Meeting Report for: The 4th Satellite Meeting to the SfN: Nicotinic Acetylcholine Receptors as Therapeutic Targets

A growing body of evidence indicates that alpha7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. In the present study, we investigated the role of the endogenous alpha7 nicotinic receptors (nAChRs) signaling in pain and inflammation using transgenic mice. For that we evaluated pain-related behaviors in the alpha7 mutant mice (KO) and its complementary alpha7 hypersensitive mice (KI) expressing the L250T alpha7 nAChRs and their respective WT mice in acute, chronic inflammatory and neuropathic mouse models. alpha7 KO and KI mice showed no significant changes in pain responses evoked by acute noxious thermal and mechanical stimuli as compared with WT littermates. While alpha7 KO mice showed no alterations in thermal and mechanical allodynia compared to WT mice after chronic nerve injury in the CCI test, alpha7 KI mice showed a significant reduction in these pain-related responses. However, marked increase in edema, hyperalgesia, and allodynia associated with intraplantar CFA injection was observed in the alpha7 KO mice compared with the WT littermates. In contrast, alpha7 KI mice displayed lesser degree of hyperalgesia and allodynia after CFA injection. Finally, the ability of systemic nicotine to reverse already-developed mechanical allodynia produced by intraplantar CFA seen in WT mice was lost in the alpha7 KO animals. Overall, our results demonstrate that endogenous alpha7 nAChRs mechanisms play an important role in chronic inflammatory and neuropathic pain models. This provides an additional rationale for the utility of alpha7 nAChR agonists in the treatment of inflammatory and chronic pain.

Chronic nicotine exposure gives rise to neural adaptations that change whole cell physiology and behaviour mainly by interacting with neuronal nicotinic acetylcholine receptors (nAChRs). The major nicotine-induced neuroadaptation is the up-regulation of brain nAChRs by means of cell-delimited post-translational mechanisms. We review what is known of the processes regulating nAChR assembly, degradation and trafficking, and how nicotine-induced modulation of these processes leads to nAChR up-regulation and changes in downstream neuronal plasticity at molecular, cellular and circuit level.

Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/-), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD).

Epidemiological studies consistently find correlations between nicotine and alcohol use, yet the neural mechanisms underlying their interaction remain largely unknown. Nicotine and alcohol (i.e., ethanol) share many common molecular and cellular targets that provide potential substrates for nicotine-alcohol interactions. These targets for interaction often converge upon the mesocorticolimbic dopamine system, where the link to drug self-administration and reinforcement is well documented. Both nicotine and alcohol activate the mesocorticolimbic dopamine system, producing downstream dopamine signals that promote the drug reinforcement process. While nicotine primarily acts via nicotinic acetylcholine receptors, alcohol acts upon a wider range of receptors and molecular substrates. The complex pharmacological profile of these two drugs generates overlapping responses that ultimately intersect within the mesocorticolimbic dopamine system to promote drug use. Here we will examine overlapping targets between nicotine and alcohol and provide evidence for their interaction. Based on the existing literature, we will also propose some potential targets that have yet to be directly tested. Mechanistic studies that examine nicotine-alcohol interactions would ultimately improve our understanding of the factors that contribute to the associations between nicotine and alcohol use.

Dopaminergic neurons in the substantia nigra pars compacta (SNc) degenerate in Parkinson's disease. These neurons robustly express several nicotinic acetylcholine receptor (nAChR) subtypes. Smoking appears to be neuroprotective for Parkinson's disease but the mechanism is unknown. To determine whether chronic nicotine-induced changes in gene expression contribute to the neuroprotective effects of smoking, we develop methods to measure the effect of prolonged nicotine exposure on the SNc neuronal transcriptome in an unbiased manner. Twenty neurons were collected using laser-capture microscopy and transcriptional changes were assessed using RNA deep sequencing. These results are the first whole-transcriptome analyses of chronic nicotine treatment in SNc neurons. Overall, 129 genes were significantly regulated: 67 upregulated, 62 downregulated. Nicotine-induced relief of endoplasmic reticulum (ER) stress has been postulated as a potential mechanism for the neuroprotective effects of smoking. Chronic nicotine did not significantly affect the expression of ER stress-related genes, nor of dopamine-related or nAChR genes, but it did modulate expression of 129 genes that could be relevant to the neuroprotective effects of smoking, including genes involved in (1) the ubiquitin-proteasome pathway, (2) cell cycle regulation, (3) chromatin modification, and (4) DNA binding and RNA regulation. We also report preliminary transcriptome data for single-cell dopaminergic and GABAergic neurons isolated from midbrain cultures. These novel techniques will facilitate advances in understanding the mechanisms taking place at the cellular level and may have applications elsewhere in the fields of neuroscience and molecular biology. The results give an emerging picture of the role of nicotine on the SNc and on dopaminergic neurons.

