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Marina R Picciotto - Top 30 Publications

Effects of a nicotinic agonist on the Brief Psychiatric Rating Scale five-factor subscale model in schizophrenia.

The Effect of Treatment with Guanfacine, an alpha2 Adrenergic Agonist, on Dopaminergic Tone in Tobacco Smokers: An (11)CFLB457 PET Study.

Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with guanfacine with [(11)C]FLB457, a dopamine D2/D3 receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [(11)C]FLB457 PET scans on the same day, one before and one at 2.5-3 h after amphetamine (0.4-0.5 mg/kg, PO). A subset (n=12) then underwent guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated. [(11)C]FLB457 binding potential (BPND) was measured pre- and post-amphetamine in extrastriatal brain regions. The fractional change in BPND after vs before amphetamine (Δ BPND) is an indirect measure of DA release and was compared between the untreated and guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BPND from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [(11)C]FLB457 BPND in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.Neuropsychopharmacology accepted article preview online, 25 September 2017. doi:10.1038/npp.2017.223.

Menthol disrupts nicotine's psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice.

Menthol is a commonly used flavorant in tobacco and e-cigarettes, and could contribute to nicotine sensitivity. To understand how menthol could contribute to nicotine intake and addiction, it is important to determine whether specific mechanisms related to sex and age could underlie behavioral changes induced by menthol-laced nicotinic products. Using a validated paradigm of nicotine-dependent locomotor stimulation, adolescent and adult C57BL/6J mice of both sexes were exposed to nicotine, or nicotine laced with menthol, as their sole source of fluid, and psychostimulant effects were evaluated by recording home cage locomotor activity for ten days. Nicotine and cotinine blood levels were measured following exposure. Results show an interaction between treatment, age, and sex on liquid consumption, indicating that mice responded differently to menthol and nicotine based on their age and sex. Adult male mice greatly increased their nicotine intake when given menthol. In female mice of both age groups, menthol did not have this effect. Despite an increase in nicotine intake promoted by menthol, adult male mice showed a significant decrease in locomotion, suggesting that menthol blunted nicotine-induced psychostimulation. This behavioral response to menthol was not detected in adolescent mice of either sex. These data confirm that menthol is more than a flavorant, and can influence both nicotine intake and its psychostimulant effects. These results suggest that age- and sex-dependent mechanisms could underlie menthol's influence on nicotine intake and that studies including adolescent and adult menthol smokers of both sexes are warranted.

Maternal smoking and autism spectrum disorder: meta-analysis with population smoking metrics as moderators.

While exposure to nicotine during developmental periods can significantly affect brain development, studies examining the association between maternal smoking and autism spectrum disorder (ASD) in offspring have produced conflicting findings, and prior meta-analyses have found no significant association. Our meta-analysis used a novel approach of investigating population-level smoking metrics as moderators. The main meta-analysis, with 22 observational studies comprising 795,632 cases and 1,829,256 control participants, used a random-effects model to find no significant association between maternal smoking during pregnancy and ASD in offspring (pooled odds ratio (OR) = 1.16, 95% CI: 0.97-1.40). However, meta-regression analyses with moderators were significant when we matched pooled ORs with adult male smoking prevalence (z = 2.55, p = 0.01) in each country, using World Health Organization data. Our study shows that using population-level smoking metrics uncovers significant relationships between maternal smoking and ASD risk. Correlational analyses show that male smoking prevalence approximates secondhand smoke exposure. While we cannot exclude the possibility that our findings reflect the role of paternal or postnatal nicotine exposure, as opposed to maternal or in utero nicotine exposure, this study underlines the importance of investigating paternal and secondhand smoking in addition to maternal smoking in ASD.

Access to nicotine in drinking water reduces weight gain without changing caloric intake on high fat diet in male C57BL/6J mice.

