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Nicotinic Receptor-Mediated Effects on Appetite

and Food Intake

Young-Hwan Jo,1 David A. Talmage,2 Lorna W. Role1


1 2
Department of Anatomy and Cell Biology, in the Center for Neurobiology and Behavior and the
Institute of Human Nutrition, Columbia University, College of Physicians and Surgeons,
New York, NY 10032

Received 2 July 2002; accepted 31 July 2002

ABSTRACT: It is well known, although not well tion. We first consider some of the possible sites of
understood, that smoking and eating just do not go nicotine’s action along the complex network of neural
together. Smoking is associated with decreased food in- and non-neural regulators of feeding. We then present
take and lower body weight. Nicotine, administered ei- the hypothesis that the lateral hypothalamus is a partic-
ther by smoking or by smokeless routes, is considered ularly important locus of the anorectic effects of nico-
the major appetite-suppressing component of tobacco. tine. Finally, we discuss the potential role of endogenous
Perhaps the most renowned example of nicotine’s influ- cholinergic systems in motivational feeding, focusing
ence on appetite and feeding behavior is the significant on cholinergic pathways in the lateral hypothalamus.
weight gain associated with smoking cessation. This ar- © 2002 Wiley Periodicals, Inc. J Neurobiol 53: 618 – 632, 2002
ticle presents an overview of the literature at, or near, Keywords: orexin; M-H; lateral hypothalamus; acetyl-
the interface of nicotinic receptors and appetite regula- choline

INTRODUCTION (Grunberg et al., 1986; Klesges et al., 1989; Pomer-


leau, 1999; Pomerleau et al., 2000). Withdrawal of
Nicotine, the major addictive component of tobacco, nicotine leads to increases in body weight of sufficient
reduces appetite and alters feeding patterns typically magnitude to confound maintained abstinence, signif-
resulting in reduced body weight (Grunberg, 1986; icantly altering the outcomes of smoking cessation
Grunberg et al., 1986; Miyata et al., 1999). Combined programs as manifest in weight-gain associated re-
epidemiologic studies of more than a quarter of a lapse (Nordstrom et al., 1999; Pomerleau, 1999).
million subjects converge on a strong inverse relation- The effects of chronic nicotine administration on
ship between cigarette smoking and body weight, appetite suppression, decreased food intake, and
with smokers weighing significantly less than non- leanness are not confined to human subjects (e.g.,
smokers of the same age and sex (Albanes et al., Blaha et al., 1998; Bray, 2000; Zhang et al., 2001).
1987; Levin et al., 1987). Particularly striking is the Likewise, nicotine withdrawal from laboratory an-
hyperphagia and resultant weight gain that accompa- imals previously subjected to chronic drug admin-
nies smoking cessation of 70 – 80% of people who istration induces hyperphagia and weight gain that
quit smoking, with women being most affected are at least qualitatively similar to the effects elic-
ited in humans by smoking cessation without nic-
otine replacement therapy (Grunberg et al., 1986;
Correspondence to: L.W. Role (LWR1@columbia.edu). Levin et al., 1987). Such findings indicate that
Contract grant sponsor: National Institutes of Health; contract postcessation weight-gain results from a fundamen-
grant numbers: NS29071, NS22061, and CA79737.
tal physiologic response, rather than just from so-
© 2002 Wiley Periodicals, Inc.
Published online in Wiley InterScience (www.interscience.wiley.com). cio-cultural factors, and underscore the importance
DOI 10.1002/neu.10147 of understanding the mechanisms that underlie nic-
618
Nicotinic Receptor-Mediated Effects on Appetite 619

otine and nicotine withdrawal-induced changes in


appetite and food intake.

