An important physiological role of prefrontal cortex (PFC) mechanisms in the regulation of hunger and satiety has been indicated in both experimental animals and humans.1, 2 Forebrain cholinergic systems are essential for cognitive processes, such as learning, memory and attention,3 and procholinergic drugs are procognitive in the clinic.3, 4 Importantly, obesity appears to be comorbid with disease states characterized by cognitive impairment, for example, attention-deficit hyperactivity disorder (ADHD).5 It is hypothesized that an integral prefrontal cortical function, especially in the right hemisphere, might be critical for appetite and eating control, as well as for better long-term adherence to therapeutic interventions.2, 6
We have recently shown that clinically established ADHD drugs increase acetylcholine (ACh) efflux preferentially in the medial PFC of rats, a neurochemical effect that may be related to their therapeutic action.4 We sought to investigate the effects of the efficacious antiobesity drugs,7 sibutramine (a monoamine reuptake inhibitor) and rimonabant (a cannabinoid CB1 receptor antagonist), on ACh efflux in the PFC and in a subcortical brain region implicated in food reward/reinforcement processes, the nucleus accumbens (NAC), of freely moving rats by in vivo microdialysis.
Male Wistar rats were implanted in the PFC and the NAC (right hemisphere) with microdialysis probes, as previously described.4, 8 Surgical procedures, microdialysis experiments and determination of ACh were detailed before.4, 8, 9 The perfusion solution contained neostigmine (0.1 μM) that may have impacted the observed effects on ACh efflux in a quantitative, but not qualitative, manner.8 Animals received the compounds (synthesized at Lilly Research Laboratories) or their respective solubilizing vehicle via oral gavage. The doses of sibutramine or rimonabant were in the same range of doses previously used in functional studies,8, 9, 10 whether the compounds were administered orally or parenterally. Data were analyzed with either three- (treatment × region × time) or two-way (treatment × region) analysis of variance (ANOVA) and Duncan's test for multiple comparisons. Basal ACh levels were in the order of 200–600 fmol per sample in the PFC and 50–150 fmol/sample in the NAC (sample volume: 36 μl); there was no difference in basal ACh levels between any of the groups.
Sibutramine produced a sustained increase in ACh efflux in the PFC up to 240% of baseline, whereas it only had a minor effect on ACh efflux in the NAC (Figure 1a); a lower dose of sibutramine, 10 mg kg−1, also increased cortical ACh efflux to about the same extent, although the duration of the effect was around 2 h (not shown). Similarly, rimonabant increased ACh efflux in the PFC up to 233% of baseline that lasted for 2 h returning toward baseline for the remainder of the time, whereas it had no effect on accumbal ACh efflux (Figure 1c). The stimulatory effects of sibutramine and rimonabant on overall cortical ACh efflux were statistically different (P<0.05) from either the effect of vehicle(s) in the same brain region or their effect on ACh in the NAC (Figures 1b and d).
We demonstrated that oral administration of the clinically efficacious antiobesity drugs, sibutramine and rimonabant, increased ACh efflux selectively in the PFC, compared to their effects on ACh efflux in the NAC. In spite of the fact that sibutramine and rimonabant exert distinct actions on classical neurotransmitter systems in the brain by inhibiting monoamine reuptake and blocking cannabinoid CB1 receptors, respectively, it is striking that these two drugs converge on their effects on cortical ACh efflux. We have previously shown that intraperitoneal administration of the norepinephrine reuptake inhibitor and effective ADHD medication, atomoxetine as well as CB1 receptor antagonists increase ACh efflux in the PFC and the hippocampus through a mechanism that involves dopamine D1 receptor stimulation and possibly norepinephrinergic α1-receptor stimulation.4, 8, 9 A similar mechanism underlying the stimulatory effect of sibutramine on cortical ACh efflux is likely, given that it also increases monoamine concentrations in the prefrontal cortex,10 similarly to atomoxetine and rimonabant.4, 8
The regionally selective actions of sibutramine and rimonabant on cortical ACh efflux may represent a unique feature of anti-obesity drugs that are clinically efficacious or are currently developed. Such selective procholinergic activity may be related to the therapeutic efficacy of antiobesity drugs by optimizing prefrontal cortical function in the regulation of appetite and food-intake control, restoring healthier eating habits and increasing compliance to therapeutic interventions and total energy expenditure readjustments.
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Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: Effects on food-reinforced behavior and comparisons with AM4113
Pharmacology Biochemistry and Behavior (2009)