Substituted heteroaromatic compounds: effect on nicotine self-administration in rats

Rationale

Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported.

Objectives

We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats.

Methods

Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03?mg/kg/infusion in 0.1?ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5–25?mg/kg, i.p., 30?min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11.

Results

Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED₅₀ values 4 and 2.8?mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4β2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds.

Conclusion

The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved.     

Examination of the effect of acute levodopa administration on the loudness dependence of auditory evoked potentials (LDAEP) in humans

Rationale

The loudness dependence of the auditory evoked potential (LDAEP) is considered a noninvasive in vivo marker of central serotonergic functioning in humans. Nevertheless, results of genetic association studies point towards a modulation of this biomarker by dopaminergic neurotransmission.

Objective

We examined the effect of dopaminergic modulation on the LDAEP using L-3,4-dihydroxyphenylalanine (levodopa)/benserazide (Madopar?) as a challenge agent in healthy volunteers.

Methods

A double-blind placebo-controlled challenge design was chosen. Forty-two healthy participants (21 females and 21 males) underwent two LDAEP measurements, following a baseline LDAEP measurement either placebo or levodopa (levodopa 200?mg/benserazide 50?mg) were given orally. Changes in the amplitude and dipole source activity of the N1/P2 intensities (60, 70, 80, 90, and 100?dB) were analyzed.

Results

The participants of neither the levodopa nor the placebo group showed any significant LDAEP alterations compared to the baseline measurement. The test?Cretest reliability (Cronbachs Alpha) between baseline and intervention was 0.966 in the verum group and 0.759 in the placebo group, respectively.

Conclusions

The administration of levodopa showed no effect on the LDAEP. These findings are in line with other trials using dopamine receptor agonists.     

Comparison of nicotine oral soluble film and nicotine lozenge on efficacy in relief of smoking cue-provoked acute craving after a single dose of treatment in low dependence smokers

Rationale

Pilot study results suggested that a new form of nicotine oral soluble film relieved smoking cue-provoked acute craving faster than nicotine lozenge or gum. The new nicotine film may provide smokers another choice to relieve acute craving.

Objectives

This study compared the efficacy of the 2.5 mg nicotine oral soluble film to 2 mg nicotine lozenge for acute relief of smoking cue-provoked craving.

Methods

A randomized, open label, active comparator controlled, parallel group study was conducted with 322 smokers enrolled. After 4 h of abstinence from smoking, eligible subjects were exposed to smoking cues as provocation. Immediately after the post-provocation baseline craving assessment using a 0–100 mm visual analogue scale (VAS), subjects took a randomized single dose of either the 2.5 mg nicotine film or the 2 mg nicotine lozenge. Craving assessments were completed at 50 s, 3 min, 5 min, 7 min, 15 min, 20 min, 25 min and 30 min after drug administration.

Results

Both treatments reduced cue-induced craving and had similar maximum effects on craving relief. However, the 2.5 mg nicotine film relieved cue-induced craving to a greater degree than the 2 mg nicotine lozenge at 50 s (mean difference: ?4.9, p?=?0.014), 3 min (mean difference: ?6.7, p?=?0.011), and 5 min (mean difference: ?5.6, p?=?0.049) post-treatment.

Conclusions

The study confirmed the results from the pilot study. The 2.5 mg nicotine film relieved cue-provoked craving much quicker than the 2 mg nicotine lozenge while both having similar maximum effects. Nicotine film could be useful to provide quick craving relief for low dependence smokers.     

The effects of nicotine exposure during Pavlovian conditioning in rats on several measures of incentive motivation for a conditioned stimulus paired with water

Rationale

Nicotine enhances approach toward and operant responding for conditioned stimuli (CSs), but the effect of exposure during different phases of Pavlovian incentive learning on these measures remains to be determined.

Objectives

These studies examined the effects of administering nicotine early, late or throughout Pavlovian conditioning trials on discriminated approach behavior, nicotine-enhanced responding for conditioned reinforcement, extinction, and the reinstatement of responding for conditioned reinforcement. We also tested the effect of nicotine on approach to a lever-CS in a Pavlovian autoshaping procedure and for this CS to serve as a conditioned reinforcer.