POSSIBLE MECHANISMS FOR THE


EFFECTS OF NICOTINE ON FEEDING
BEHAVIOR

Even a simplified schematic of the basic neural and


non-neural regulators of energy balance cannot hide
the mechanistic complexity of feeding behavior (see
Fig. 1 and Woods et al., 1998; Kalra et al., 1999;
Schwartz et al., 2000; Chiesi et al., 2001; Speigelman
and Flier, 2001, for recent reviews). Peripheral signals
of adiposity and satiety—in the form of both chemical
and mechanical indicators of sufficient metabolic
stores and food intake—arise from adipose, liver,
pancreas, and gastrointestinal tissues. These multiple
signals assure accurate feedback in the regulation of
“start-feeding” versus “stop-feeding” behaviors.
These peripheral signals are carried by both humoral
and neural routes, and include sugars, peptides (e.g., Figure 1 Possible loci of nicotine effects on feeding be-
leptin, insulin, cholecystokinin, TNF␣), eicosanoids, havior. The brain receives a multitude of signals from the
fatty acids, and other lipid-derived molecules (e.g., periphery reporting on adequacy of food intake and energy
balance. These include humoral signals (red ribbon arrow)
prostaglandins, triglycerides, LDL). Peripheral neuro-
such as hormones and cytokines (e.g., leptin, TNF␣, insulin,
nal reporters of satiety, originating with mechanical cholescystokinin, norepinephrine) and metabolites (e.g.,
and chemical signals from the gut and liver, are pri- glucose and fatty acids) as well as neural signals (green
marily conveyed via vagal afferents to the nucleus of ribbon arrow). Within the hypothalamus (HYP) and the
the solitary tract (NTS) resulting in the activation of nucleus of the tractus solitarius (NTS) this information is
both ascending and descending circuits involved in integrated and transmitted to multiple brain regions (dark
food intake. Humoral indicators of adequate fat stor- blue arrows), and the appropriate behavior is elicited. In
age (such as leptin) act directly on central neurons to addition to these central responses, the PNS (light blue)
regulate autonomic and limbic circuits controlling neurons including sympathetic, parasympathetic, and en-
motivational aspects of feeding (see Fig. 1 and Woods teric, innervate the gastrointestinal tract, adipose depots, and
et al., 1998; Kalra et al., 1999; Schwartz et al., 2000; endocrine organs. Possible sites at which nicotine might
modify feeding behavior or energy balance are indicated
Chiesi et al., 2001; Speigelman and Flier, 2001, for
with stars. A number of non-neural tissues express nAChRs,
recent reviews). and could repsond directly to nicotine. In the CNS, nicotine
This review, and the diagram in Figure 1, empha- could act within the hypothalamus, the NTS, and in the
sizes the key integrative role of hypothalamic neurons regions throughout the neuroaxis to which these structures
in the relay of feeding-linked information to and from project (mPFC, medial septal, and basal forebrain nuclei;
limbic and autonomic structures throughout the VTA, ventral tegmental area; NTS, nucleus tractus soli-
neuraxis. Thus, the hypothalamus coordinates moti- tarius; PBr, parabrachial nucleus; VLM, ventrolateral med-
vation and emotion-related features of feeding behav- ullary nucleus; CrN, cranial nerve nuclei; VISC. SENS and
ior (via direct interactions with medial prefrontal; VISC MTR, visceral sensory and motor neurons; NE,
mPFC and cingulate cortex, basal forebrain and me- norephnephrine, ENT, N’s, enteric neurons; CCK, chole-
dial septal nuclei; MS/BF) with more fundamental cystokinin; FAs, fatty acids).
aspects of appetitive and aversive responses (via in-
teraction with nucleus accumbens, ACC, amygdala autonomic nuclei (e.g., the nucleus tractus solitarius,
AMYG, ventral tegmental area; VTA, substantia NTS, parabrachial, PBr, and ventrolateral medullary
nigra and raphe; e.g., Bittencourt and Elias, 1998; nuclei, VLM) and ultimately to the basic visceral
Broberger et al., 1998; Peyron et al., 1998; Stratford motor and sensory mediators of biting, chewing, and
and Kelley, 1999; Pajolla et al., 2001; Fadel and swallowing (e.g., cranial nerve nuclei 7, 9 and 10;
Deutch, 2002). In this manner, it is the interactions of CrN, see Fig. 1).
the hypothalamus that convey the emotional salience The first challenge, for those of us interested in
of feeding “context” from the cortex to brainstem understanding the mechanism of nicotine-dependent
620 Jo, Talmage, and Role

hypo- versus. hyperphagia, is to find where in this receptor activation in the CNS and PNS decreases
complex sequence of sites nicotine can act. The an- appetite and increases energy expenditure, thus func-
swers from the literature, as outlined below, include tioning as a key afferent component of the negative
several possible loci of the nicotinic regulation of feedback loops that stabilize adipose tissue mass. In-
food intake (indicated by red stars in Fig. 1). From travenous leptin increases norepinephrine release
these possible sites of action, some of which we touch from the adrenal gland and increases sympathetic
on below, our discussion focuses on nicotine effects nerve activity to both thermogenic and non-thermo-
on the excitability of lateral hypothalamic projection genic tissues (e.g., brown adipose vs. adrenal gland;
neurons and potentially important contributions of see Fig. 1). Administration of exogenous leptin to
endogenous cholinergic systems in the control of nor- ob/ob mice, which have a phenotype of massive over-
mal feeding behavior. eating and obesity due to the lack of leptin production,
markedly decreased food intake and body weight
(Campfield et al., 1995; Halaas et al., 1995; Pelley-
DOES NICOTINE AFFECT FEEDING VIA mounter et al., 1995). Animals of the db/db genotype
INTERACTIONS AT PERIPHERAL are similarly obese, but in this case it is due to the lack
(NON-NEURAL) SITES OF ENERGY of expression of leptin receptors and, as such, their
METABOLISM? weight is unaffected by exogenous leptin administra-
tion (Caro et al., 1996). Thus, regulated synthesis of
Many reports implicate nicotine as the appetite sup- leptin and its cytokine receptor are necessary compo-
pressing component of smoking (Grunberg, 1986; nents in the maintenance of normal body weight and
Blaha et al., 1998; Li et al., 2000; Zhang et al., 2001). energy homeostasis (see Flier and Maratos-Flier,
Studies of feeding behavior reveal that smoking or 1998; Ahima et al., 2000; Schwartz et al., 2000;
nicotine administration decreases meal size, measured Elmquist, 2001, for reviews).
as the amount of food intake per meal, without sub- Nicotine, as an appetite suppressant, may decrease
stantial changes in meal number (Blaha et al., 1998; feeding by increasing leptin levels and/or by enhanc-
Miyata et al., 2001). Although studies of nicotine- ing step(s) along the leptin–receptor-mediated signal-
induced changes in overall metabolic rate are more ing cascade. Several laboratories have attempted to
variable (Stamford et al., 1986; Sztalryd et al., 1996), test these hypotheses; overall, it appears that nicotine-
nicotine administration has been shown to alter met- induced changes in leptin levels—measured either as
abolic processing in humans, intact animals and in leptin mRNA in adipocytes or as plasma leptin con-
both hepatocytes and adipocytes, in vitro (Sztalryd et centration—are highly dependent on experimental
al., 1996; Ashakumary and Vijayammal, 1997; Arai et protocol. Some studies indicate that chronic smokers
al., 2001). Nicotine decreases lipolysis by inhibiting have significantly higher serum leptin concentrations
lipoprotein lipase activity, decreasing triglyceride up- than nonsmokers, consistent with nicotine’s hypoph-
take and hence lessening net storage in adipose tissue agic effects (Hodge et al., 1997; Wei et al., 1997;
(Sztalryd et al., 1996). Activation of nicotinic recep- Eliasson and Smith, 1999; Nicklas et al., 1999). Other
tors also induces the expression of uncoupling protein reports find no correlation (either positive or negative)
1 (UCP1) in both white and brown adipose tissue between chronic nicotine exposure and serum leptin
(Arai et al., 2001). As UCP1 shifts the balance of concentrations (Yoshinari et al., 1998; Donahue et al.,
energy metabolism from the generation of ATP to the 1999). Nevertheless, the consensus remains that the
generation of heat, this represents a shift in metabolic anorectic affects of nicotine are somehow linked to
efficiency compatible with the average lower body- altered leptin signaling. Even investigators who found
weight of smokers (Klesges et al., 1989). Overall, the that chronic cigarette smokers had significantly re-
data on the effects of nicotine on energy metabolism duced plasma leptin levels propose that the low leptin
in peripheral, non-neural tissue are reasonably compel- levels reflect nicotine-induced enhancement of leptin–
ling and certainly consistent with a significant contribu- receptor binding or increased sensitivity of down-
tion of these mechanisms to nicotine’s anorectic activity. stream transduction cascades (Hodge et al., 1997; Wei
et al., 1997). Recent analyses of nicotine affects on
adipocytes in vitro—i.e., under relatively controlled
Could the Anorectic Effects of Nicotine
conditions—revealed that the changes in leptin re-
Involve Regulation of “Adiposity”
lease depended on the duration of nicotine treatment
Signaling by Leptin?
and were not necessarily correlated with the degree of
Leptin is a peptide hormone subject to regulated syn- nicotine-induced decreases in food intake in vivo
thesis and release by adipocytes during the well-fed (Arai et al., 2001).
state (Zhang et al., 1994; Ahima et al., 2000). Leptin– It remains to be tested whether nicotine can in-
Nicotinic Receptor-Mediated Effects on Appetite 621

