Nicotine-induced Brain Stimulation Reward is Modulated by Melanocortin-4 Receptors in Ovariectomized Rats

Apart from reproduction, estrogen influences a multitude of processes. Increase in estrogen levels in women is known to promote reward probably mediated via the melanocortin and dopamine systems. Reduced estrogen in post-menopausal women attenuates reward, evoking the need for stimulation with greater rewarding salience. This is reflected in the well-recognized phenomena of difficulty in quitting and increased craving for nicotine in women following the onset of menopause. The present study aims at understanding the role of melanocortin receptors (MC-R) in nicotine-induced reward behavior following ovariectomy in rats. The MC4-R mRNA level was increased in ipsilateral nucleus accumbens (Acb) of the intact rats implanted with electrode in medial forebrain bundle and trained in intracranial self-stimulation (ICSS) paradigm. Additional groups of ICSS trained rats were ovariectomized (OVX) and subjected to reward evaluation. Trained OVX rats revealed a significant increase in threshold frequency and rightward shift in rate frequency curve, suggesting reward deficit behavior. However, pre-administration with nicotine, alpha-melanocyte stimulating hormone (α-MSH) or NDP-MSH (MC4-R agonist) to OVX animals restored the rewarding activity in ICSS protocol; HS014 (MC4-R antagonist) suppressed the lever press activity. Prior treatment with sub-effective doses of α-MSH or NDP-MSH potentiated the reward effect of nicotine, but was attenuated by HS014. Alpha-MSH-immunoreactivity was decreased in the Acb shell, arcuate and paraventricular nucleus of hypothalamus, and ventral bed nucleus of stria terminalis in the OVX rats, while nicotine treatment restored the same. We suggest a role for the endogenous MC system, perhaps acting via MC4-R, in the nicotine-induced reward in OVX rats.