Methods

Thirsty rats were exposed to 13 conditioning sessions where a light/tone CS was paired with the delivery of water. Nicotine was administered either prior to the first or last seven sessions, or throughout the entire conditioning procedure. Responding for conditioned reinforcement, extinction, and the reinstatement of responding by the stimulus and nicotine were compared across exposure groups. Separately, the effects of nicotine on conditioned approach toward a lever-CS during autoshaping, and responding for that CS as a conditioned reinforcer, were examined.

Results

Nicotine exposure was necessary for nicotine-enhanced responding for conditioned reinforcement and the ability for nicotine and the stimulus to additively reinstate responding on the reinforced lever. Nicotine increased contacts with a lever-CS during autoshaping, and removal of nicotine abolished this effect. Prior nicotine exposure was necessary for nicotine-enhanced responding reinforced by the lever.

Conclusions

Enhancements in the motivating properties of CSs by nicotine occur independently from duration and timing effects of nicotine exposure during conditioning.     

The interactive effects of ketamine and nicotine on human cerebral blood flow

Aim

The purpose of this study was to determine if acute nicotine attenuated ketamine-induced regional cerebral blood flow (rCBF).

Method

Following 2–4 h of nicotine abstinence, healthy chronic smokers participated in four sets of rCBF studies, H ₂ ¹⁵ O positron emission tomography, during a simple sensory motor control task. The four drug conditions studied were placebo, ketamine alone, nicotine alone, and ketamine?+?nicotine.

Results

Intravenous ketamine increased rCBF in frontal, orbital–frontal, and anterior cingulate areas. Nicotine alone induced marked rCBF elevations in the lateral occipital cortex and rCBF suppressions in the basal ganglia and anterior cingulate cortex. Nicotine added to ketamine attenuated the ketamine-induced elevated rCBF in the anterior cingulate cortex but caused a marked rCBF increase in the orbital frontal region.

Conclusion

This study illustrates the interactive effects of ketamine, an NMDA receptor antagonist, and nicotine in multiple brain regions. Nicotine substantially ameliorated the effects of ketamine on anterior cingulate rCBF and, when given alone, markedly suppressed anterior cingulate rCBF. The enhanced, synergistic orbitofrontal effects observed with ketamine and nicotine together suggest a marked increase in excitatory neurotransmission in a brain region often linked to psychosis, reward, and addictive behaviors.     

Compensation predicts smoking cessation failure

Rationale

Compensation is a potential result of decreasing the available nicotine and tar dose in cigarettes. There is little published data linking compensation with cessation.

Objectives

We sought to examine whether compensation in response to restricted cigarette yield is associated with difficulty quitting smoking.

Methods

Questionnaires and blood samples were collected from 174 smokers interested in quitting smoking as part of a larger smoking cessation study. Participants were instructed to use a filter designed to remove 50 % of tar and nicotine from the cigarette but otherwise smoke normally. Participants returned after 3 days of using the filter for follow-up data collection.

Results

Nicotine levels and cigarettes per day decreased after use of the filter. Baseline nicotine and change in nicotine pre/post filter use, but not cigarettes per day or change in cigarettes per day were associated with smoking abstinence at 30 days.

Conclusions

Smokers who demonstrate sensitivity to the biological or behavioral consequences of decreased nicotine content in tobacco smoke have greater difficulty quitting. These findings suggest the need for personalized cessation treatment linked to behavioral compensation.     

Tobacco smoke exposure induces nicotine dependence in rats

Rationale

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

Objectives

The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

Methods

The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs).

Results

The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus.

Conclusion

Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.     

Concentration Dependency in Nicotine Skin Penetration Flux from Aqueous Solutions Reflects Vehicle Induced Changes in Nicotine Stratum Corneum Retention

Purpose

This study sought to understand the mechanism by which the steady state flux of nicotine across the human skin from aqueous solutions is markedly decreased at higher nicotine concentrations.

Methods

Nicotine’s steady state flux through human epidermis and its amount in the stratum corneum for a range of aqueous nicotine solutions was determined using Franz diffusion cells, with the nicotine analysed by high performance liquid chromatography (HPLC). Nicotine’s thermodynamic activity in the various solutions was estimated from its partial vapour pressure and stratum corneum hydration was determined using a corneometer. The amount of nicotine retained in the stratum corneum was estimated from the nicotine amount found in individual stratum corneum tape strips and a D-Squame determined weight for each strip.

Results

The observed steady state flux of nicotine across human epidermis was found to show a parabolic dependence on nicotine concentration, with the flux proportional to its thermodynamic activity up to a concentration of 48% w/w. The nicotine retention in the stratum corneum showed a similar dependency on concentration whereas the diffusivity of nicotine in the stratum corneum appeared to be concentration independent. This retention, in turn, could be estimated from the extent of stratum corneum hydration and the nicotine concentration in the applied solution and volume of water in the skin.

Conclusions

Nonlinear dependency of nicotine skin flux on its concentration results from a dehydration induced decrease in its stratum corneum retention at higher concentration and not dehydration induced changes nicotine diffusivity in the stratum corneum.     

Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus

Rationale

The effects of nicotine on cognitive processes may play an important role in nicotine addiction. Nicotine withdrawal impairs hippocampus-dependent learning and genetic factors influence this effect. However, the neural changes that contribute to these impairments are unknown. Chronic nicotine upregulates hippocampal nicotinic acetycholine receptors (nAChRs), which may contribute to cognitive deficits when nicotine administration ceases. If nAChR upregulation underlies withdrawal deficits in learning, then strains of mice exhibiting withdrawal deficits in hippocampus-dependent learning should also show upregulation of hippocampal nAChRs.

Objectives

Here, we examined the effects of nicotine withdrawal on fear conditioning and [³H]epibatidine binding in the dorsal and ventral hippocampus in two inbred mouse strains and their F1 hybrids.

Methods

Male C57BL/6NTac, 129S6/SvEvTac, and B6129SF1/Tac mice were administered chronic nicotine (18 mg/kg/day) for 12 days through osmotic pumps and then were trained and tested in fear conditioning 24 h after cessation of nicotine treatment.

Results

Nicotine withdrawal impaired hippocampus-dependent contextual conditioning in C57BL/6NTac mice but not 129S6/SvEvTac or B6129SF1/Tac mice; no changes were observed in hippocampus-independent cued fear conditioning. Upregulated [³H]epibatidine binding was found in the dorsal, but not ventral, hippocampus of C57BL/6NTac mice and in the ventral hippocampus of B6129SF1/Tac mice after chronic nicotine.

Conclusions

Upregulation of high-affinity binding sites in the dorsal hippocampus of C57BL/6NTac mice, the only strain that exhibited nAChR upregulation in this region and withdrawal deficits in contextual conditioning, suggests that upregulation of high-affinity binding sites in the dorsal hippocampus mediates, in part, nicotine withdrawal deficits in contextual conditioning and genetic background modulates these effects.     

Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats

Rationale

Epidemiological studies have demonstrated a comorbidity of smoking with depression and anxiety, particularly during adolescence. However, few animal studies have considered possible synergistic interactions between nicotine and other tobacco smoke constituents, such as monoamine oxidase (MAO) inhibitors, in the regulation of mood.

Objectives

The aim of the study was to test the hypothesis that nicotine combined with the irreversible MAO inhibitor, tranylcypromine, will differentially affect depression- and anxiety-related behaviors in adolescent and adult rats.

Methods

Nicotine (0, 0.05, 0.2 mg/kg, s.c.) and tranylcypromine (3 mg/kg, i.p.) were tested separately, or together, on male rats aged postnatal days 30 and 68, in three mood-related behavioral tests: forced swim test (FST), elevated plus maze (EPM), and open field.