Nicotine and tobacco use is associated with lower body weight, and many smokers report concerns about weight. In animal studies, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Previous studies have used standardized nicotine doses, however, in this study, male and female mice had free access to nicotine drinking water for 30 days while fed either a high fat diet (HFD) or chow, allowing animals to titrate their nicotine intake. In male mice, HFD increased body weight and caloric intake. Nicotine attenuated this effect and decreased weight gain per calorie consumed without affecting overall caloric intake or acute locomotion, suggesting metabolic changes. Nicotine did not decrease weight in chow-fed animals. In contrast, the same paradigm did not result in significant differences in weight gain in female animals, but did alter corticosterone levels and locomotion, indicating sex differences in the response to HFD and nicotine. We measured levels of mRNAs encoding nicotinic acetylcholine receptor subunits, uncoupling proteins (UCP) 1-3, and neuropeptides involved in energy balance in adipose tissues and the arcuate nucleus of the hypothalamus (ARC). HFD and nicotine regulated UCP levels in adipose tissues and ARC from female, but not male, mice. Regulation of agouti-related peptide, neuropeptide-Y, melanin-concentrating hormone, and cocaine- and amphetamine-regulated transcript in ARC varied with diet and nicotine in a sex-dependent manner. These data demonstrate that chronic consumption of nicotine moderates the effect of HFD in male mice by changing metabolism rather than food intake, and identify a differential effect on female mice.

Effect of doxazosin on stress reactivity and the ability to resist smoking.

Preclinical findings support a role for α1-adrenergic antagonists in reducing nicotine-motivated behaviors, but these findings have yet to be translated to humans. The current study evaluated whether doxazosin would attenuate stress-precipitated smoking in the human laboratory. Using a well-validated laboratory analogue of smoking-lapse behavior, this pilot study evaluated whether doxazosin (4 and 8 mg/day) versus placebo attenuated the effect of stress (vs neutral imagery) on tobacco craving, the ability to resist smoking and subsequent ad-libitum smoking in nicotine-deprived smokers ( n=35). Cortisol, adrenocorticotropin, norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day vs placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day vs placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day vs placebo) further decreased tobacco craving following stress versus neutral imagery. Doxazosin increased the latency to start smoking following stress, and reduced the number of cigarettes smoked. Dosage of 8 mg/day doxazosin increased or normalized cortisol levels following stress imagery and decreased cortisol levels following neutral imagery. These preliminary findings support a role for the noradrenergic system in stress-precipitated smoking behavior, and support further development of doxazosin as a novel pharmacotherapeutic treatment strategy for smoking cessation.

Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms.

Varenicline (VAR) is approved to aid in smoking cessation and has been shown to be effective for reducing alcohol consumption in heavy drinkers. Little is known, however, about treatment moderators that may influence efficacy. The current study reanalyzed data from a human laboratory study (Verplaetse et al., 2016) to determine whether VAR was more effective at reducing alcohol use among drinkers reporting symptoms of depression. Participants were 60 adults meeting DSM-IV criteria for alcohol use disorders ( n = 60) who were randomly assigned to receive VAR (1 mg/day, 2 mg/day) or placebo. Following 7 days of medication pretreatment, participants attended a laboratory testing session. They provided self-reported ratings of alcohol craving and performed an ad libitum alcohol consumption task after receiving a priming dose of alcohol (target blood alcohol concentration = 0.030 g/dL). Higher blood VAR plasma levels were associated with less alcohol craving and less drinking among participants with more depressive symptoms. Among participants with fewer depressive symptoms, VAR was associated with more drinking during the ad libitum drinking task. These findings show that depression symptoms may be a moderator of VAR efficacy in alcohol users and provides evidence for the role of nAChRs in depression and alcohol use.

Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice.

Clinical studies have identified links between cholinergic signalling and depression in human subjects. Increased cholinergic signalling in hippocampus also increases behaviours related to anxiety and depression in mice, which can be reversed by ACh receptor antagonists.

Editorial: Progressions.

Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism.

Nicotine is a major oral irritant in smokeless tobacco products and has an aversive taste. Mentholated smokeless tobacco products are highly popular, suggesting that menthol increases their palatability and may facilitate initiation of product use. While menthol is known to reduce respiratory irritation by tobacco smoke irritants, it is not known whether this activity extends to oral nicotine and its aversive effects.

CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory.

Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARPγ-8, but not TARPγ-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARPγ-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARPγ-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARPγ-8. Together, these findings demonstrate that TARPγ-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.

CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation.

Tobacco smoking leads to increased numbers of β2*-containing nicotinic acetylcholine receptors (β2*-nAChRs) throughout the brain, which return to nonsmoker levels over extended abstinence. The goal of the current study was to determine whether the degree of tobacco smoking-induced changes in β2*-nAChR availability is genetically influenced.

Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex.

Nicotinic acetylcholine receptors (nAChRs) support the initiation and maintenance of smoking, but the long-term changes occurring in the protein complex as a result of smoking and the nicotine in tobacco are not known. Human studies and animal models have also demonstrated that increasing cholinergic tone increases behaviors related to depression, suggesting that the nAChR-associated proteome could be altered in individuals with mood disorders. We therefore immunopurified nAChRs and associated proteins for quantitative proteomic assessment of changes in protein-protein interactions of high-affinity nAChRs containing the β2 subunit (β2*-nAChRs) from either cortex of mice treated with saline or nicotine, or postmortem human temporal cortex tissue from tobacco-exposed and nonexposed individuals, with a further comparison of diagnosed mood disorder to control subjects. We observed significant effects of nicotine exposure on the β2*-nAChR-associated proteome in human and mouse cortex, particularly in the abundance of the nAChR subunits themselves, as well as putative interacting proteins that make up core components of neuronal excitability (Na/K ATPase subunits), presynaptic neurotransmitter release (syntaxins, SNAP25, synaptotagmin), and a member of a known nAChR protein chaperone family (14-3-3ζ). These findings identify candidate-signaling proteins that could mediate changes in cholinergic signaling via nicotine or tobacco use. Further analysis of identified proteins will determine whether these interactions are essential for primary function of nAChRs at presynaptic terminals. The identification of differences in the nAChR-associated proteome and downstream signaling in subjects with various mood disorders may also identify novel etiological mechanisms and reveal new treatment targets.

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine.

Major depressive disorder (MDD) is a recurring psychiatric illness that causes substantial health and socioeconomic burdens. Clinical reports have revealed that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in individuals with MDD. Preclinical models suggest that these rapid antidepressant effects can be recapitulated with blockade of M1-type muscarinic acetylcholine receptors (M1-AChR); however, the cellular mechanisms underlying activity-dependent synaptic and behavioral responses to scopolamine have not been determined. Here, we demonstrate that the antidepressant-like effects of scopolamine are mediated by GABA interneurons in the medial prefrontal cortex (mPFC). Both GABAergic (GAD67+) interneurons and glutamatergic (CaMKII+) interneurons in the mPFC expressed M1-AChR. In mice, viral-mediated knockdown of M1-AChR specifically in GABAergic neurons, but not glutamatergic neurons, in the mPFC attenuated the antidepressant-like effects of scopolamine. Immunohistology and electrophysiology showed that somatostatin (SST) interneurons in the mPFC express M1-AChR at higher levels than parvalbumin interneurons. Moreover, knockdown of M1-AChR in SST interneurons in the mPFC demonstrated that M1-AChR expression in these neurons is required for the rapid antidepressant-like effects of scopolamine. These data indicate that SST interneurons in the mPFC are a promising pharmacological target for developing rapid-acting antidepressant therapies.

An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior.

Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.

Association of Cigarette Smoking With Interpersonal and Self-Directed Violence in a Large Community-Based Sample.

Substance use is a major risk factor for various forms of violence, yet how cigarette smoking influences violence outcomes is incompletely understood. We investigated associations between cigarette smoking and three types of violence in a large, nationally representative, community-based sample.

DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons.

Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system.

Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviors and Response to Social Stress.

Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala (BLA) in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both β2 subunit-containing (β2*) and α7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated downregulation of the β2 or α7 nAChR subunit in the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the BLA. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the BLA, and a decrease in signaling through β2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.