crease the efficacy of leptin–receptor signaling, as The extent (and duration) of nicotine-elicited alter-
proposed. In principle, nicotine could enhance or aug- ations in peripheral neuron activity depends on mul-
ment leptin–receptor signaling by several transcrip- tiple factors, such as the concentration and duration of
tionally independent mechanisms—acting in concert nicotine exposure, the subtype(s) of nicotinic AChR
with reported electrophysiologic effects of leptin on expressed and the pre- versus postsynaptic distribu-
specific populations of CNS and PNS neurons (Har- tion of the nAChRs (for recent reviews, see Gotti et
vey et al., 1997; Spanswick et al., 1997; Niijima, al., 1997; McGehee, 1999; De Biasi et al., 2000;
1998; Liu et al., 1999; Sha and Szurszewski, 1999; Temburni et al., 2000; Cooper, 2001; Dani, 2001;
Shiraishi et al., 2000; Spanswick et al., 2000; Cowley Leonard and Bertrand, 2001; Picciotto et al., 2001,
et al., 2001). Alternatively, nicotine may act by en- and articles in this volume). In addition to altering
hancing leptin receptor-mediated JAK-STAT signal neuronal excitability directly by the activation of syn-
transduction or the transcriptional regulation of one or aptic and “extra-synaptic” nAChRs, nicotine is an
more of the identified target genes of leptin receptor established modulator of transmitter release in the
signaling (Tartaglia, 1997; Elias et al., 1999; Ahima et periphery. Nicotine enhances the release of both ACh
al., 2000; Elias et al., 2000). Nevertheless, although and norepinephrine (NE) from pre- and postgangli-
nicotine and leptin elicit similar responses (whether at onic neurons by interaction with presynaptic nAChRs
the level of excitability or transcriptional regulation) (e.g., McGehee et al., 1995; Krisufek et al., 1999; De
in certain hypothalamic, vagal afferent and sympa- Biasi et al., 2000; Leonard and Bertrand, 2001; Pic-
thetic efferent neurons, their sites of action are often ciotto et al., 2001). Peripheral administration of nic-
distinct. Thus, the anorexigenic actions of nicotine otine results in decreased food intake and increased
parallel those of leptin and appear to involve both sympathetic activity to liver, adipose and gut, remi-
common and distinct cellular targets. niscent of its effects on cardiovascular parameters
(Bray, 2000). Although consistent with direct, nico-
tine-induced enhancement of norepinephrine release
DOES NICOTINE AFFECT APPETITE from peripheral nerve terminals, such changes are
VIA INTERACTION WITH PERIPHERAL also due to more indirect routes of controlling food
AUTONOMIC, ENTERIC, OR SENSORY intake and sympathetic outflow (Fig. 1). Systemic
NEURONS? administration of nicotine stimulates visceral afferents
and activates brain stem autonomic control centers,
Nicotine—like many other anorexigenic substances, such as the solitary tract, ventrolateral medullary, and
including leptin, CCK, and insulin— generally exerts parabrachial nuclei (noted in Fig. 1 as NTS, VLM,
opposite effects on the regulation of sympathetic out- and PBr, respectively; Yettefti et al., 1997; Bray,
flow and appetite (Haynes et al., 1997; Yettefti et al., 2000; Cooper, 2001; Tribollet et al., 2001). Nicotine-
1997; Niijima, 1998; Krisufek et al., 1999; Sha and evoked responses are elicited in less than 25% of the
Szurszewski, 1999; Bray, 2000). Thus, the net effects NTS neurons when tested by direct ionotophoretic
of nicotine include elevated blood pressure, heart rate, application, implicating both central and peripheral
and gastric motility while eliciting a sustained de- neuronal circuits in nicotine’s effects on feeding (Yet-
crease in food intake. Autonomic, sensory, and enteric tefti et al., 1997). Other studies underscore the con-
neurons each constitute potentially important loci for tribution of nAChRs on cranial nerve and spinal cord
nicotine-mediated changes in feeding behavior. Pe- visceral motor neurons in the regulation of sympa-
ripheral tissues involved in the regulation of food thetic and parasympathetic outflow (e.g., McGehee et
intake receive input from sympathetic and/or para- al., 1995; Tribollet et al., 2001). In sum, nicotine’s
sympathetic neurons that are themselves controlled by anorexigenic activity is likely due—at least in
cholinergic transmission. All autonomic, many en- part—to alterations in the excitability of visceral sen-
teric, and even a subset of sensory neurons are cho- sory and motor neurons as well as to modulation of
linoceptive, expressing a variety of nAChR subunits transmitter release at brain stem, spinal cord (pregan-
and nAChR subtypes that are potently activated by glionic), and/or peripheral synapses.
nicotine (e.g., Rust et al., 1994; Conroy and Berg, Last, but not least, the activation of nicotinic re-
1995; De Biasi et al., 2000; Roth et al., 2000; Cooper, ceptors on peripheral neurons has also been linked to
2001; Picciotto et al., 2001; Shoop et al., 2001). Thus, altered phospholipid and fatty-acid metabolism (e.g.,
nicotine administration via smoking can evoke signif- Vijayaraghavan et al., 1995; Marin et al., 1997; Stella
icant activation (and sustained inactivation, via desen- and Piomelli, 2001; Tieman et al., 2001, and refer-
sitization) of many peripheral neuron components of ences therein). As several of these metabolites affect
visceral-sensory and visceral-motor pathways in- appetite and/or modulate nAChRs, the reciprocal in-
volved in the regulation of feeding. teraction of nicotinic and lipid-signaling pathways
622 Jo, Talmage, and Role

