Cellular and synaptic mechanisms of nicotine addiction

The tragic health effects of nicotine addiction highlight the importance of investigating the cellular mechanisms of this complex behavioral phenomenon. The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkaloid with nicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CNS, including the mesoaccumbens DA system, which ultimately leads to behavioral reinforcement and addiction. Recent findings from a number of laboratories have provided new insights into the biologic processes that contribute to nicotine self-administration. Examination of the nAChR subtypes expressed within the reward centers has identified potential roles for these receptors in normal physiology, as well as the effects of nicotine exposure. The high nicotine sensitivity of some nAChR subtypes leads to rapid activation followed in many cases by rapid desensitization. Assessing the relative importance of these molecular phenomena in the behavioral effects of nicotine presents an exciting challenge for future research efforts. © 2002 Wiley Periodicals, Inc

Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine

Dopamine signaling in brain reward areas is a key element in the development of drug abuse and dependence. Recent anatomical and electrophysiological research has begun to elucidate both complexity and specificity In synaptic connections between ventral tegmental neurons and their inputs. Specifically, the activity of dopamine neurons in the ventral tegmental area relies on the combination of both excitatory and inhibitory inputs. Controlling endogenous neurotransmission to dopamine neurons is one mechanism by which drugs of abuse affect both transient and long-term changes in synaptic activity. Here, we review recent findings concerning glutamatergic, GABAergic, and cholinergic inputs to dopamine neurons, and their roles in the reinforcement associated with drug abuse. Importantly, several studies support that a single drug exposure can lead to changes in synaptic strength that are associated with learning and memory. Ultimately, these cellular changes could underlie the long-lasting effects of drugs. Furthermore, nicotinic acetylcholine receptors in the ventral tegmental area emerge as a possible common target for the behavioral and cellular actions not only of nicotine, but also of several other drugs of abuse. Finally, we explore age-related differences in nicotine sensitivity in order to understand both human epidemiological data, and laboratory animal behavioral findings that suggest adolescents are more susceptible to developing nicotine dependence

Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction

Nicotine reinforces smoking behaviour by activating nicotinic acetylcholine receptors in the midbrain dopaminergic reward centres. Upstream of the dopaminergic neurons nicotine induces long-term potentiation of the excitatory input to dopamine cells in the ventral tegmental area, and depresses inhibitory inputs. Both effects of nicotine were shown to last much longer than the nicotine exposure and together will activate the dopaminergic ventral tegmental area projection toward the nucleus accumbens. However, downstream of dopamine, effects of nicotine are also likely to occur. Cholinergic interneurons within the nucleus accumbens are important in the tonic control of the γ-amino buteric acid (GABA) nucleus accumbens output neurons, which project back to the ventral tegmental area. The nicotinic acetylcholine receptors that mediate this control are likely to desensitise upon preexposure to the nicotine concentrations found in the blood of smokers. Thus, synaptic mechanisms both upstream and downstream of dopamine release are potentially important factors contributing to the etiology of nicotine addiction. © 2003 Elsevier B.V. All rights reserved

Differential modulation by nicotine of substantia nigra versus ventral tegmental area dopamine neurons

Midbrain dopamine (DA) neurons are found in two nuclei, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The SNc dopaminergic projections to the dorsal striatum are involved in voluntary movement and habit learning, whereas the VTA projections to the ventral striatum contribute to reward and motivation. Nicotine induces profound DA release from VTA dopamine neurons but substantially less from the SNc. Nicotinic acetylcholine receptor (nAChR) expression differs between these nuclei, but it is unknown whether there are differences in nAChR expression on the afferent projections to these nuclei. Here we have compared the nicotinic modulation of excitatory and inhibitory synaptic inputs to VTA and SNc dopamine neurons. Although nicotine enhances both the excitatory and inhibitory drive to SNc DA cells with response magnitudes similar to those seen in the VTA, the prevalence of these responses in SNc is much lower. We also found that a mixture of nAChR subtypes underlies the synaptic modulation in SNc, further distinguishing this nucleus from the VTA, where α7 nAChRs enhance glutamate inputs and non-α7 receptors enhance GABA inputs. Finally, we compared the nicotine sensitivity of DA neurons in these two nuclei and found larger response magnitudes in VTA relative to SNc. Thus the observed differences in nicotine-induced DA release from VTA and SNc are likely due to differences in nAChR expression on the afferent inputs as well as on the DA neurons themselves. This may explain why nicotine has a greater effect on behaviors associated with the VTA than the SNc. Copyright © 2007 The American Physiological Society