Reduced activity at the 5-HT(2C) receptor enhances reversal learning by decreasing the influence of previously non-rewarded associations.

RATIONALE: Reversal learning deficits are a feature of many human psychopathologies and their associated animal models and have recently been shown to involve the 5-HT(2C) receptor (5-HT(2C)R). Successful reversal learning can be reduced to two dissociable cognitive mechanisms, to dissipate associations of previous positive (opposed by perseverance) and negative (opposed by learned non-reward) valence. OBJECTIVES: This study aims to explore the effect of reducing activity at the 5-HT(2C)R on the cognitive mechanisms underlying spatial reversal learning in the mouse. METHODS: Experiment 1 used the 5-HT(2C)R antagonist SB242084 (0.5 mg/kg) in a between-groups serial design, experiment 2 used 5-HT(2C)R KO mice in a repeated measures design. Animals initially learned to discriminate between two lit nosepoke holes. This was followed by three conditions; (1) full reversal, where contingencies reversed; (2) perseverance, where the previous CS+ became CS- and the previous CS- was replaced by a novel CS+; (3) learned non-reward, where the previous CS- became CS+ and the previous CS+ was replaced by a novel CS-. RESULTS: SB242084 treated and 5-HT(2C)R KO mice showed enhanced reversal learning seen as a decrease in trials, correct responses, and omissions to criterion in the full reversal condition. Similar effects were observed in the learned non-reward condition but SB242084 treated and 5-HT(2C)R KO mice did not differ from controls in the perseverance condition. SB242084 treated, but not 5-HT(2C)R KO mice, showed decreases in all latency indices in every condition. CONCLUSION: Reducing activity at the 5-HT(2C)R facilitates reversal learning in the mouse by reducing the influence of previously non-rewarded associations.

Intra-accumbens baclofen, but not muscimol, mimics the effects of food withdrawal on feeding behaviour.

Intra-accumbens stimulation of GABA receptors results in a robust increase in food intake. However the differential consequences of stimulating GABA(A) and GABA(B) receptors in the nucleus accumbens have not been extensively explored with respect to feeding behaviour. Here we compare the effects of the GABA(B) receptor agonist baclofen and GABA(A) receptor agonist muscimol, infused into the nucleus accumbens shell, on food intake and related behavior patterns. Baclofen (110-440 ρmol) dose dependently enhanced intake and delayed the onset of satiety within the test period as did the effects of 4-8h food withdrawal. Muscimol (220-660 ρmol) enhanced intake but also disrupted the sequence of associated behaviours at every dose tested. We conclude that GABA(B) receptors in the nucleus accumbens shell may play a role in relation to feeding motivation whereas GABA(A) receptors may, as previously suggested, have a more restricted role in relation to the motor components of approach to food and ingestion.

Intraaccumbens baclofen selectively enhances feeding behavior in the rat.

Intraaccumbens infusions of the GABA(B) agonist baclofen are known to stimulate food intake in the rat. The aim of the present study was to evaluate the effects of baclofen infusion on nonfood-related chewing and on the consumption of a palatable fluid. Rats were bilaterally infused with baclofen (188 ng in 1 microL) or saline, and tested in a situation in which food was available in one or two locations and wood blocks might also be present. Baclofen-infused animals showed no enhancement of chewing directed at the wood blocks, but showed increased food consumption regardless of food location. In a second, separate test we recorded the microstructural parameters for drinking of a palatable glucose/saccharin mixture. Baclofen infusion had no effect on overall intake, although bout size was reduced and the number of bouts was increased. These data confirm that baclofen-stimulated food intake following accumbens infusion is a robust and substantial phenomenon that appears to be selective to solid food. It is likely to result from relatively direct activation of neural circuits for feeding, rather than an indirect facilitation consequent upon changes in taste processings, as has been suggested for some other examples of drug-induced hyperphagia.

Little and often: ingestive behavior patterns following hippocampal lesions in rats.

Lesions of both dorsal and ventral hippocampus were produced by multiple infusions of the excitotoxin AMPA. Meal patterns recorded before and after lesioning showed no change in total food intake, but a striking behavioral syndrome in which the lesioned rats took smaller meals 2-3 times as frequently and showed a similar change in drinking. In addition, lesioned rats alternated more frequently between feeding and drinking during a single bout of ingestive behavior. There were no group differences in the satiety sequence that followed a meal. In an open field test, lesioned rats showed enhanced locomotion in the periphery and reduced rearing. An olfactory habituation-dishabituation task showed that the lesioned rats investigated olfactory stimuli less but dishabituation to a changed stimulus was normal. The data are discussed in terms of changes in behavioral switching or a possible interoceptive agnosia following hippocampal damage.

Disturbance of meal patterning following nucleus accumbens lesions in the rat.

In this study, we examined the effects of electrolytic lesions of the nucleus accumbens which had no obvious effect on body weight, or on the short term intake of solid food, sucrose and salt solutions. However in 24 h records of feeding and drinking lesioned animals took many more meals of shorter duration. Challenge with the dopamine D2 antagonist YM-09151-2 resulted in a decrease in feeding rate, together with a facilitation of meal size in drinking, in both control and lesioned subjects.