may constitute an important “feedback” (pun in- rect depolarization as well as alterations in GABA,
tended) mechanism for regulating peripheral signals glutamate, norepinephrine, and serotonin release
and circuits controlling food intake (e.g., Vija- (Pabreza et al., 1991; Meguid et al., 2000; Hatton and
yaraghavan et al., 1995; Marin et al., 1997; Bray, Yang, 2002). These findings are consistent with lo-
2000; Du and Role, 2001; Tieman et al., 2001). calization of nAChRs at both pre- and postsynaptic
sites (Schwartz et al., 1984; Li and Pan, 2001). In situ
hybridization with nAChR-subunit probes reveals
ARE THE ANORECTIC EFFECTS OF moderate to high levels of expression of ␣4, ␣7, and
NICOTINE DUE TO MODULATION OF ␤2-mRNAs in hypothalamus, with particularly prom-
CENTRAL AUTONOMIC NEURONS inent expression in the supraoptic and suprachias-
matic nuclei. Examination of the nAChR distribution
The Hypothalamus within the subnuclei involved in the regulation of
ingestive behavior further guided our search for can-
The hypothalamus is a region of the brain critical for didate sites of nicotine’s anorectic activity to focus on
regulation of homeostatic processes such as feeding, the lateral hypothalamus (Jo and Role, 2002, and
thermoregulation, and reproduction (Elmquist et al., unpublished observations).
1999). To accomplish these ends, the hypothalamus Numerous studies have emphasized the contribu-
receives neural, endocrine, and metabolic signals, in- tions of the arcuate, ventromedial, dorsomedial, para-
tegrates these inputs, and engages distinct effector ventricular, and/or lateral hypothalamic nuclei in ap-
pathways, resulting in behavioral, autonomic, and en- petite regulation. In view of the stated emphasis of
docrine responses. The essential role of the hypothal- this volume we will confine our discussion to the first
amus in appetite regulation was initially suggested by and last of these regions as of particular interest to the
studies utilizing “localized” lesion and stimulation of nicotinologist.
the hypothalamus. Disruption of the ventromedial hy-
pothalamus produced hyperphagia and obesity, while The Arcuate Nucleus. The arcuate nucleus is located
lesions of the lateral hypothalamus resulted in hypo- at the base of the hypothalamus on either side of the
phagia and dramatic weight loss. Although early pro- third cerebral ventricle (Arc; Fig 2), extending rostro-
posals for a ventromedial “satiety” center and a lateral caudally from the posterior borders of the optic chi-
hypothalamic “appetite” controller were oversimpli- asm to the mamillary bodies. Two relatively recent
fied (and somewhat confounded by varying disruption observations have placed the arcuate nucleus in a
of medial forebrain bundle projections), they correctly position of prominence among the sites that are asso-
established the hypothalamus as a key contributor to ciated with the detection and integration of orexigenic
motivational aspects of feeding (see Flier and Mara- versus anorexigenic signals [indicated by the open-
tos-Flier, 1998; Woods et al., 1998; Elmquist et al., mouthed vs. closed-mouth faces, respectively, in Fig.
1999; Kalra et al., 1999; Schwartz et al., 2000; Chiesi 2(C)]. First, the arcuate nucleus contains a high den-
et al., 2001; Speigelman and Flier, 2001). The under- sity of neurons that produce the orexigenic peptides,
standing of the chemical signals and neuronal cir- neuropeptide Y (NPY; Erickson et al., 1996), opioids,
cuitry involved in the regulation of appetite has grown dynorphin (Neal and Newman, 1989), ␤-endorphin
substantially during the past decade. As such, it is (Lantos et al., 1995), and galanin (Merchenthaler et
particularly surprising that we know so little about the al., 1993). The agouti-related peptide, a selective an-
role of nicotinic receptors in the hypothalamic control tagonist of ␣MSH receptors (see below), is coex-
of food intake in smokers, ex-smokers and nonsmok- pressed with NPY mRNA in the arcuate nucleus
ers. In Figure 2, and in the discussion below, we (Broberger et al., 1998). These two peptides also
consider the key relays to, from and within the hypo- coexist in nerve terminals surrounding and in close
thalamus that may be involved in the anorexigenic apposition to perikarya and processes of both orexin
actions of nicotine. (ORX) and melanin-concentrating hormone (MCH)-
First and foremost, nicotinic receptors with the immunoreactive cells in the LH [Fig 2(C); Broberger
pharmacology of both ␣7-containing (␣7*) and ␣/␤- et al., 1998; Horvath et al., 1999]. Thus, ORX and
like pharmacology are detected throughout the hypo- MCH expressing neurons within the lateral hypothal-
thalamus (Harfstrand et al., 1988; Pabreza et al., 1991; amus are considered likely downstream targets of
Britto et al., 1992; Okuda et al., 1993; Shioda et al., NPY-positive projections from the arcuate nucleus
1997; O’Hara et al., 1998; Davila-Garcia et al., 1999; and, as such, are important mediators of NPY-induced
Hatton and Yang, 2002). Application of nicotine to in feeding signals.
vitro preparations of hypothalamus elicits the usual Melanocortins such as ␣-melanocyte-stimulating
panoply of neurophysiologic responses, including di- hormone (␣MSH) are peptides that are cleaved from
Nicotinic Receptor-Mediated Effects on Appetite 623