Results

Nicotine (0.2 mg/kg) in adults significantly decreased floating time in the FST and increased time spent in the open arm of the EPM, with no change in locomotor activity. Tranylcypromine pretreatment combined with nicotine (0.2 mg/kg) significantly increased locomotor activity and time spent in the center of the open field. Whereas nicotine alone had no significant effect on adolescents, it significantly increased locomotor activity and decreased floating time in the FST when combined with tranylcypromine pretreatment.

Conclusions

There is an age-dependent effect of nicotine, alone and in combination with MAO inhibition, on mood-related behaviors. Whereas nicotine alone induces mood improvement in adults, it has no effect on adolescents. Nicotine combined with tranylcypromine has unique, age-dependent effects. Thus, experimental studies of smoking should consider both age and other tobacco constituents, such as MAO inhibitors, as critical factors.     

Nicotine-induced enhancement of responding for conditioned reinforcement in rats: Role of prior nicotine exposure and α4β2 nicotinic receptors

Rationale

Stimuli associated with nicotine can become motivationally significant and may play a role in tobacco dependence. Previous work indicates that nicotine enhances responding for a conditioned reinforcer (CR).

Objectives

These studies examined the effects of prior exposure to nicotine on responding for a CR, persistence of this response, and the role of α4β2 or α7 nicotinic receptor subtypes.

Methods

Water deprived rats were given 13 Pavlovian conditioning sessions where a light/tone conditioned stimulus (CS) was paired with the delivery of water. Then, rats were presented with two levers: one delivered the CS (now a CR), the other was inactive. Experiments examined the effect of nicotine administered prior to Pavlovian conditioning sessions on approach behavior during CS presentations, operant responding for CR in the presence and absence of nicotine, and the persistence of responding for CR. The effects of nicotinic acetylcholine receptor (nAChR) antagonism with mecamylamine and α4β2 or α7 nAChR antagonism with dihydro-beta-erythroidine (DHβE) or methyllycaconitine (MLA) on nicotine-enhanced responding for CR were examined.

Results

Nicotine enhanced approach behavior during CS presentations and potentiated operant responding for CR, an effect sensitized as a result of nicotine exposure during conditioning. Responding for CR and its potentiation by nicotine was stable over multiple tests. Enhanced responding for the CR induced by nicotine was blocked by mecamylamine and DHβE, but not MLA.

Conclusions

Nicotine enhances Pavlovian discriminated approach and shows sensitized nicotine-induced enhancements in responding for CR, an effect depending on α4β2 nAChRs.     

Sex-influence of nicotine and nitric oxide on motor coordination and anxiety-related neurophysiological responses

Rationale

Nitric oxide (NO) is a messenger synthesized in both the neuronal and glial populations by nitric oxide synthase type 1 (NOS1). Nicotine regulates NO production in a sex-dependent manner, both molecules being involved in motor function.

Objective

The present study evaluates sex differences in motor coordination, general movement, and anxiety-related responses resulting from both constant and continuous nicotine treatment and the genetic depletion of NOS1 activity.

Methods

Male and female mice were analyzed with the open-field and the rotarod tests. To understand the role of NO, knockout mice for NOS1 (NOS1?/?) were analyzed. Nicotine was administered continuously at a dose of 24 mg/kg/day via osmotic mini-pumps over 14 days because the behavioral effects elicited are similar to those observed with discontinuous administration.

Results

Data analyses revealed noteworthy sex differences derived from NOS1 depletion. Control NOS1?/? males exhibited an exacerbated anxiety-related response in relation to control NOS1?/? females and control wild-type (WT) males; these differences disappeared in the nicotine-administered NOS1?/? males. Additionally, nicotine administration differentially affected the horizontal movements of NOS1?/? females with respect to WT animals. NO depletion affected male but not female motor coordination improvement along the test days. However, the drug affected female motor coordination only at the end of the administration period.

Conclusions

We show for the first time that NO affects motor and anxiety behaviors in a sex-dependent manner. Moreover, the behavioral effects of constant nicotine administration are dimorphic and dependent on NO production.     

Detrimental effects of acute nicotine on the response-withholding performance of spontaneously hypertensive and Wistar Kyoto rats

Rationale

Attention-deficit hyperactivity disorder (ADHD) is associated with a higher prevalence of smoking, which may be related to potential therapeutic effects of nicotine on ADHD symptoms. Whereas nicotine offers robust improvements in sustained attention, the effects of nicotine on impulsivity are unclear.

Objectives

The present study examined the effects of nicotine on the response inhibition capacity of spontaneously hypertensive rats (SHR), an animal model of ADHD, compared to that of a normotensive control Wistar Kyoto (WKY), using the fixed minimum interval (FMI) schedule of reinforcement.

Methods

Tests were conducted following acute injections of subcutaneous nicotine (0.1–0.6 mg/kg). On each FMI trial, the first lever press initiated an inter-response time (IRT); a head entry into a food receptacle terminated the IRT. IRTs longer than 6 s were intermittently reinforced with sucrose.

Results

A model that assumes that only a proportion of IRTs are sensitive to the timing contingencies of the FMI provided a close fit to the data, regardless of strain or treatment. No baseline difference in FMI performance was observed between SHR and WKY. Nicotine reduced the duration of timed IRTs and the duration of latencies to the IRT-initiating lever press similarly for both strains. Nicotine dose-dependently increased the proportion of timed IRTs; the dose-response curve was shifted leftwards in SHR relative to WKY.

Conclusions

These results suggest that nicotine (a) reduces response-inhibition capacity, (b) enhances the reinforcing efficacy of sucrose, and (c) dose-dependently enhances attention-like sensitivity to contingencies of reinforcement, through mechanisms that are yet unknown.     

Attenuation by baclofen of nicotine rewarding properties and nicotine withdrawal manifestations

Rationale

Nicotine is a major active ingredient in tobacco and plays a major role in tobacco addiction. In rodents, repeated nicotine administration produces behavioral responses related to its addictive properties, such as reinforcing effects and physical dependence.

Objectives

The aim of the present study was to evaluate the possible role of GABA_B receptor in responses induced by repeated nicotine administration in Swiss Webster mice.

Results

Nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.) administration induced rewarding properties in the conditioning place preference test. The GABA_B receptor agonist, baclofen (3 mg/kg, i.p.) abolished the rewarding properties induced by nicotine hydrogen tartrate salt (0.5 mg/kg, s.c.). In addition, naloxone-precipitated nicotine withdrawal induced somatic manifestations, anxiety-like effects in the elevated plus maze test and dysphoric manifestations in the conditioned place aversion paradigm. Baclofen (2 and 3 mg/kg, i.p.) prevented the somatic manifestations and the anxiety-like effects associated with naloxone-precipitated nicotine withdrawal but not the dysphoric manifestations.

Conclusions

These results showed that nicotine rewarding properties and negative aspects of nicotine withdrawal, such as anxiety-like effects and somatic manifestations, can be modulated by the GABA_B receptor activity. This study now reveals a novel possible application of baclofen to develop new therapeutic strategies to achieve smoking cessation.     

Nicotine effects on learning in zebrafish: the role of dopaminergic systems

Rationale

Nicotine improves cognitive function in a number of animal models including rats, mice, monkeys, and recently, zebrafish. The zebrafish model allows higher throughput and ease in discovering mechanisms of cognitive improvement.

Materials and methods

To further characterize the neural bases of nicotine effects on learning in zebrafish, we determined changes in dopaminergic systems that accompany nicotine-enhanced learning.

Results

Nicotine improved learning and increased brain levels of dihydroxyphenylacetic acid (DOPAC), the primary dopamine metabolite. There was a significant correlation between choice accuracy and DOPAC levels. The nicotinic antagonist mecamylamine blocked the nicotine-induced increase in DOPAC concentrations, in line with our previous finding that mecamylamine reversed nicotine-induced learning improvement.

Conclusions

Dopamine systems are related to learning in zebrafish; nicotine exposure increases both learning rates and DOPAC levels; and nicotinic antagonist administration blocks nicotine-induced rises in DOPAC concentrations. Rapid cognitive assessment of drugs with zebrafish could serve as a useful screening tool for the development of new therapeutics for cognitive dysfunction.     

Discrimination of ethanol–nicotine drug mixtures in mice: dual interactive mechanisms of overshadowing and potentiation

Rationale

One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (S^D) effects of each drug.

Objectives

The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur.

Methods

Male C57BL/6J mice were trained to discriminate ethanol (1.5?g/kg) alone or ethanol plus nicotine (0.4, 0.8, or 1.2?mg/kg base) in experiment 1 and nicotine (0.8?mg/kg) alone or nicotine plus ethanol (0.5, 1.0, or 2.0?g/kg) in experiment 2. Stimulus generalizations of the training mixtures to ethanol, nicotine, and the drug combination were assessed.

Results

Ethanol (1.5?g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine S^D was overshadowed by ethanol training doses > 0.5?g/kg in experiment 2, nicotine did potentiate the effects of low-dose ethanol.

Conclusions

These findings are suggestive of dual mechanisms whereby ethanol (>0.5?g/kg) overshadows the S^D effects of nicotine, and at lower doses (<1?g/kg) the salience of ethanol??s S^D effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.     

The effect of nicotine on sensorimotor gating is modulated by a CHRNA3 polymorphism

Rationale

Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence.

Objectives

We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI.

Methods

We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured.

Results

Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation.

Conclusions

The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior.     

Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery

Rationale

In nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation. Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown.

Objectives

This study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving.

Methods

Ten healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated. Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI). Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerström Test of Nicotine Dependence (FTND) and with cue-induced craving.

Results

Significant positive correlations between the BOLD activity and FTND scores were found in brain areas related to visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus) and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area). Intensity of cue-induced craving was significantly associated with greater BOLD activation in mesocorticolimbic areas engaged in incentive motivation and in brain regions related to episodic memory.

Conclusions

Our study suggests that severity of nicotine dependence and intensity of craving are independently associated with cue-induced brain activation in separate neuronal networks. The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse.     

Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats

Rationale

Sazetidine-A is a selective ??4??2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined.

Objectives

This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4?weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats.

Methods

Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6?mg/kg/day for 4?weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2?weeks of infusion followed by 1?week of forced abstinence from nicotine and 1?week of resumed nicotine access.

Results

The 6?mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p?p?p?p?Conclusions The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.     

Disruption of sensory gating by moderate alcohol doses

Rationale

Evidence from a growing body of literature suggests that alcohol, even at moderate-dose levels, disrupts the ability to ignore distractors. However, little work has been done to elucidate the neural processes underlying this deficit.

Objective

The present study was conducted to determine if low-to-moderate alcohol doses affect sensory gating, an electrophysiological phenomenon believed to reflect the pre-attentive filtering of irrelevant sensory information.

Methods

Sixty social drinkers were administered one of three doses intended to produce breath alcohol concentrations of 0.0 % (placebo), 0.04 % (i.e., low dose), and 0.065 % (i.e., moderate dose). A paired-click paradigm consisting of 100 pairs of identical tones (S1 and S2) was used to assess sensory gating. Amplitudes of P50, N100, and P200 auditory evoked potentials (AEPs) were used to calculate gating difference (S1–S2) and ratio (S2/S1) scores.

Results

The moderate alcohol dose significantly decreased P50 and N100 gating relative to placebo. Comparisons between the difference and ratio scores helped characterize the gating mechanisms affected at these stages of information processing. Alcohol did not alter P200 sensory gating.

Conclusions

These data suggest that alcohol disrupts pre-attentional sensory-filtering processes at breath alcohol concentrations (BrACs) below the current 0.08 % legal limit. Future studies should perform a combined assessment of sensory gating and selective attention to better understand the relationship between these two alcohol-induced deficits.