The melanin-concentrating hormone1 receptor antagonists, SNAP-7941 and GW3430, enhance social recognition and dialysate levels of acetylcholine in the frontal cortex of rats

Abstract

Melanin-concentrating hormone (MCH)1 receptors are widely expressed in limbic structures and cortex. Their inactivation is associated with anxiolytic and antidepressive properties but little information is available concerning cognition. This issue was addressed using the selective antagonists, SNAP-7941 and GW3430, in a social recognition paradigm in rats. The muscarinic blocker, scopolamine (1.25 mg/kg s.c.), reduced social recognition, an action dose-dependently blocked by SNAP-7941 and GW3430 (0.63-10.0 and 20.0-80.0 mg/kg i.p., respectively) which did not themselves display amnesic properties. Further, in a protocol where a spontaneous deficit was induced by a prolonged inter-session delay, SNAP-7941 and GW3430 dose-dependently enhanced social recognition. In dialysis studies, SNAP-7941 (0.63-40.0 mg/kg i.p.) and GW3430 (10.0-40.0 mg/kg i.p.) elevated extracellular levels of acetylcholine (ACh) in the frontal cortex (FCX) of freely moving rats. The SNAP-7941 effect was specific, as it did not increase levels of ACh in ventral and dorsal hippocampus: moreover, it did not modify levels of noradrenaline, dopamine, serotonin and glutamate in FCX. Active doses of SNAP-7941 and GW3430 corresponded to doses (2.5-40.0 and 10.0-80.0 mg/kg i.p., respectively) exerting anxiolytic properties in Vogel conflict and ultrasonic vocalization tests, and antidepressant actions in forced swim, isolation-induced aggression and marble-burying procedures. In contrast to SNAP-7941 and GW3430, the benzodiazepine, diazepam, decreased social recognition and dialysate levels of ACh, while the tricyclic, imipramine, reduced social recognition and failed to enhance cholinergic transmission. In conclusion, at anxiolytic and antidepressant doses, SNAP-7941 and GW3430 improve social recognition and elevate extracellular ACh levels in FCX. This profile differentiates MCH1 receptor antagonists from conventional anxiolytic and antidepressant agents.

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

“…The increase in the time spent in REMS and the decrease in the REMS latency during the rebound following sleep deprivation are both changes similar to those described in depression. Furthermore, the antidepressant-like profile of MCH-R1 antagonists suggest the role of MCH in the regulation of mood (Antal-Zimanyi and Khawaja 2009;Borowsky et al 2002;Chung et al 2011;Lagos et al 2011a;Millan et al 2008).…”

The Role of Melanin-Concentrating Hormone in Energy Homeostasis and Mood Disorders

“…Moreover, ATC0065, ATC0175, as well as SNAP-7941, demonstrated a selective increase in swimming performance score with no change in climbing behavior (Borowsky et al 2002;Chaki et al 2005), which is similar to the actions of selective serotonin reuptake inhibitors (SSRIs; Borowsky et al 2002;Cryan et al 2005). GW3430 and GW803430 attenuated forced-swim isolation-induced aggression and marbleburying behavior in mice, another model sensitive to many clinically used antidepressants (Millan et al 2008;Gehlert et al 2009), whereas ATC0065 and ATC0175 exhibited only poor activity in marble burying (Chaki et al 2005). Contradictory findings have been reported for SNAP94847, an analog of SNAP7941; in one study, no effect was observed in forced-swim stress , whereas, in another study, it was shown to attenuate the behavioral effects in the same model (Smith et al 2009).…”

“…MCH hippocampal microinjection was shown to increase the expression of NMDA receptor subunits and induce a consequent retrograde facilitation in rat (Varas et al 2003). Moreover, SNAP7941 and GW3430 facilitated cognition by blocking deficits in social recognition provoked either by a pronounced intersession delay or by scopolamine and by enhancing frontocortical cholinergic transmission (Millan et al 2008).…”

“…Unlike benzodiazepines, there was no effect on spontaneous locomotor activity or rotarod performance in rats within the efficacious anxiolytic dose range (Chaki et al 2005). Similarly, GW3430, SNAP-7941, and SNAP-94847 exhibited anxiolytic-like properties using diverse behavioral models such as Vogel conflict, social interaction, stress-induced hyperthermia, novelty-suppressed feeding, and the stress-elicited ultrasonic vocalizations in guinea pig pups (Borowsky et al 2002;Millan et al 2008;Smith et al 2009). More recently, treatment with GW3430 reversed the anxiogenic effect of MCH in the elevated plus-maze and stress-induced hyperthermia tests (Smith et al 2006).…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…186 -188 In addition, notwithstanding experimental evidence for a role of galanin and melanin concentrating hormone in the regulation of mood and cognition, galanin receptor ligands and melanin concentrating hormone 1 receptor antagonists are conspicuously absent from current drug pipelines-although this may be related to difficulties in finding drugs with appropriate safety and pharmacokinetic profiles, not only to the issue of efficacy. 189,190 Finally, evidence supporting the relevance of central corticotrophin releasing factor 1 (CRF 1 ) receptors in the response to stress, control of the HPA axis, regulation of mood, and induction of anxious and depressed states is overwhelming, but clinical data with selective antagonists are frustratingly sparse, and the most recent report was negative. 3,90,191,192 For these (and other) neuropeptide receptors, association with SRI properties or other mechanisms controlling depressed states should be envisaged.…”