The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the alpha7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD.

In Renshaw cells (RCs) of newborn mice, activation of motoneurons elicits a four-component synaptic current (EPSC) mediated by two glutamate receptors and two nicotinic receptors (nAChRs). We have analyzed the nicotinic component of the EPSC which is blocked by dihydro-beta-erythroidine (DHbetaE) with the dual objective of identifying the nAChR subunits involved and of understanding the kinetics of the response. The sensitivity to DHbetaE of the peak of the EPSC was differentially affected by genetic deletion of three specific nAChR subunits: alpha2, beta2 and beta4. The comparison of these effects with published findings on recombinant receptors suggests that, in WT mice, two heteromeric assemblies, alpha4beta2 and alpha2beta4, coexist in variable proportions in a given RC. Some results seem to require, however, the involvement of an additional subunit. The effects of DHbetaE on the decay of the EPSCs were compared in WT mice and in PRiMA(-/-) mice, in which the decay is prolonged by the absence of central acetylcholinesterase. In PRiMA(-/-) mice DHbetaE shortened the decay of the EPSC. In WT mice it did not alter the decay but reduced the amplitude of both components of the EPSC. The results can be interpreted by assuming that the nAChRs exist in two stoichiometries, subsynaptic "low sensitivity" nAChRs and extrasynaptic "high sensitivity" nAChRs activated by spillover.

Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (alpha7 and alpha4beta2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction.

Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. Here we show that expression and activation of nAChRs containing the alpha6 subunit contribute to ethanol-induced activation of VTA DAergic neurons. In wild-type (WT) mouse midbrain sections that contain the VTA, ethanol (50 or 100 mM) significantly increased firing frequency of DAergic neurons. In contrast, ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express CHRNA6, the gene encoding the alpha6 nAChR subunit (alpha6 knock-out (KO) mice). Ethanol-induced activity in WT slices was also reduced by pre-application of the alpha6 subtype-selective nAChR antagonist, alpha-conotoxin MII[E11A]. When co-applied, ethanol potentiated the response to ACh in WT DAergic neurons; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in alpha6 KO slices. Finally, pre-application of alpha-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that alpha6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse.

This research update summarizes thirty years of studies on genetic influences on responses to the acute or chronic administration of nicotine. Early studies established that various inbred mice are differentially sensitive to the effects of the drug. Classical genetic analyses confirmed that nicotine effects on locomotion, body temperature and seizures are heritable. A significant inverse correlation between the locomotor and hypothermic effects and the density of nicotine binding sites suggested that differential expression alpha4beta2-neuronal nicotinic acetylcholine receptor (nAChR) mediated some of this genetic variability. Subsequent studies with alpha4 and beta2 nAChR null (decreased sensitivity) and gain of function mutants (increased sensitivity) supports the role of the alpha4beta2*nAChR subtype. However, null mutant mice still respond to nicotine, indicating that other nAChR subtypes also mediate these responses. Mice differing in initial sensitivity to nicotine also differ in tolerance development following chronic treatment: those mice that are initially more sensitive to nicotine develop tolerance at lower treatment doses than less sensitive mice, indicating that tolerance is an adaptive response to the effects of nicotine. In contrast, the sensitivity of mice to pre-pulse inhibition of acoustic startle response is correlated with the expression of alpha7-nAChR. While genetic variability in nAChR expression and function is an important factor contributing to differences in response to nicotine, the observations that altered activity of opioid, glutamate, and cannabinoid receptors among others also change nicotine sensitivity reinforces the proposal that the genetics of nicotine response is more complex than differences in nAChRs.

Reactivation of neurogenesis by endogenous Neural Stem/Progenitor Cells (NS/PC) in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world's aging population. Recent studies show that targeting the alpha7 nicotinic acetylcholine receptors (alpha7nAChR) with a specific TC-7020 agonist inhibits proliferation and stimulates neuronal differentiation of NS/PC in subventricular zone (SVZ) in the adult mouse brain. TC-7020-induced neuronogenesis is observed in different brain regions, including: (1) betaIII Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra (SN) expressing predopaminergic Nurr1+phenotype. Reactivation of developmental integrative nuclear FGFR1 signaling (INFS), via gene transfection reinstates neurogenesis in the adult brain by promoting neuronal differentiation of brain NS/PC. TC-7020 neuronogenic effect is associated with a robust accumulation of endogenous FGFR1 in the nuclei of differentiating cells. Furthermore, direct in vitro stimulation of neural stem/progenitor cells with alpha7nAChR agonist activates INFS and neuronal-like differentiation and activation of neuronal genes. The alpha7nAChR upregulation of early neuronal betaIII-Tubulin gene involves neurogenic FGFR1-Nur signaling and direct FGFR1 interaction with the gene promoter. The reactivation of developmental INFS and neurogenesis in adult brain by the alpha7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases.

