The data suggest that nAChRs and mAChRs may be localized to different populations of GABAergic terminals, but from these studies, it is difficult to determine what the effects of synaptically

evoked ACh on LH GABA release might be. Optogenetic stimulation of cholinergic transmission in the LH and hypothalamus will be useful in identifying the source of ACh input to these areas, the role of intrinsic ACh in hypothalamic function, and the differential role of mAChRs and nAChRs in shaping responses to ACh in these brain regions. In the arcuate nucleus of the hypothalamus, nicotine increases the firing rate of both POMC- and neuropeptide Y (NPY)-positive neurons, although the increase in POMC neuron activity predominates in vitro due ABT199 to more rapid desensitization of nAChR responses in NPY neurons, and in vivo, as evidenced by an increase in c-fos immunoreactivity

predominantly in POMC-positive cells ( Huang et al., 2011; Mineur et al., 2011). Thus, as in the mesolimbic system and the cortex, distinct actions of ACh appear to converge through effects on receptor populations with different electrophysiological properties expressed on distinct subsets of neurons to promote a coordinated output, in this case, activation of POMC neurons. ACh also regulates glutamatergic transmission in other neuronal subtypes involved in food intake. Stimulation of nAChRs on orexin-positive neurons in the LH induces concurrent release of glutamate and ACh, which could lead Selleck VE822 to feed-forward stimulation

of this circuit once activated (Pasumarthi and Fadel, 2010). There is also some indication from studies of hypothalamic neurons in culture that ACh signaling can be upregulated to compensate for prolonged blockade of glutamatergic signaling (Belousov et al., 2001). Thus, ACh acting through nAChRs may also potentiate glutamate signaling in particular neuronal subtypes of the hypothalamus, although the functional consequences of this regulation are not yet known. As might be expected from the complex regulation of hypothalamic neuronal activity by ACh, Adenosine cholinergic modulation of feeding behavior is multifactorial and state-dependent. In rats, the mAChR competitive antagonist atropine modestly altered the frequency and choice of meals, but not their size (Nissenbaum and Sclafani, 1988). Consistent with the ability of nicotine in tobacco smoke to decrease body weight in humans and food intake in rats (Grunberg et al., 1988), β4-containing nAChRs on POMC neurons are critical for the ability of nicotine to reduce food intake in mice (Mineur et al., 2011). These observations underscore a potential role for ACh in metabolic regulation involving POMC neurons; however, very little is known about the role of endogenous ACh-mediated modulation of the arcuate nucleus.