Nicotine addiction : a review

Nicotine, the major psychoactive compound in tobacco, acts as a potent addictive drug in humans. The addictive nature of nicotine leads to more than 6 million deaths a year. Evidence indicates that nicotine and other drugs of abuse act on central dopaminergic pathways and modulate their neurophysiological mechanisms. Nicotine stimulates dopaminergic pathways and the prefrontal cortex (PFC), inducing enhanced reward perception and increased cognitive function, respectively. These findings are consistent with the fact that nicotine binds to different subtypes of nicotinic acetylcholine receptors present on the neurons found in the PFC and ventral tegmental area of the midbrain. The latter, being the area most involved in addictive behaviour, projects on the limbic system, particularly the nucleus accumbens, and receives afferents from the prefrontal cortex and brainstem. Although dopaminergic pathways and nicotinic acetylcholine receptors are the protagonists of nicotine addiction, several minor pathways and their constituent receptors have been indicated as being either directly or indirectly affected by nicotine. These include serotonergic pathways and central cannabinoid receptors. Despite the scarcity of approved drugs and partial efficacy of approved treatment, insight into nicotine neurophysiological modulation led to better appreciation of nicotine-seeking behaviour and subsequent improved design of pharmacological and behavioural approaches to smoking cessation. Tobacco is the single most preventable cause of death in the world today. Better understanding of the neurobiological mechanisms underlying nicotine addiction will ultimately lead to more effective treatments of both nicotine dependence and nicotine rewarding effects.peer-reviewe

Evidence for GABA-A receptor dysregulation in gambling disorder:Correlation with impulsivity

Background: As a behavioral addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. Methods: This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. Results: We found significantly higher [11C]Ro15-4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of The ‘Negative Urgency’ construct of impulsivity in GD and these were positively associated with higher [11C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. Conclusions: These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioral addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment

Smoking Comorbidity in Alcoholism: Neurobiological and Neurocognitive Consequences

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65249/1/j.1530-0277.2006.00034.x.pd

Role of the Ventral Tegmental Area and Ventral Tegmental Area Nicotinic Acetylcholine Receptors in the Incentive Amplifying Effect of Nicotine

Nicotine has multiple behavioral effects as a result of its action in the central nervous system. Nicotine strengthens the behaviors that lead to nicotine administration (primary reinforcement), and this effect of nicotine depends on mesotelencephalic systems of the brain that are critical to goal directed behavior, reward, and reinforcement. Nicotine also serves as a ‘reinforcement enhancer’ – drug administration enhances behaviors that lead to other drug and nondrug reinforcers. Although the reinforcement enhancing effects of nicotine may promote tobacco use in the face of associated negative health outcomes, the neuroanatomical systems that mediate this effect of nicotine have never been described. The ventral tegmental area (VTA) is a nucleus that serves as a convergence point in the mesotelencephalic system, plays a substantial role in reinforcement by both drug and nondrug rewards and is rich in both presynaptic and postsynaptic nicotinic acetylcholine receptors (nAChRs). Therefore, these experiments were designed to determine the role of the VTA and nAChR subtypes in the reinforcement enhancing effect of nicotine. Transiently inhibiting the VTA with a gamma amino butyric acid (GABA) agonist cocktail (baclofen and muscimol) reduced both primary reinforcement by a visual stimulus and the reinforcement enhancing effect of nicotine, without producing nonspecific suppression of activity. Intra-VTA infusions of a high concentration of mecamylamine a nonselective nAChR antagonist, or methylycaconitine, an α7 nAChR antagonist, did not reduce the reinforcement enhancing effect of nicotine. Intra-VTA infusions of a low concentration of mecamylamine and dihydro-beta-erythroidine (DHβE), a selective antagonist of nAChRs containing the *β2 subunit, attenuated, but did not abolish, the reinforcement enhancing effect of nicotine. In follow-up tests replacing systemic nicotine injections with intra-VTA infusions (70mM, 105mM) resulted in complete substitution of the reinforcement enhancing effects – increases in operant responding were comparable to giving injections of systemic nicotine. These results suggest that *β2-subunit containing nAChRs in the VTA play a role in the reinforcement enhancing effect of nicotine. However, when nicotine is administered systemically these reinforcement enhancing effects may depend on the action of nicotine at nAChRs in multiple brain nuclei

Αlpha 5 subunit-containing GABAA receptors in temporal lobe epilepsy with normal MRI

GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI (‘MRI-negative’) and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [11C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. ‘Bandpass’ exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [VF; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (VS; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of VF and VS measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher VS in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P < 0.004). This was associated with reduced VF:VS ratios within the same areas (P < 0.009). Comparisons of VS for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation −0.4 ± 1.0 versus 0.7 ± 0.3; P = 0.02). In individuals with epilepsy, hippocampal VS did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced VF in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [11C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy

The role of high affinity nicotinic acetylcholine receptors on anxiety-like behavior: a study in female mice

Tobacco dependence is high in women who suffer from anxiety disorders yet little is known about the contributions of nicotinic acetylcholine receptors (nAChRs) on anxiety-like behavior. β2*nAChRs (*denotes assembly with other subunits) are the most abundantly expressed nAChRs in the brain yet little is known about the contributions of β2*nAChRs on anxiety-like behavior in female mice. In this study, antagonism and nicotine effects on anxiety-like behavior was investigated across the life span in 6, 12 and 24-month-old drug-naïve knockout (KO), heterozygous (HET) and a gain of function α6L9S mice and wild type (WT). HET mice showed increased sensitivity to di-hydrobeta-erythroidine compared to WT mice. Aged mice showed decreased locomotor activity and exploratory behavior compared to younger mice. Low doses of nicotine produced anxiolytic-like effects, whilst a high dose of nicotine produced anxiogenic-like effects. Activation of the α6*nAChRs supports an anxiolysis-like phenotype. These results implicate α4β2*nAChRs and α6β2*nAChRs in anxiety-like behavior

Neuroadaptive Changes in the Mesocortical Glutamatergic System during Nicotine Self-administration and after Extinction in Rats

The mesocorticolimbic pathway is critical in almost all aspects of drug abuse, including nicotine. Though many of the neurochemical and molecular effects of nicotine have been well studied, nicotine’s long-term neuroadaptive effects, specifically within the mesocorticolimbic pathway, are largely undefined. Thus, in current study, we determined the neuroadaptive changes in the mesocortical glutamatergic system during chronic nicotine self-administration (SA), which emulates important aspects of nicotine intake by humans, and after extinction. In the initial study, after 18 days of nicotine SA, in the medial prefrontal cortex (mPFC), NMDA receptor subunit 2A (NR2A) and NR2B were increased by 67% and 83%, respectively. In the ventral tegmental area (VTA), glutamate receptor subunit 2/3 (GluR2/3) was increased by 34%. These findings suggest the glutamate neurotransmission between mPFC and VTA may be enhanced during chronic nicotine SA. Thus, we determined the effects of nicotine SA and extinction on NMDA-induced glutamate neurotransmission between mPFC and VTA. On d 19 of ad lib access to nicotine SA, both brain regions were microdialyzed for glutamate while mPFC was sequentially perfused with: Kreb’s Ringer Buffer (KRB), 200 mM NMDA, KRB, 500 mM NMDA, KRB, 100 mM KCl. Basal glutamate levels were unaffected, but nicotine SA potentiated mPFC glutamate release to 200 mM NMDA, which was ineffective in controls. Furthermore, in VTA, nicotine SA amplified glutamate responses to both mPFC infusions of NMDA. After extinction, glutamate responses were no longer enhanced, and the expression of glutamate receptor subunits reverted to control levels. Behavioral studies showed that an mPFC microinjection of AP-5, an NMDA-R antagonist, did not affect nicotine or sucrose SA on d 19. In contrast, in VTA, NBQX, an AMPA-R antagonist, attenuated both nicotine and sucrose SA. In summary, chronic nicotine SA amplified both mPFC and VTA glutamate responses to mPFC NMDA. This hyper-responsiveness, along with the up-regulation of glutamate receptors, reverted to control levels after extinction. Blockade of VTA AMPA-R but not mPFC NMDA-R, decreased nicotine and sucrose SA. Collectively, these studies indicate that mesocortical glutamate neurotransmission adapts to chronic nicotine SA and up-regulation of VTA AMPA-R may be involved in the maintenance of nicotine SA

Neurobiological Mechanisms Linking Stress And Nicotine To Increased Alcohol Consumption