This review outlines recent insights into ligand recognition, channel gating and ion permeation for the family of pentameric ligand-gated ion channels (pLGICs). These receptors are involved in the fast inhibitory and excitatory neurotransmission. Prototypical anion-selective members are the gamma-amino butyric acid type A (GABA(A)), gamma-amino butyric acid type C (GABA(C)) and glycine receptor. The cation-selective members are the 5-HT3 serotonin and nicotinic acetylcholine (nACh) receptors. They are the target for a wide variety of drugs and dysfunction in these receptors is associated with several diseases. We summarize recent structural knowledge in combination with electrophysiological data and molecular dynamic simulations, thereby describing key features of ligand binding, channel gating and ion permeation. A conserved cation-pi interaction between ligand and aromatic residues of the ligand binding site critically contributes to ligand recognition, as revealed by X-ray crystal structures of acetylcholine binding proteins, as well as the integral pLGICs, ELIC and GluCl. In addition, we summarize the possible downstream effects on gating of structural rearrangements in the extracellular ligand-binding domain, which mainly occur in loop C and loop F. These data are discussed in the context of different conformational states of the pore-forming domain observed in crystal structures of GLIC and GluCl, which likely represent the open pore conformation, and ELIC, which likely corresponds to a closed pore conformation. We conclude with a current structural view on the determinants of ion selection and permeation.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the alpha7 and alpha4beta2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs.

Attention is a central cognitive function that enables long-term engagement in a task and suppression of irrelevant information to obtain future goals. The prefrontal cortex (PFC) is the main link in integrating emotional and motivational state of an animal to regulate top-down attentional processes. Acetylcholine modulates PFC neuronal networks by activating nicotinic acetylcholine receptors (nAChRs) to support attention. However, how neuronal activity changes in the PFC during attention and which nAChR subtypes mediate this is only rudimentarily understood, but progress is being made. Recently, exciting new insights were obtained in the dynamics of cholinergic signaling in the PFC and modes of acetylcholine transmission via nAChRs in the cortex. In addition, mechanisms are uncovered on how the PFC circuitry is regulated by nAChRs. Novel studies show that endogenous activation of nAChRs in the PFC plays a central role in controlling attention. Here, we review current insights into how different subtypes of nAChRs expressed by distinct types of neurons in the PFC circuitry shape attention. In addition we discuss the impact of nicotine on the cholinergic system and prefrontal cortical circuits. Low concentrations of nicotine, as experienced by smokers, interfere with cholinergic signaling. In the long-term exposure to nicotine during adolescence leads to maladaptive adaptations of the PFC circuitry, which ultimately leads to a decrement in attention performance, again emphasizing the importance of nAChRs in attention.

Accumulating evidence supports the idea that drugs acting at nicotinic acetylcholine receptors (nAChRs) may be beneficial for Parkinson's disease, a neurodegenerative movement disorder characterized by a loss of nigrostriatal dopaminergic neurons. Nicotine administration to parkinsonian animals protects against nigrostriatal damage. In addition, nicotine and nAChR drugs improve L-dopa-induced dyskinesias, a debilitating side effect of L-dopa therapy which remains the gold-standard treatment for Parkinson's disease. Nicotine exerts its antidyskinetic effect by interacting with multiple nAChRs. One approach to identify the subtypes specifically involved in L-dopa-induced dyskinesias is through the use of nAChR subunit null mutant mice. Previous work with beta2 and alpha6 nAChR knockout mice has shown that alpha6beta2* nAChRs were necessary for the development/maintenance of L-dopa-induced abnormal involuntary movements (AIMs). The present results in parkinsonian alpha4 nAChR knockout mice indicate that alpha4beta2* nAChRs also play an essential role since nicotine did not reduce L-dopa-induced AIMs in such mice. Combined analyses of the data from alpha4 and alpha6 knockout mice suggest that the alpha6alpha4beta2beta3 subtype may be critical. In contrast to the studies with alpha4 and alpha6 knockout mice, nicotine treatment did reduce L-dopa-induced AIMs in parkinsonian alpha7 nAChR knockout mice. However, alpha7 nAChR subunit deletion alone increased baseline AIMs, suggesting that alpha7 receptors exert an inhibitory influence on L-dopa-induced AIMs. In conclusion, alpha6beta2*, alpha4beta2* and alpha7 nAChRs all modulate L-dopa-induced AIMs, although their mode of regulation varies. Thus drugs targeting one or multiple nAChRs may be optimal for reducing L-dopa-induced dyskinesias in Parkinson's disease.