Acetylcholine Acts through Nicotinic Receptors to Enhance the Firing Rate of a Subset of Hypocretin Neurons in the Mouse Hypothalamus through Distinct Presynaptic and Postsynaptic Mechanisms(.)

Hypocretin/orexin neurons regulate many behavioral functions, including addiction. Nicotine acts through nicotinic acetylcholine receptors (nAChRs) to alter firing rate of neurons throughout the brain, leading to addiction-related behaviors. While nAChRs are expressed in the hypothalamus and cholinergic fibers project to this structure, it is unclear how acetylcholine modulates the activity of hypocretin neurons. In this study, we stimulated hypocretin neurons in mouse brain slices with ACh in the presence of atropine to dissect presynaptic and postsynaptic modulation of these neurons through nAChRs. Approximately one-third of tested hypocretin neurons responded to pressure application of ACh (1 mM) with an increase in firing frequency. Stimulation of postsynaptic nAChRs with ACh or nicotine resulted in a highly variable inward current in approximately one-third of hypocretin neurons. In contrast, ACh or nicotine (1 μM) reliably decreased the frequency of miniature EPSCs (mEPSCs). Antagonism of nAChRs with mecamylamine also suppressed mEPSC frequency, suggesting that an endogenous, tonic activation of presynaptic nAChRs might be required for maintaining functional mEPSC frequency. Antagonism of heteromeric (α4β2) or homomeric (α7) nAChRs alone suppressed mEPSCs to a lesser extent. Finally, blocking internal calcium release reduced the frequency of mEPSCs, occluding the suppressive effect of presynaptic ACh. Taken together, these data provide a mechanism by which phasic ACh release enhances the firing of a subset of hypocretin neurons through postsynaptic nAChRs, but disrupts tonic, presynaptic nAChR-mediated glutamatergic inputs to the overall population of hypocretin neurons, potentially enhancing the signal-to-noise ratio during the response of the nAChR-positive subset of neurons.

Modulation of aggressive behavior in mice by nicotinic receptor subtypes.

Aggression is frequently comorbid with neuropsychiatric conditions and is a predictor of worse outcomes, yet current pharmacotherapies are insufficient and have debilitating side effects, precluding broad use. Multiple models of aggression across species suggest that the nicotinic acetylcholine receptor (nAChR) agonist nicotine has anti-aggressive (serenic) properties. Here we demonstrate dose-dependent serenic effects of acute nicotine administration in three distinct mouse strains: C57BL/6, BALB/c, and CD1. While acute nicotine administration (0.25mg/kg) modestly reduced solitary homecage locomotion, this could not account for nicotine's serenic effects since social encounters eliminated the hypolocomotor effect, and nicotine did not alter social interaction times. Pretreatment with the homomeric (α7 subunit) nAChR antagonist methyllycaconitine (5mg/kg), but not the heteromeric (β2 or β4 subunit-containing) nAChR antagonist dihydro-β-erythroidine (DHβE, 3mg/kg), blocked the serenic effects of nicotine. By contrast, pretreatment with DHβE blocked the effect of acute nicotine administration on locomotion, uncoupling nicotine's serenic and hypolocomotor effects. Finally, the α7 nAChR partial agonist GTS-21 reduced aggression in C57BL/6 mice. These results support the idea that acute nicotine administration has serenic effects and provide evidence for specificity of this effect distinct from effects on locomotion. Furthermore, pharmacological studies suggest that activation of α7 nAChRs underlies the serenic effects of nicotine. Further studies of nAChRs could enhance understanding of the neurobiology of aggression and may lead to the development of novel, more specific treatments for pathological aggression.

Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.

The a2A-noradrenergic agonist guanfacine can decreases stress-induced smoking in female, but not male, human smokers. It is not known whether these effects are due to effects on mood regulation and/or result from nicotinic-cholinergic interactions.

Reduction of Aggressive Episodes After Repeated Transdermal Nicotine Administration in a Hospitalized Adolescent with Autism Spectrum Disorder.

