ObjectiveThe increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved.MethodsMurine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.ResultsLorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity.ConclusionsThese data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

Lesions of the orbital prefrontal cortex (OPFC) and the nucleus accumbens core (AcbC) can disrupt performance in inter-temporal choice tasks, possibly by increasing the organism's sensitivity to delay and/or magnitude of reinforcement. This experiment examined whether exposure to an inter-temporal choice would induce neuronal activation in these areas, as indicated by enhanced expression of the Fos protein. Twelve rats were trained to press levers A and B under an adjusting-delay schedule in which a response on A delivered 50 μl of a sucrose reinforcer after 2 or 18 s, whereas a response on B delivered the same reinforcer after a delay that was adjusted in accordance with the rat's choices. Another 12 rats were trained under a similar schedule in which a response on A delivered an immediate reinforcer of size 20 or 180 μl, whereas a response on B delivered an immediate reinforcer whose size was adjusted in accordance with the rat's choices. A third group received training under a schedule that did not entail variation of reinforcer size or delay, or choice between reinforcers, and a control group underwent food restriction without behavioural training. Exposure to the adjusting-delay schedule was associated with enhanced Fos expression in both the OPFC and AcbC, whereas exposure to the adjusting-magnitude schedule was associated with enhanced Fos expression in the OPFC but not the AcbC, compared to the control group. The results are consistent with previous findings that implicated the AcbC and OPFC in delay discounting, and the OPFC in sensitivity to reinforcer size.

Abstract. The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT 2 ) and histamine (H 1 ) receptor antagonist effects, are shared by the non-selective 5-HT receptor antagonist cyproheptadine. Atypical antipsychotics have a characteristic profile of action on operant behaviour maintained by progressive-ratio schedules, as revealed by Killeen"s (1994) mathematical model of scheduled controlled behaviour. These drugs increase the values of a parameter that expresses the "incentive value" of the reinforcer (a) and a parameter that is inversely related to the "motor capacity" of the organism (δ). This experiment examined the effects of acute treatment with cyproheptadine and clozapine on performance on a progressive-ratio schedule of food reinforcement in rats; the effects of a conventional antipsychotic, haloperidol, and two drugs with food intake-enhancing effects, chlordiazepoxide and Δ 9 -tetrahydrocannabinol (THC), were also examined. Cyproheptadine (1, 5 mg kg -1 ) and clozapine (3.75, 7.5 mg kg -1 ) increased a and δ. Haloperidol (0.05, 0.1 mg kg -1 ) reduced a and increased δ.Chlordiazepoxide (3, 10 mg kg -1 ) increased a but reduced δ. THC (1, 3 mg kg -1 ) had no effect. Interpretation based on Killeen"s (1994) model suggests that cyproheptadine and clozapine enhanced the incentive value of the reinforcer and impaired motor performance. Motor impairment may be due to sedation (possibly reflecting H 1 receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H 1 and 5-HT 2 receptors, which has been proposed as the mechanism underlying the food intake-enhancing effect of cyproheptadine. In agreement with previous findings, haloperidol impaired motor performance and reduced the incentive value of the reinforcer. Chlordiazepoxide"s effect on a is consistent with its food intake-enhancing effect.