The nicotinic receptor is a promising drug target currently being investigated for the treatment of cognitive symptoms in schizophrenia. A key step in this process is the development of noninvasive functional neuroimaging biomarkers that can be used to determine if nicotinic agents are eliciting their targeted biological effect, ideally through modulation of a fundamental aspect of neuronal function. To that end, neuroimaging researchers are beginning to understand how nicotinic modulation affects "intrinsic" brain networks to elicit potentially therapeutic effects. An intrinsic network is a functionally and (often) structurally connected network of brain areas whose activity reflects a fundamental neurobiological organizational principle of the brain. This review summarizes findings of the effects of nicotinic drugs on three topics related to intrinsic brain network activity: (1) the default mode network, a group of brain areas for which activity is maximal at rest and reduced during cognitive tasks, (2) the salience network, which integrates incoming sensory data with prior internal representations to guide future actions and change predictive values, and (3) multi-scale complex network dynamics, which describe these brain's ability to efficiency integrate information while preserving local functional specialization. These early findings can be used to inform future neuroimaging studies that examine the network effects of nicotinic agents.

Along with their well known role in nicotine addiction and autonomic physiology, neuronal nicotinic receptors (nAChRs) also have profound analgesic effects in animal models and humans. This is not a new idea, even in the early 1500s, soon after tobacco was introduced to the new world, its proponents listed pain relief among the beneficial properties of smoking. In recent years, analgesics that target specific nAChR subtypes have shown highly efficacious antinociceptive properties in acute and chronic pain models. To date, the side effects of these drugs have precluded their advancement to the clinic. This review summarizes the recent efforts to identify novel analgesics that target nAChRs, and outlines some of the key neural substrates that contribute to these physiological effects. There remain many unanswered mechanistic questions in this field, and there are still compelling reasons to explore neuronal nAChRs as targets for the relief of pain.

Tobacco use is a major public health problem. Nicotine acts on widely distributed nicotinic acetylcholine receptors (nAChRs) in the brain and excites dopamine (DA) neurons in the ventral tegmental area (VTA). The elicited increase of DA neuronal activity is thought to be an important mechanism for nicotine reward and subsequently the transition to addiction. However, the current understanding of nicotine reward is based predominantly on the data accumulated from in vitro studies, often from VTA slices. Isolated VTA slices artificially terminate communications between neurons in the VTA and other brain regions that may significantly alter nicotinic effects. Consequently, the mechanisms of nicotinic excitation of VTA DA neurons under in vivo conditions have received only limited attention. Building upon the existing knowledge acquired in vitro, it is now time to elucidate the integrated mechanisms of nicotinic reward on intact systems that are more relevant to understanding the action of nicotine or other addictive drugs. In this review, we summarize recent studies that demonstrate the impact of prefrontal cortex (PFC) on the modulation of VTA DA neuronal function and nicotine reward. Based on existing evidence, we propose a new hypothesis that PFC-VTA functional coupling serves as an integration mechanism for nicotine reward. Moreover, addiction may develop due to nicotine perturbing the PFC-VTA coupling and thereby eliminating the PFC-dependent cognitive control over behavior.

The group of schizophrenia disorders affects approximately 1% of the population and has both genetic and environmental etiologies. Sufferers report various behavioral abnormalities including hallucinations and delusions (positive symptoms), reduced joy and amotivation (negative symptoms), plus inattention and poor learning (cognitive deficits). Despite the heterogeneous symptoms experienced, most patients smoke. The self-medication hypothesis posits that patients smoke to alleviate symptoms, consistent with evidence for nicotine-induced enhancement of cognition. While nicotine acts on multiple nicotinic acetylcholine receptors (nAChRs), the primary target of research is often the homomeric alpha7 nAChR. Given genetic linkages between schizophrenia and this receptor, its association with P50 sensory gating deficits, and its reduced expression in post-mortem brains, many have attempted to develop alpha7 nAChR ligands for treating schizophrenia. Recent evidence that ligands can be orthosteric agonists or positive allosteric modulators (PAMs) has revitalized the hope for treatment discovery. Herein, we present evidence regarding: (1) pathophysiological alterations of alpha7 nAChRs that might occur in patients; (2) mechanistic evidence for the normal action of alpha7 nAChRs; (3) preclinical studies using alpha7 nAChR orthosteric agonists and type I/II PAMs; and (4) where successful translational testing has occurred for particular compounds, detailing what is still required. We report that the accumulating evidence is positive, but that greater work is required using positron emission tomography to understand current alterations in alpha7 nAChR expression and their relationship to symptoms. Finally, cross-species behavioral tasks should be used more regularly to determine the predictive efficacy of treatments.

Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs. Parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging.