Possible loci of nicotine effects on feeding behavior. The brain receives a multitude of signals from the periphery reporting on adequacy of food intake and energy balance. These include humoral signals (red ribbon arrow) such as hormones and cytokines (e.g., leptin, TNFα, insulin, cholescystokinin, norepinephrine) and metabolites (e.g., glucose and fatty acids) as well as neural signals (green ribbon arrow). Within the hypothalamus (HYP) and the nucleus of the tractus solitarius (NTS) this information is integrated and transmitted to multiple brain regions (dark blue arrows), and the appropriate behavior is elicited. In addition to these central responses, the PNS (light blue) neurons including sympathetic, parasympathetic, and enteric, innervate the gastrointestinal tract, adipose depots, and endocrine organs. Possible sites at which nicotine might modify feeding behavior or energy balance are indicated with stars. A number of non-neural tissues express nAChRs, and could repsond directly to nicotine. In the CNS, nicotine could act within the hypothalamus, the NTS, and in the regions throughout the neuroaxis to which these structures project (mPFC, medial septal, and basal forebrain nuclei; VTA, ventral tegmental area; NTS, nucleus tractus solitarius; PBr, parabrachial nucleus; VLM, ventrolateral medullary nucleus; CrN, cranial nerve nuclei; VISC. SENS and VISC MTR, visceral sensory and motor neurons; NE, norephnephrine, ENT, N's, enteric neurons; CCK, cholecystokinin; FAs, fatty acids).

CNS sites of glucose, leptin, and (possibly) nicotine effects—up close and personal. (A) Glucose (Gluc), leptin, and nicotine signaling converge on the arcuate nucleus within the hypothalamus. The triangle shows the region from which the coronal sections in (B) and (C) are taken. (B) Higher magnification, coronal section showing the spatial relationship of the lateral hypothalamus (LH), the dorsal medial, and ventromedial hypothalamus (DM, VM) and the arcuate nuclus (Arc). ZI—zona inserta. (C) Glucose and leptin responsive neurons in the arcuate project to the LH. The first group of neurons, which are inhibited by the anorexigenic leptin signal (face with closed mouth), express the orexigenic peptides NPY and AgRP (face with open mouth). Leptin also excites a second group of neurons that contain the anorexigenic peptides, αMSH and CART. Both classes of Arc neurons project to the LH interacting with neurons and interneurons that express GABA (yellow), orexin (green), or MCH (red). Orexin and MCH neurons are orexigenic and project to other brain regions such as the mPFC, BF, VTA, etc. Key relays implicated in the regulation of feeding within the hypothalamic nuclei. The yellow stars represent possible loci of nicotine effects. (D) Nicotine treatment of LH neurons in vitro enhances neurotransmitter (GABA) release. The nicotine target is believed to be preynaptic nAChRs on GABAergic interneurons. The figure was modified from , in press. (NPY, neuropeptide Y; AgRP, agouti-related peptide; αMSH, α-melanocyte-stiimulating hormone; CART, cocaine- and amphetamine-regulated transcript; ORX, orexin, MCH, melanin-concentrating hormone; f, fornix).

Acetylcholine containing neurons are found throughout the lateral hypothalamus. (A) ACh-positive neurons (yellow/green circles) and ACh-positive projections (green, yellow/green shading; green represents highest density) are distributed throughout the LH. Some ACh-positive neurons are also found in the Arc. (B) ACh-positive neurons identified by VAChT (vesicular ACh transport) immunoreactivity and MCH-positive neurons (red—MCH immunoreactivity) are interspersed. (C) VAChT-positive bouton-like structures (red/brown immunostaining) are present in the perifornical region of the LH.