Figure 2 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 hypo-
thalamus. 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 hypothal-
amus (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, ␣MSH 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 Jo and Role, 2002b, in press. (NPY, neuropeptide Y; AgRP, agouti-related peptide;
␣MSH, ␣-melanocyte-stiimulating hormone; CART, cocaine- and amphetamine-regulated tran-
script; ORX, orexin, MCH, melanin-concentrating hormone; f, fornix).

the pro-opiomelanocortin (POMC) precursor mole- presses food intake, whereas a synthetic antagonist
cule and exert their effects by binding to members of has the opposite effect (Fan et al., 1997). The report
the family of melanocortin receptors (Lawrence et al., that mice lacking the MC4-type of ␣MSH receptor are
1999). A synthetic agonist of these receptors sup- hyperphagic and very obese indicates that under nor-
624 Jo, Talmage, and Role

mal conditions tonic signaling by MC4 receptors lim- are essentially unique in their expression of the orexi-
its food intake and body fat mass (Huszar et al., 1997). genic neuropeptides, melanin-concentrating hormone
The cocaine- and amphetamine-regulated tran- (MCH) (Qu et al., 1996), and orexin (ORX) (Sakurai
script (CART) was originally identified as an mRNA et al., 1998) (also called hypocretin; de Lecea et al.,
involved in CNS responses to drugs of abuse. Intra- 1998) reaffirmed the essential role of the LH in mo-
cerebroventricular (i.c.v.) administration of CART tivational aspects of feeding. Starvation sharply in-
encoded peptides inhibits normal, starvation-, and creases the levels of mRNA encoding both of these
NPY-induced feeding in rats (Kristensen et al., 1998; orexigenic signals (Qu et al., 1996; Sakurai et al.,
Lambert et al., 1998), whereas i.c.v. administration of 1998), when leptin levels rapidly fall (Ahima et al.,
neutralizing anti-CART sera increases night-time 1996).
feeding (Kristensen et al., 1998). These results sup- Cells expressing MCH and ORX comprise distinct
port a role for CART peptides as endogenous inhibi- populations of neurons within the LH. ORX cells are
tors of feeding. Interestingly, POMC and CART are located primarily in the perifornical LH, whereas
colocalized in a subset of Arc neurons distinct from MCH cells are more broadly distributed within the
the NPY/AgRP coexpressing neurons (Elias et al., LH, with the most anterior MCH neurons lining the
1998). Taken together, these studies of the expression borders of the LH, by the zona incerta and substantia
patterns and the distinct downstream effects of NPY/ innominata. More posterior MCH neurons are in the
AgRP vs. ␣MSH/CART on feeding indicate that cir- ventral lateral portion of the perifornical area and
cuits originating in the Arc have highly specialized surround the ORX population (Broberger et al., 1998;
roles in energy homeostasis. Fadel and Deutch, 2002). Interestingly, CART-posi-
In addition, due to the absence of a blood– brain tive cell bodies in the LH coexpress MCH and glu-
barrier, the arcuate nucleus is strategically positioned tamic acid decarboxylase mRNA (Elias et al., 2001).
to be in direct communication with peripheral signals ORX-immunoreactive terminals originating from the
such as leptin and insulin (reviewed in Kalra et al., LH make direct synaptic contact with neurons of the
1999). A majority of both NPY/AgRP and POMC/ arcuate nucleus that express NPY and contain leptin
CART neurons express leptin receptors (Cowley et receptors (Horvath et al., 1999). ORX-containing neu-
al., 2001). Of particular importance in this regard are rons also express leptin receptor immunoreactivity
studies demonstrating that leptin differentially regu- (Horvath et al., 1999). The excitatory actions of ORX
lates the NPY/AgRP versus POMC/CART neurons could increase NPY release, resulting in enhanced
projecting from the arcuate to the LH nuclei [indi- feeding behavior, whereas leptin, released from adi-
cated by ⫹ vs. ⫺ in Fig. 2(C); Elias et al., 1999; pose tissue as an indicator of fat stores, would have
Cowley et al., 2001]. In addition, the presence of the opposite effect on the same neurons, leading to a
direct glucose-sensing neurons within the arcuate (as decrease in NPY and NPY-mediated hypothalamic
well as within the VMN) underscores their likely functions.
contribution to direct monitoring and transduction of Why is the LH an important candidate locus of
primary metabolic signals to control food intake (e.g., nicotine-elicited appetite suppression? First, nicotine
Spanswick et al., 2000). The arcuate nucleus is thus administration into the LH significantly decreases
considered to play a key integrative role between the food intake (Miyata et al., 1999; Yang et al., 1999;
initial afferent signals from the periphery (e.g., leptins Miyata et al., 2001). Second, nicotine treatment elicits
and glucose) and CNS responses in the regulation of both short- and long-term changes in the release of a
appetite. variety of transmitters in LH (Miyata et al., 1999;
Meguid et al., 2000; Li and Pan, 2001; Zhang et al.,
The Lateral Hypothalamus. The lateral hypothala- 2001). Third, nicotine alters the expression of feed-
mus is comprised of a band of cells contiguous with ing-related neuropeptides and their receptors within
the dorsomedial, and lateral to the ventromedial, nu- the LH (Frankish et al., 1995; Kane et al., 2000; Li et
clei of the hypothalamus [Fig. 2(B) and (C)], extend- al., 2000a, Li et al., 2000b; Kane et al., 2001). In
ing rostrally from the mesencephalic tegmentum to particular, nicotine regulates dopamine and serotonin
the lateral preoptic area. It is the site of passage for the release from extrinsic projections to the LH (Miyata et
medial forebrain bundle, a major conduit of projec- al., 1999; Meguid et al., 2000) and it modulates
tions connecting forebrain and midbrain structures GABA and glutamate transmission within the LH
with each other and with several hypothalamic sites. [Fig. 2(D) and Y. Jo and L. Role, unpublished obser-
Lesions in the LH produced temporary aphagia, ad- vations]. Likewise, nicotine regulates the levels of
ipsia, and loss in body weight consistent with an expression of NPY, orexin and an orexin receptor.
important contribution of LH to appetite regulation. The complexity arises in assessing which of the many
The demonstration that lateral hypothalamic neurons changes that are elicited by nicotine in the lateral
Nicotinic Receptor-Mediated Effects on Appetite 625

