation on the acquisition of Pavlovian conditioning and responding for a conditioned reinforcer. Male Long-Evans rats (Harlan; 220-240 g) receiving 3% (3S) or 20% (20S) sucrose were either non-water deprived or given water for 1 hr per day. During Pavlovian conditioning sessions, half the rats in each concentration and deprivation condition received a 10-s CS paired with 0.2 ml of sucrose (16 trials/session; 3.2 ml/session). The remainder received unpaired CS and US presentations. Entries into a port where sucrose was delivered were recorded. Next, responding for conditioned reinforcement was tested, wherein pressing an active lever produced the CS and pressing an inactive lever had no consequences. CS-elicited port entries increased, and latency to the first CS-elicited port entry decreased across sessions in paired groups. Water deprivation augmented these effects, whereas sucrose concentration had no significant impact on behavior. Responding for conditioned reinforcement was observed in the 20S water-deprived, paired group. Thus, water deprivation can facilitate the acquisition of Pavlovian conditioning, potentially by enhancing motivational state, and a high-intensity US and a high motivational state can interact to heighten the attribution of incentive salience to an appetitive Pavlovian CS. (PsycINFO Database Record