Alcohol use is a leading cause of preventable disease, disability and death worldwide. Among other factors, exposure to stress or nicotine promotes drinking in humans, yet the neurobiological mechanisms mediating these interactions are unknown. Decades of research indicate that alcohol, stress hormones and nicotine act within the mesolimbic dopamine system to promote behavioral reinforcement. Based on this literature, the central hypothesis guiding my dissertation was that exposure to stress or nicotine promoted drinking via adaptations within ventral tegmental area (VTA). The findings presented in the second chapter of my thesis describe a novel adaptation within the mesolimbic dopamine system contributing to increased alcohol self-administration. Exposure to stress blunted subsequent dopamine responses to alcohol and increased alcohol consumption via VTA stress hormone receptors. These adaptations arose from excitatory GABA transmission onto VTA GABA neurons. Further investigation revealed that excitatory shifts in GABA transmission were associated with the downregulation of the chloride transporter KCC2. Pharmacological enhancement of KCC2 function within the VTA prevented stress-induced drinking, identifying a novel mechanism of stress-induced alcohol consumption. The results in the third and fourth chapters reveal that similar adaptations within the VTA may also contribute to the co-use of nicotine and alcohol. As was observed after stress, exposure to acute nicotine blunted dopamine responses to alcohol and increased alcohol self-administration. Blocking glucocorticoid receptors during nicotine normalized the dopamine signaling and drinking to control levels, indicating that nicotine recruits stress hormone receptors to influence subsequent responses to alcohol. The fourth chapter examines the effects of adolescent nicotine exposure on adult responses to alcohol, since early-life tobacco use confers a major risk for subsequent alcohol abuse. Animals treated with nicotine during adolescence show attenuated dopamine signaling and increased self-administration throughout adulthood. Pharmacological enhancement of KCC2 in adulthood prevented the elevated alcohol intake, highlighting a potential therapeutic role of this drug to reduce alcohol consumption long after the initial nicotine exposure. Taken together, this body of work suggests that exposure to stress or nicotine boosts drinking via anionic plasticity mechanisms within the VTA and implicates KCC2 activation as a potential therapeutic target in the treatment of excessive alcohol consumption

Associations between anxiety, body mass index, and sex hormones in women

Background: Several studies have shown a positive association between anxiety and obesity, particularly in women. We aimed to study whether sex hormone alterations related to obesity might play a role in this association. Patients and methods: Data for this study were obtained from a population-based cohort study (the LIFE-Adult-Study). A total of 3,124 adult women (970 premenopausal and 2,154 postmenopausal) were included into the analyses. The anxiety symptomatology was assessed using the GAD-7 questionnaire (cut-off ≥ 10 points). Sex hormones were measured from fasting serum samples. Results: We did not find significant differences in anxiety prevalence in premenopausal obese women compared with normal-weight controls (4.8% vs. 5.5%). Both obesity and anxiety symptomatology were separately associated with the same sex hormone alteration in premenopausal women: higher total testosterone level (0.97 ± 0.50 in obese vs. 0.86 ± 0.49 nmol/L in normal-weight women, p = 0.026 and 1.04 ± 0.59 in women with vs. 0.88 ± 0.49 nmol/L in women without anxiety symptomatology, p = 0.023). However, women with anxiety symptomatology had non-significantly higher estradiol levels than women without anxiety symptomatology (548.0 ± 507.6 vs. 426.2 ± 474.0 pmol/L), whereas obesity was associated with lower estradiol levels compared with those in normal-weight group (332.7 ± 386.5 vs. 470.8 ± 616.0 pmol/L). Women with anxiety symptomatology had also significantly higher testosterone and estradiol composition (p = 0.006). No associations of sex hormone levels and BMI with anxiety symptomatology in postmenopausal women were found. Conclusions: Although both obesity and anxiety symptomatology were separately associated with higher testosterone level, there was an opposite impact of anxiety and obesity on estradiol levels in premenopausal women. We did not find an evidence that the sex hormone alterations related to obesity are playing a significant role in anxiety symptomatology in premenopausal women. This could be the explanation why we did not find an association between obesity and anxiety. In postmenopausal women, other mechanisms seem to work than in the premenopausal group

The Association of Benzodiazepine Use with Smoking Cessation Among Hospitalized Smokers in a Clinical Trial

Objective: Benzodiazepines are an increasingly prescribed class of anxiolytic medications that target GABA-A receptors in the brain. Smoking also has indirect effects on GABA receptors. This secondary data analysis evaluates the effects of benzodiazepine use on smoking cessation rates among participants in a hospital-based cessation trial. To our knowledge, no other study has examined the effect of benzodiazepine use on smoking cessation rates. Methods: Data from the Enhancing Quitline Utilization among In-Patients (EQUIP) study was analyzed as part of a secondary data analysis. Participants with a benzodiazepine prescription listed on their hospital discharge medication list were compared with those without a benzodiazepine prescription (total n=1054). Similar analyses were conducted between participants with either a long- or short-acting benzodiazepine prescription. Results: A logistic regression modeling the odds of a participant quitting showed no statistical association with benzodiazepine prescription presence (Odds Ratio, OR, 0.93, 95% confidence interval 0.68, 1.28). Controlling for potential covariates maintained a negatively associated, non-significant OR of 0.88 (95% confidence interval 0.63, 1.22). Additionally, the logistic regression modeling produced non-significant odds ratios for both unadjusted and adjusted associations of long-acting versus short-acting benzodiazepine prescription presence on quit rates (adjusted O.R. 0.88, 95% confidence interval 0.49, 1.61). Conclusions: In this sample of patients, the presence of a benzodiazepine prescription at discharge did not have a significant effect on 6-month biochemically verified quit rates. The odds of being quit based on the presence of a benzodiazepine prescription at discharge trended negatively across all unadjusted and adjusted analyses