REVIEWS THE NEUROBIOLOGY OF NICOTINE ADDICTION: BRIDGING THE GAP FROM MOLECULES TO BEHAVIOUR Steven R. Laviolette and Derek van der Kooy Nicotine, the primary psychoactive component of tobacco smoke, produces diverse neurophysiological, motivational and behavioural effects through several brain regions and neurochemical pathways. Recent research in the fields of behavioural pharmacology, genetics and electrophysiology is providing an increasingly integrated picture of how the brain processes the motivational effects of nicotine. The emerging characterization of separate dopamine- and GABA (γ-aminobutyric acid)-dependent neural systems within the ventral tegmental area (VTA), which can mediate the acute aversive and rewarding psychological effects of nicotine, is providing new insights into how functional interactions between these systems might determine vulnerability to nicotine use. The addictive nature of nicotine remains a global health neurotransmitter systems, the potential roles of specific epidemic. Over three million smoking-related deaths neuronal nicotinic acetylcholine receptor (nAChR) are reported annually, worldwide. In the Western world, subtypes and specific neuroanatomical regions that illness related to smoking is believed to be the cause of have been implicated in mediating the addictive prop- 20% of all deaths, making nicotine addiction the single erties of nicotine. In particular, we will review the con- largest cause of preventable mortality1,2.Despite these siderable body of evidence that implicates dopamine grim statistics, tobacco use is increasing in many devel- (DA) and non-DA neuronal substrates in the ventral oping countries3,with smoking-related mortalities tegmental area (VTA) as crucial for the rewarding and predicted to exceed 10 million per year over the coming aversive motivational properties of nicotine. Whereas 30–40 years1.Although nicotine is generally not classi- previous research has implicated DA-mediated neuro- fied among ‘harder’ addictive drugs, such as cocaine transmission as a direct mediator of a nicotine reward or heroin, with continued use tobacco often becomes as signal4–7,more recent evidence points to a more com- difficult to abandon. As anybody who has ever struggled plex role for DA systems in the motivational effects of with repeated attempts at smoking cessation can attest nicotine, including the aversive effects of nicotine and to, nicotine is exceptionally intractable to quitting drug-induced plastic changes at the synapse8–10. interventions. We propose an integrated model that might account Since the identification of nicotine as the primary for the vulnerability to the rewarding and addictive psychoactive component of tobacco smoke, a great properties of nicotine through acute actions on non- Neurobiology Research Group, Department of amount of research has been undertaken to unravel the DA reward pathways. With continued nicotine expo- Anatomy and Cell Biology, neuropharmacological, anatomical and behavioural sure, plastic molecular alterations in central DA University of Toronto, underpinnings of its psychoactive effects. Various systems might underlie the continued propensity to Toronto, Canada, neural pathways and transmitter systems have emerged consume nicotine by inducing craving, the aversive M5S 1A8, USA. as compelling candidates for the processing of the effects of withdrawal, and aberrant incentive-salience email: [email protected] psychoactive and addictive properties of nicotine. attribution to environmental stimuli that are associated doi:10.1038/nrn1298 Here,we will examine research that implicates specific with nicotine. NATURE REVIEWS | NEUROSCIENCE VOLUME 5 | JANUARY 2004 | 55 © 2004 Nature Publishing Group REVIEWS a signalling properties of nicotine in various CNS regions. Ligand binding site In particular, studies on the actions of nicotine on DA pathways, specifically within the VTA, have provided H2N NH2 H N HOOC COOH 2 insights into how nicotine might modify signalling through DA and non-DA VTA systems. COOH Extracellular The VTA and its input and output pathways. The mam- M1 M2 M3 M4 malian VTA is a midbrain region that has been implicated in the rewarding motivational effects of a wide variety of Cytoplasmic addictive drugs, including cocaine19,alcohol20,opiates21,22 and nicotine8,23,24.Much evidence implicates the VTA and its associated efferent and afferent projections as an inte- grative centre for the psychoactive effects of nicotine. Presynaptic Postsynaptic Within the VTA, DA neurons (designated as the A10 DA b nAChRs nAChRs group), and their associated ascending projections to the nucleus accumbens and prefrontal cortex (PFC), comprise the well-characterized mesolimbic and meso- cortical pathways. In addition, a