Effects of 5-HT1A, 5-HT2A and 5-HT2C receptor agonists and antagonists on responding for a conditioned reinforcer and its enhancement by methylphenidate.

OBJECTIVES: These experiments examined the effects of selective 5-HT1A, 5-HT2A and 5-HT2C receptor ligands on responding for a conditioned reinforcer (CRf). Effects of these ligands were measured under basal conditions and following elevated dopamine (DA) activity produced by the DA reuptake inhibitor methylphenidate. METHODS: Water-restricted rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were made available; responding on one lever delivered the CS (now a CRf), while responding on the second lever had no consequences. The effects of agonist and antagonists of 5-HT1A (8-hydroxy-2(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635)), 5-HT2A (DOI and M100907) and 5-HT2C (Ro60-0175 and SB242084) receptors on responding were examined alone, as well as in the presence of methylphenidate. RESULTS: Responding for a CRf was reduced by the agonists 8-OH-DPAT, DOI and Ro60-0175. 8-OH-DPAT also reduced responding for water and seemed to impair responding in a non-specific fashion. None of the receptor antagonists affected responding. Methylphenidate dose-dependently enhanced responding for a CRf, and this was attenuated by DOI and Ro60-0175. Conversely, the 5-HT2C receptor antagonist SB242084 potentiated the effect of methylphenidate. CONCLUSIONS: No evidence was found for a behaviourally selective effect of 5-HT1A receptor ligands on responding for a CRf. Activation of 5-HT2A receptors selectively inhibits responding for a CRf. 5-HT2C receptor ligands exerted bidirectional modulation of responding for a CRf, especially when DA activity was increased. This indicates that 5-HT2C receptor activity is an important modulator of DA-dependent reward-related behaviours.

Low Impulsive Action, but not Impulsive Choice, Predicts Greater Conditioned Reinforcer Salience and Augmented Nucleus Accumbens Dopamine Release.

Poor impulse control is associated with an increased propensity to develop an addiction and may contribute to relapse as high impulsive subjects appear to attribute greater salience toward drug-paired stimuli. In these studies, we determined whether trait impulsivity also predicts the desire to obtain natural reward-paired stimuli. Rats trained on the 5-choice serial reaction time task to measure impulsive action (Experiment 1) or a delay-discounting task to measure impulsive choice (Experiment 2) were separated into low, intermediate, or high impulsive action (L-IA, I-IA, H-IA) or choice (L-IC, I-IC, H-IC) groups. The motivation to obtain a conditioned stimulus (CS) paired with water-reward was subsequently determined by measuring responding for the CS as a conditioned reinforcer (CRf). Dopamine release in the nucleus accumbens was also measured using in vivo microdialysis. The effects of amphetamine were assessed on all tests. In Experiment 1, amphetamine increased impulsive action in all groups. L-IA rats initially demonstrated the highest responding for the CRf. Amphetamine increased responding for the CRf and this effect was augmented in L-IA rats. Dopamine release following amphetamine was greatest in L-IA subjects. In Experiment 2, amphetamine increased impulsive choice for L-IC and I-IC rats. However, all groups responded similarly for the CRf and dopamine release was moderately greater in L-IC rats. In conclusion, impulsive choice was unrelated to responding for a CRf. L-IA subjects initially attributed enhanced salience to a CS and exhibited greater dopamine release. Lower dopamine release in H-IA rats could result in reduced reinforcing properties of the CRf.

Responding for conditioned reinforcement in C57BL/6 and CD-1 mice, and Sprague-Dawley rats: Effects of methylphenidate and amphetamine.

RATIONALE: Characterization of responding for conditioned reinforcement in mice is important to implement genetic tools in examining the neurobiological mechanisms underlying reward-related learning and incentive motivation. METHODS: Inbred C57BL/6 mice, outbred CD-1 mice, and outbred Sprague-Dawley rats underwent Pavlovian conditioning in which a conditioned stimulus (CS) was paired with saccharin. Subsequently, subjects were allowed to respond for that CS in tests of responding for conditioned reinforcement. Experiments measured the effects of methylphenidate (MPH) and amphetamine (AMPH) on lever pressing for conditioned reinforcement in mice and rats. We further examined the stability of responding for conditioned reinforcement in mice after repeated testing and the extinction of this behaviour following omission of the reinforcer. We also determined whether the CS exhibited reinforcing properties if it was not paired with saccharin. RESULTS: C57BL/6 and CD-1 mice learned to respond for a conditioned reinforcer similarly to rats, and the behaviour was stable over time. MPH increased responding in CD-1 mice and rats, but not in C57BL/6 mice. AMPH only increased responding in rats. Responding was reduced following omission of the conditioned reinforcer, and responding was only established when the CS was paired with saccharin. CONCLUSIONS: These experiments characterize a conditioned reinforcement test which produces stable responding in two different mouse backgrounds. These findings also show that dopaminergic psychomotor stimulants can differently affect rats and mice in tests of responding for conditioned reinforcement.

Impulsive action in the 5-choice serial reaction time test in 5-HT2c receptor null mutant mice.

RATIONALE: Depletion of brain serotonin (5-HT) results in impulsive behaviour as measured by increased premature responding in the five-choice serial reaction time (5-CSRT) test. Acute selective blockade of 5-HT2C receptors also increases this form of impulsive action, whereas 5-HT2C receptor stimulation reduces premature responding. OBJECTIVES: These experiments determined the impact of genetic disruption of 5-HT2C receptor function on impulsive responding in the 5-CSRT test. METHODS: Food-restricted 5-HT2C receptor null mutant and wild-type (WT) mice were trained on the 5-CSRT test in which subjects detect and correctly respond to brief light stimuli for food reinforcement. Impulsivity is measured as premature responses that occur prior to stimulus presentation. RESULTS: Both lines of mice quickly learned this task, but there were no genotype differences in premature responding or any other aspect of performance. A series of drug challenges were then given. The 5-HT2C receptor agonist Ro60-0175 (0.6 mg/kg) reduced premature responding in WT mice but not mutant mice. The 5-HT2C receptor antagonist SB242084 increased premature responding in WT mice only. Cocaine increased premature responding at 7.5 mg/kg but not at a higher dose that disrupted overall responding; these effects were observed in both lines of mice. Amphetamine (0.25 and 0.5 mg/kg) did not affect premature responding, but disrupted other aspects of performance in both genotypes. CONCLUSIONS: Genetic deletion of 5-HT2C receptor function does not induce an impulsive state or exacerbate that state induced by psychomotor stimulants but does prevent the acute effects of 5-HT2C receptor stimulation or blockade on impulsive action.

Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement.

The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT(2A) and 5-HT(2C) receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175 and the 5-HT(2A) receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement, response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15 mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT(2C) receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT(2C) and 5-HT(2A) receptors may be potential targets for therapies to treat some aspects of nicotine dependence.

The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse control.

Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT(2C) receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the five-choice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT(2C) receptor agonists, similarly affect both food- and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT(2C) agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.