hypothalamus underlie the nicotine-induced hypopha- hypothalamus. NPY administration is potently orexi-
gia and, perhaps even more importantly, the persistent genic and expression of NPY mRNA in the arcuate
hyperphagia accompanying nicotine cessation (Grun- nucleus is increased in response to fasting or chronic,
berg et al., 1986; Levin et al., 1987; Nordstrom et al., but moderate food restriction (see Woods et al., 1998;
1999; Pomerleau et al., 2000). Kalra et al., 1999; Lawrence et al., 1999; M.W.
Schwartz et al., 2000, for reviews). A simple predic-
Does Nicotine Affect Appetite via tion is that if NPY signaling is a target for nicotine’s
Regulation of Release from anorectic action, then nicotine treatment might sup-
Dopaminergic or Serotoninergic press the expression of NPY or NPY receptors. In the
Projections to the Lateral short term, this appears to be true. Frankish and col-
Hypothalamus? laborators found that acute (24-h) nicotine adminis-
tration, reduced food intake by 30%, and lowered
First let’s consider the effects of nicotine on the
NPY and NPY mRNA levels in the Arc nucleus by
release of dopamine and serotonin, two critical food
35% (Frankish et al., 1995). The situation following
intake-related neurotransmitters. The absence of do-
chronic nicotine administration is murky; however, as
pamine production (in mice that cannot express ty-
2 weeks of nicotine treatment, lowers food intake but
rosine hydroxylase (Szczypka et al., 2000) results in
significantly increases levels of NPY mRNA. Li and
an inability to initiate feeding, although the basic
colleagues (Li et al., 2000) found that after 14 days
motor ability to eat is unaffected. In the hypothala-
nicotine suppressed food intake and elicited a dose-
mus, dopamine release is associated with the duration
dependent increase in hypothalamic NPY mRNA lev-
of meal consumption, an important determinant of
els (by 20 –50% depending on the dose of nicotine)
feeding pattern. As dopamine is required to initiate
and increased NPY immunoreactivity by 24 – 69%
meals, decreased dopamine is associated with reduced
(the magnitude of the increase varied in different
meal number and meal duration (reviewed in Meguid
regions of the hypothalamus). In a valiant attempt to
et al., 2000). In contrast, serotonin is implicated in the
resolve the conflict between nicotine-induced hypo-
inhibition of food intake (see Meguid et al., 2000).
phagia and the observed induction of a renowned
Serotonin release in the hypothalamus is enhanced
orexigenic peptide, the authors propose that nicotine
during feeding (D.H. Schwartz et al., 1989) and is
somehow modifies the sensitivity of NPY and/or nico-
thought to promote satiety. Mice lacking serotinergic
tinic acetylcholine receptors; consequently, modulating
receptors display food intake and body weight-related
NPY synthesis and food intake. A long-term increase in
abnormalities (Nonogaki et al., 1998).
NPY levels might desensitize the NPY receptor systems.
Studies of nicotine infusion and amine release in
We provide an alternative explanation, based on initial
hypothalamus support the idea that activation of
studies of nicotine effects on LH circuits, below.
nAChRs on serotinergic projections to LH may con-
tribute to the anorectic effects of nicotine. The role of
dopamine release in nAChR-induced appetite sup- Does Nicotine Affect Appetite via
pression—as opposed to meal initiation—is less clear Regulation of Orexin Neurons in the
(Miyata et al., 1999; Yang et al., 1999; Meguid et al., Lateral Hypothalamus?
2000). Continuous nicotine administration into the
Orexin A and B (also called hypocretins) are two
LH induces long-lasting increases in 5-HT release that
peptides derived from a single 131-residue precursor
parallel the sustained suppression of food intake in the
peptide (prepro-orexin), that are produced exclusively
same animals. If enhanced serotinergic transmission
in the LH (Sakurai, 1999; Shiraishi et al., 2000; Willie
in hypothalamus signals satiety as proposed
et al., 2001; Kotz et al., 2002). In view of the orexi-
(Schwartz et al., 1989; Nonogaki et al., 1998), nico-
genic activity of these peptides, the simplest predicted
tine may act as a false indicator of the well-fed state,
link between nicotine-induced hypophagia and orex-
resulting in early meal termination (i.e., decreasing
ins would be that nicotine depresses orexin signaling.
meal size and duration, as previously reported; Miyata
No such luck.
et al., 2001) due to nAChR-mediated presynaptic fa-
Kane and colleagues (Kane et al., 2000) showed
cilitation of serotonin release.
that chronic nicotine treatment (14 days) elicited a
dose-dependent increase in the expression of prepro-
Does Nicotine Affect Appetite via orexin mRNA expression in hypothalamus. This in-
Regulation of NPY Neurons that Project crease in prepro-orexin mRNA in nicotine-treated an-
to the Lateral Hypothalamus? imals is expected to yield increased levels of orexin
NPY, a 36-amino acid neuropeptide, is abundant in protein in the LH and/or at sites of projection of
the brain of rats, and is highly concentrated in the orexin-producing neurons. This increase might lead to
626 Jo, Talmage, and Role