Aggression remains a major cause of morbidity in patients with autism spectrum disorder (ASD). Current pharmacotherapy for aggression is not always effective and is often associated with morbidity. Nicotinic acetylcholinergic neurotransmission may play a prominent role in ASD pathophysiology based on human and animal studies, and preclinical studies show nicotine administration can reduce aggression-related behaviors. Transdermal nicotine has been used to treat agitation in neuropsychiatric conditions with cholinergic dysfunction. Here we report the use of transdermal nicotine as an adjunctive medication to treat aggression in a hospitalized adolescent with ASD. Nicotine patch was recurrently well tolerated, and reduced the need for emergency medication and restraint. These findings suggest further study of transdermal nicotine for aggression comorbid with ASD is warranted.

Targeting the noradrenergic system for gender-sensitive medication development for tobacco dependence.

Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research.

Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states.

The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety is beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation.

Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist guanfacine (3 mg/day) versus placebo (0 mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared with placebo, altered prefrontal activity during a cognitive-control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging, and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.

Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine.

Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

Neuromodulation by acetylcholine: examples from schizophrenia and depression.

The contribution of acetylcholine to psychiatric illnesses remains an area of active research. For example, increased understanding of mechanisms underlying cholinergic modulation of cortical function has provided insight into attentional dysfunction in schizophrenia. Acetylcholine normally enhances cortical sensitivity to external stimuli and decreases corticocortical communication, increasing focused attention; however, increases in ACh signaling can lead to symptoms related to anxiety and depression. For example, while stress-induced ACh release can result in adaptive responses to environmental stimuli, chronic elevations in cholinergic signaling may produce maladaptive behaviors. Here, we review several innovations in human imaging, molecular genetics and physiological control of circuits that have begun to identify mechanisms linking altered cholinergic neuromodulation to schizophrenia and depression.

Self-administration of ethanol, cocaine, or nicotine does not decrease the soma size of ventral tegmental area dopamine neurons.

Our previous observations show that chronic opiate administration, including self-administration, decrease the soma size of dopamine (DA) neurons in the ventral tegmental area (VTA) of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent.

Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice.

The calcium-dependent phosphatase calcineurin is highly expressed in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. Organ transplant patients are administered the calcineurin inhibitor cyclosporine A (CsA) chronically and demonstrate an increased incidence of anxiety and mood disorders. It is therefore important to determine whether chronic blockade of calcineurin may contribute to symptoms of anxiety and depression in these patients.

GABAergic and glutamatergic efferents of the mouse ventral tegmental area.

The role of dopaminergic (DA) projections from the ventral tegmental area (VTA) in appetitive and rewarding behavior has been widely studied, but the VTA also has documented DA-independent functions. Several drugs of abuse, act on VTA GABAergic neurons, and most studies have focused on local inhibitory connections. Relatively little is known about VTA GABA projection neurons and their connections to brain sites outside the VTA. This study employed viral-vector-mediated cell-type-specific anterograde tracing, classical retrograde tracing, and immunohistochemistry to characterize VTA GABA efferents throughout the brain. We found that VTA GABA neurons project widely to forebrain and brainstem targets, including the ventral pallidum, lateral and magnocellular preoptic nuclei, lateral hypothalamus, and lateral habenula. Minor projections also go to central amygdala, mediodorsal thalamus, dorsal raphe, and deep mesencephalic nuclei, and sparse projections go to prefrontal cortical regions and to nucleus accumbens shell and core. These projections differ from the major VTA DA target regions. Retrograde tracing studies confirmed results from the anterograde experiments and differences in projections from VTA subnuclei. Retrogradely labeled GABA neurons were not numerous, and most non-tyrosine hydroxylase/retrogradely labeled cells lacked GABAergic markers. Many non-TH/retrogradely labeled cells projecting to several areas expressed VGluT2. VTA GABA and glutamate neurons project throughout the brain, most prominently to regions with reciprocal connections to the VTA. These data indicate that VTA GABA and glutamate neurons may have more DA-independent functions than previously recognized.