population of VTA GABA neurons provide inhibitory input to the A10 DA neurons25,and there is anatomical evidence for descend- Preterminal ing projections to the brainstem mesopontine region, nAChRs including the tegmental pedunculopontine nucleus (TPP)26,27 — a brain region that is important in DA- Figure 1 | The structure of neuronal nicotinic acetylcholine receptors (nAChRs). independent reward signalling. Both of these neuronal a | Although the precise molecular structure of nAChRs is not known, they are believed to be populations — the DA and GABA neurons — are pentameric ion channels. Each nAChR is composed of five subunits arranged in either homomeric involved in signalling reward19,21,28,29.The VTA also or heteromeric complexes of α- or β-subunit arrangements (left). Different subunit combinations receives excitatory glutamatergic and cholinergic projec- confer unique functional properties to the ubiquitously distributed nAChRs throughout the brain. tions from both the TPP and the adjacent laterodorsal The schematic on the right shows the transmembrane topology of a single nAChR subunit. The tegmental nucleus (LDT)25,30,as well as inhibitory GABA transmembrane domains are labelled M1–M4. The larger amino-terminal domain contains the 31 acetylcholine-binding site, whereas the M2 domain determines the ionic selectivity of the receptor inputs from the TPP .In FIG. 2,the ascending anatomical and faces the inside of the channel pore. b | nAChRs are located at the soma, on presynaptic DA projections from the VTA to the nucleus accumbens terminals and on postsynaptic boutons. This widespread localization confers the receptor with a and prefrontal cortex, as well as the VTA’s GABA connec- wide range of functions, influencing neuronal signalling at the pre- and postsynaptic levels. tions with the TPP are shown. Recent electrophysiological work on brain slices has provided insights into the cellular mechanisms by which nicotine interacts with both of Nicotine signalling: pharmacology and anatomy these neuronal populations in the VTA, and has impli- Nicotine acts on endogenous nAChRs that are found cated the VTA as a crucial site for central nicotine sig- ubiquitously throughout the central (CNS) and periph- nalling through several pre- and postsynaptic substrates. eral nervous systems in almost all vertebrate and inver- tebrate species. The nAChRs are pentameric receptor Neurophysiology of nicotine signalling in the VTA. complexes that serve as ligand-gated ion channels (FIG. 1). Neurons within the VTA have a wide variety of nAChRs17, So far, 12 different neuronal nAChR subunits have been and nicotine can activate both the DA and GABA neu- identified: α2–α10 and β2–β4 (REFS 11–15).The nAChR rons of the VTA32,33.The nAChR receptor profiles that receptors form different combinations of α- and are associated with these DA and GABA neurons differ β-subunits. However, the α7–α9 subunits can also form considerably, and these differences might have important homomeric nAChRs16,17. functional consequences for nicotine signalling in the Functionally, the nAChR receptor complex can exist mesolimbic system. For example, DA neurons of the in three conformational states, which are dynamically VTA express the α2–α7 and β2–β4 subunits34,35,which regulated by exposure to the agonist: closed, open and can give rise to at least three pharmacologically distinct desensitized11.When agonists bind to the nAChR, the nAChR subtypes, of which one is probably a homomeric receptor complex undergoes a conformational change α7 receptor. Although less than half of the VTA neurons in its structure, which allows the channel gate to open, express nAChRs that contain α7 (REF.17), this subunit is permitting the passage of cations (such as Na+,K+ and preferentially localized within the midbrain in the VTA, also Ca2+,which might account for 1–10% of the nAChR- relative to the adjacent substantia nigra17.By contrast, less mediated current18) through the channel pore. than 25% of the GABA neurons express the α3, α5, α6 Ligand binding can produce a diverse range of neuro- and β4 subunits35,indicating that most nAChRs of these physiological effects. For example, nAChRs made of VTA neurons contain the α4 and β2 subunits. different subunit combinations can be located either on The administration of nicotine within concentration the soma and/or neuronal processes, enabling nAChR to ranges that are readily self-administered in rodents and act at the cell body and at the presynaptic and postsynap- humans has been shown to increase DA release in tic regions (FIG. 1). In vitro studies have examined the the nucleus accumbens24,36.Furthermore, within the 56 | JANUARY 2004 | VOLUME 5 www.nature.com/reviews/neuro © 2004 Nature Publishing Group REVIEWS a activity of