Figure 3 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 inter-
spersed. (C) VAChT-positive bouton-like structures (red/brown immunostaining) are present in the
perifornical region of the LH.

downregulation of orexin and/or NPY receptor ex- showing that MCH receptor-deficient mice, like those
pression. Indeed, the same authors demonstrated that lacking MCH expression, are hypophagic, further
hypothalamic orexin-A binding sites were downregu- supporting the importance of MCH in appetite regu-
lated by chronic nicotine treatment (Kane et al., lation (Marsh et al., 2002).
2001). It should be kept in mind that orexin may The activity of MCH-expressing neurons is elabo-
regulate sleep/wakefulness states, rather than feeding rately regulated by interneurons within the LH, inputs
behavior (Hungs and Mignot, 2001; Sutcliffe and De from other hypothalamic nuclei and by projections
Lecea, 2002). Mice lacking orexin show a phenotype from other brain regions (e.g., Qu et al., 1996; Bayer
similar to human narcolepsy, including behavioral et al., 1999; Fig. 2; see below, and Fig. 3). Orexigenic,
arrests and premature entry into rapid eye movement NPY-positive inputs from the Arc strongly enhance
(REM) sleep (Chemelli et al., 1999). Hara and col- the activity of MCH neurons (Flier and Maratos-Flier,
leagues (Hara et al., 2001) observed similar results in 1998). AgRP neurons have the same net effect as
mice lacking orexin neurons. Thus, effects of nicotine costored NPY on the activity of MCH neurons but the
on orexin signaling might be manifested as alterations mechanisms are distinct. AgRP is an antagonist of
in sleep/wake states rather than feeding behavior. receptors for the anorexigenic peptide, ␣MSH, and
thereby inhibits the inhibition (!) normally mediated
by ␣MSH–MC4 receptor interactions. Decreased ac-
Does Nicotine Affect Appetite via
tivation of MCH neurons results from enhanced in-
Regulation of MCH Neurons in
hibitory GABAergic input and by inhibitory influ-
Hypothalamus?
ences of CART/␣MSH projections (Fan et al., 1997).
MCH, another peptide uniquely expressed in lateral Finally, MCH projections may mediate a positive
hypothalamic neurons, is also orexigenic (see discus- feedback control by inhibition of GABAergic inputs
sion above and Fig. 2). Fasting animals upregulate (Gao and van den Pol, 2001).
hypothalamic MCH mRNA levels and MCH receptor Recent work investigates the possibility that nico-
antagonists block NPY, ␤-endorphin, and fasting-in- tinic receptor activation regulates the excitability of
duced increases in food intake. Mice lacking MCH MCH neurons in LH [Fig. 2(D); Y. Jo and L. Role,
have lower body weights and enhanced leanness, as- unpublished observations]. In principle, nicotine
sociated with marked hypophagia, compared with could suppress appetite either by decreasing any of
control animals (Shimada et al., 1998). Recent studies the multiple inputs that normally activate MCH neu-
Nicotinic Receptor-Mediated Effects on Appetite 627

rons or by increasing the overall inhibition of MCH Cholinergic projections to neurons within the hy-
neurons. We propose that both mechanisms are in- pothalamus arise from both extrinsic and intrinsic
volved in nicotine’s actions [Fig. 2(C) and (D)]. sources; approximate areas of cholinergic input are
GABA is the primary inhibitory transmitter in the indicated in Figure 3 by green (high level) and yellow
hypothalamus (Elias et al., 2001) and a prominent (lower level) shading (Tago et al., 1987; Risold et al.,
component of synaptic input in in vitro preparations 1989; Woolf, 1991; Schafer et al., 1998; Bayer et al.,
of rat, chick, and mouse lateral hypothalamus (Gao 1999). Cholinergic neurons intrinsic to the hypothal-
and van den Pol, 2001; Jo and Role, 2002a; Jo and amus, identified by their positive immunoreactivity
Role, unpublished). Activation of nicotinic receptors for choline acetyltransferase (ChAT), or the vesicular
by treatment with nicotine [Fig. 2(D)] or by increas- transporter for ACh (VAChT) are present in the ar-
ing ACh release (not shown) strongly facilitates cuate nucleus and scattered through the paraventricu-
GABAergic transmission to LH neurons (Jo and Role, lar, periventricular, and posterior nuclei (Fig. 3;
2002b; Jo and Role, unpublished data). Initial efforts adapted from Tago et al., 1987; Risold et al., 1989;
in mouse brain slices to identify the post synaptic LH Woolf, 1991; Schafer et al., 1998; Bayer et al., 1999).
neurons under study are consistent with our proposal Higher densities of both large and small ChAT-
that MCH-positive neurons receive GABAergic input stained somata are found in the lateral hypothalamic
and that GABA release is potently enhanced by presyn- area and in the adjacent substantia innominata (Tago
aptic nAChRs. In this scenario, activation of presynaptic et al., 1987). Extrinsic cholinergic projections to the
nAChRs on GABAergic interneurons would offset the hypothalamus arise primarily from the ponto-mesen-
pro-appetite, orexigenic signaling of NYP/AgRP inputs, cephalic cell groups (i.e., the pedunculopontine and
favoring a net inhibition of MCH-positive neurons. This laterodorsal tegmental nucleus; Woolf, 1991).
sort of synaptic tuning of LH neurons could explain, at The density of cholinergic fibers (whether intrinsic
least in part, nicotine’s anorexigenic activity. or extrinsic in origin) within the LH ranges from
The model can also resolve the apparent conflict moderate to strong (see especially Tago et al., 1987;
between elevated NPY expression and the sustained Bayer et al., 1999). LH areas with substantial numbers
hypophagia that characterizes chronic nicotine expo- of ACh-positive projections include the perifornical
sure. Under these conditions, we would predict that area, the dorsal border of the LH (adjacent to the zona
the nAChR-mediated enhancement of GABA release incerta) and, at a more anterior level than illustrated
is maintained and results in an elevated set point for here, along the lateral border of the LH and substantia
steady-state inhibition of orexigenic outflow via MCH innominata. The overlap between MCH and cholin-
projections. Increased expression of NPY peptide ergic neurons and fibers is particularly striking, espe-
(due to diminished negative regulation by leptin, as cially with respect to proposed mechanisms of nico-
leptin levels fall with chronic nicotine exposure) can- tine effects in LH. In the zona incerta and perifornical
not elicit sufficient activation of MCH neurons to regions of the rat LH, many choline acetyltransferase
override the elevated GABAergic inhibition. Obvi- (ChAT) fibers are detected in the immediate vicinity
ously, this model can (and must) be tested. Whether of MCH-positive perikarya and their proximal den-
correct in detail or not, such studies would provide a drites [Bayer et al., 1999; and Fig. 3(B) and (C)].
systematic foray into the effects of nicotine and nic- Of course, new levels of complexity are added by
otine withdrawal in appetite regulation. changing the question from “how does nicotine affect
appetite?” to an analysis of how central cholinergic
circuits might participate in feeding regulation. An
How Might Endogenous Cholinergic
obvious, and substantial wrinkle, is that ACh (as
Circuits Be Involved in the Normal
opposed to nicotine) interacts with multiple subtypes
Regulation of Appetite?
of muscarinic as well as nicotinic AChRs. Several
The effects of neuronal nAChR activation on hypo- subtypes of both nicotinic and muscarinic AChRs
thalamic activity, food intake, and body weight regu- (mAChRs) are expressed within the LH including ␣4,
lation beg the question of how central cholinergic ␣7, and ␤2 type nAChRs, and m1 and m2 type
systems might participate in normal appetite control. mAChRs (Ehlert and Tran, 1990; Britto et al., 1992;
The role of cholinergic and/or cholinoceptive neurons Okuda et al., 1993; J. Wei et al., 1994).
in the hypothalamus has received relatively little at- So, what happens when cholinergic neurons or
tention. Several recent studies, however, implicate cholinergic projections in the lateral hypothalamus are
acetylcholine effects within the hypothalamus in the activated? Little is known. Initial attempts, using
control of both neuroendocrine and behavioral func- changes in GABAergic transmission as an assay of
tions, including food intake and arousal (Hara et al., elevated ACh release in LH slice, appear to confirm in
2001; Saper et al., 2001). vitro results demonstrating corelease of GABA and
628 Jo, Talmage, and Role

ATP, but differential modulation of GABAergic and appetite. Smokers are leaner and smoking cessation in
purinergic transmission by nicotinic versus musca- the absence of nicotine replacement therapy typically
rinic receptors (Jo and Role 2002a, 2002b, and Y. Jo results in significant and sustained hyperphagia and
and L. Role, unpublished). The net effect of nicotinic weight gain.
receptor activation in hypothalamus— even with ATP Identifying the cellular substrates of nicotine ac-
and glutamate transmission added to the analysis— is tion is no small task. Despite numerous reports on the
increased inhibition. Muscarinic receptors mediate seriousness of nicotine-cessation related weight gain,
exactly the opposite effects: GABAergic transmission considerable progress in our understanding of
is depressed and purinergic transmission is enhanced. nAChRs (to wit this volume) and staggering discov-
Similar pharmacologic approaches to assessing the eries in the identification of the molecular scaffolds of
role of cholinergic signaling in LH examine the ef- feeding behavior, the interface between the fields of
fects of carbachol treatment on expression of MCH smoking and eating remains sketchy, at best. We are
mRNA in hypothalamic slices in vitro. Carbachol still lacking systematic studies aimed at identifying
induces a rapid increase in MCH mRNA, which is the major regulatory nodes of where nicotine effects
abolished both by atropine, a muscarinic antagonist, and appetite control converge. Our knowledge of the
and hexamethonium, a nicotinic antagonist (Bayer et role of central cholinergic circuits in appetite is em-
al., 1999). This finding is consistent with studies ex- bryonic, despite impressive efforts in the neuroanat-
amining the regulation of MCH mRNA in animals omy and immunocytochemistry of cholinergic neu-
lacking specific muscarinic signaling pathways. MCH rons and their diffuse terminal fields. In sum, it appears
mRNA is increased in WT, fasted animals, thereby that the physiologists—from systems to synaptic-ana-
inducing a compensatory increase in food intake. lysts— have not (ahem) towed their weight in addressing
However, MCH mRNA levels are significantly re- these fundamental issues in the neural regulation of
duced, even with fasting, in certain types of musca- feeding behavior. There’s lots of work to do.
rinic receptor knock-out mice (Yamada et al., 2001).
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