The effects of smoking high nicotine cigarettes on prepulse inhibition, startle latency, and subjective responses

RATIONALE: Several previous investigations with animals and humans have suggested that nicotine enhances prepulse inhibition of the startle reflex (PPI). However, the administration of nicotine activates mesolimbic dopamine, and activation of mesolimbic dopamine is known to attenuate prepulse inhibition of the startle reflex (PPI), which might suggest that nicotine would decrease PPI. OBJECTIVE: The primary aim of this study was to test rigorously the effects of smoking high nicotine cigarettes on PPI and other measures (e.g., heart rate, craving, and mood) when the concentration of nicotine peaks in the brain (i.e., immediately after smoking). METHODS: Thirty smokers participated in two experimental sessions 1 week apart. Two high nicotine cigarettes were smoked in one session, and two control cigarettes were smoked in the other session after overnight deprivation. RESULTS: The results indicated that smoking the high nicotine cigarettes decreased PPI and that PPI increased across trials in both conditions. The interaction between nicotine dose and trial was not significant, although it appeared that high nicotine may have reversed an increase in PPI across trials in the control condition. High nicotine cigarettes also significantly increased heart rate, decreased the latency to peak startle response on control trials, but did not alter the magnitude of the startle response. DISCUSSION: The findings suggest that either high nicotine cigarettes reduced PPI, or possibly, that high nicotine cigarettes may have reversed an increase in PPI across trials as evident in the control condition.     

Nicotine effect on prepulse inhibition and prepulse facilitation in schizophrenia patients.

Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse-pulse interval. PPF was tested using 4500 ms prepulse-pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90). Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse-pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.     

A behavioural and functional neuroimaging investigation into the effects of nicotine on sensorimotor gating in healthy subjects and persons with schizophrenia

Rationale Schizophrenia patients display an excessive rate of smoking compared to the general population. Nicotine increases acoustic prepulse inhibition (PPI) in animals as well as healthy humans, suggesting that smoking may provide a way of restoring deficient sensorimotor gating in schizophrenia. No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans. Objectives To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI. Materials and methods In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 μg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1. Results Nicotine enhanced PPI in both groups. A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum in both groups after nicotine administration. Subsequent correlational analyses demonstrated that the PPI-enhancing effect of nicotine was related to increased hippocampal activity in both groups. Conclusions Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity. Jeffrey A. Gray is deceased.     

Caffeine and prepulse inhibition of the acoustic startle reflex

Rationale: A stimulus presented immediately prior to a startle reflex-eliciting stimulus inhibits the startle reflex. This is termed prepulse inhibition (PPI) and is postulated to index automatic and controlled attentional processing of the prepulse. Objective: Two experiments investigated the effect of 0, 2, and 4 mg/kg oral caffeine on PPI of the acoustic startle eyeblink reflex across stimulus onset asynchronies (SOAs) ranging from 30 to 420 ms. In experiment 1, acoustic prepulses were used and automatic attention was investigated, whereas in experiment 2, acoustic and tactile prepulses were used and automatic and controlled attention was investigated. Controlled attention was investigated by instructing the subjects to attend to one stimulus (attended stimulus) and not to another stimulus (non-attended stimulus). Methods: Caffeine was administrated to human subjects in within-subjects designs (n=24 and n=18). Startle reflexes to 100 dB noise were recorded by electromyography. A mood scale and readings of blood pressure indexed arousal. Results: Caffeine increased the indexes of arousal. There were, however, no significant main effects of caffeine on startle, nor did caffeine significantly interact with any other variable. Attended acoustic prepulses increased PPI at the 120 ms and longer SOAs. Caffeine 4 mg/kg abolished this difference between attended and non-attended stimuli. Attended tactile prepulses facilitated startle at short SOAs, and caffeine reduced facilitation of startle by tactile prepulses. Conclusions: Caffeine did not facilitate automatic attention. Caffeine 4 mg/kg abolished the effect of controlled attention on PPI. Facilitation of startle by attended acoustic prepulses is best explained by facilitation of motoneurons in the facial nucleus. Received: 11 May 1999 / Final version: 1 July 1999     

Effect of cigarette smoking on prepulse inhibition of the acoustic startle reflex in healthy male smokers

The present study investigated the effects of cigarette smoking on prepulse inhibition (PPI) of the acoustic startle reflex in healthy men. Cigarette smoking in a group of overnight smoking-deprived smokers increased PPI as compared to the smoking-deprived condition. This finding is consistent with previous animal studies showing that nicotine increases PPI of the acoustic startle reflex. In addition, cigarette smoking also reduced startle amplitude during the first 6–7 min of the post-smoking session. Received: 4 March 1996 / Final version: 17 June 1996     

Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice

The aim of the present study was to investigate if different levels of circulating corticosterone (CORT) modulate the effect of nicotine on prepulse inhibition (PPI), a measure of sensorimotor gating that is disrupted in schizophrenia and other mental illnesses. Four groups of mice were investigated: sham-operated, adrenalectomized (ADX) and implanted with a cholesterol pellet, ADX and implanted with a 10 mg CORT pellet, or ADX and 50 mg of CORT. Different CORT levels or doses of nicotine did not significantly affect startle responses. Baseline PPI was significantly reduced in mice implanted with the highest dose of CORT. In ADX mice implanted with cholesterol, nicotine treatment influenced PPI depending on the prepulse intensity. In ADX mice implanted with 50 mg of CORT, treatment with 10 mg/kg of nicotine caused a significant increase in PPI at all prepulse intensities. Binding studies showed that corticosterone treatment had significantly affected nicotinic acetylcholine receptor (nAChR) density in the mouse brain. Treatment with 50 mg CORT decreased 125I-epibatidine binding in the globus pallidus and 125I-alpha-bungarotoxin binding in the claustrum. These results suggest a possible interaction of corticosterone and nicotine at the level of the alpha4- and alpha7-type nAChR in the regulation of PPI. In situations of high circulating levels of corticosterone, nicotine may be beneficial to restore disruption of PPI.     

The effects of smoking on acoustic prepulse inhibition in healthy men and women

Acoustic prepulse inhibition (PPI) refers to the reduction of the startle reflex to an intense stimulus if it is preceded by a weak stimulus. Nicotine and smoking have been reported to enhance PPI in rats and in healthy men, respectively. We studied the influence of smoking on PPI in healthy men and women, comparing non-smokers, deprived smokers, and smokers smoking during the test session after deprivation or after ad libitum smoking. Smoking during the session enhanced PPI, without affecting startle reaction or habituation over time. In addition, the effect of smoking on PPI was gender dependent. In men, ad libitum smoking enhanced PPI compared with non-smokers, while, in women, deprivation reduced PPI and smoking restored PPI to the level of non-smokers. Received: 24 July 1997/Final version: 19 November 1997     

The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder

Abstract Rationale and objectives. The present study investigated attentional modification of prepulse inhibition of startle among boys with and without attention-deficit hyperactivity disorder (ADHD). Two hypotheses were tested: (1) whether ADHD is associated with diminished prepulse inhibition during attended prestimuli, but not ignored prestimuli, and (2) whether methylphenidate selectively increases prepulse inhibition to attended prestimuli among boys with ADHD. Methods. Participants were 17 boys with ADHD and 14 controls. Participants completed a tone discrimination task in each of two sessions separated by 1 week. ADHD boys were administered methylphenidate (0.3 mg/kg) in one session and placebo in the other session in a randomized, double-blind fashion. During each series of 72 tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to one pitch and ignore the other. Bilateral eyeblink electromyogram startle responses were recorded in response to acoustic probes (50-ms, 102-dB white noise) presented following the onset of two-thirds of tones, and during one-third of intertrial intervals. Results. Relative to controls, boys with ADHD exhibited diminished prepulse inhibition 120 ms after onset of attended but not ignored prestimuli following placebo administration. Methylphenidate selectively increased prepulse inhibition to attended prestimuli at 120 ms among boys with ADHD to a level comparable to that of controls, who did not receive methylphenidate. Conclusions. These data are consistent with the hypothesis that ADHD involves diminished selective attention and suggest that methylphenidate ameliorates the symptoms of ADHD, at least in part, by altering an early attentional mechanism. Electronic Publication     

Effects of nicotine on attention and inhibitory control in healthy nonsmokers

Nicotine improves cognitive functioning in smokers and psychiatric populations, but its cognitive-enhancing effects in healthy nonsmokers are less well understood. Nicotine appears to enhance certain forms of cognition in nonsmokers, but its specificity to subtypes of cognition is not known. This study sought to replicate and extend previous findings on the effects of nicotine on cognitive performance in healthy nonsmokers. Healthy young adults (N = 40, 50% women) participated in a placebo-controlled, double-blind, repeated measures experiment examining the effects of 7 mg transdermal nicotine or placebo. Participants completed tests of attention (Attention Network Test), behavioral inhibition (stop signal task, Stroop test), reward responsiveness (signal detection task), and risk-taking behavior (Balloon Analogue Risk Task). Physiological (heart rate, blood pressure) and subjective (Profile of Mood States, Drug Effects Questionnaire) measures were also obtained. Nicotine significantly improved performance only on the Stroop test, but it impaired performance on one aspect of the Attention Network Test, the orienting effect. Nicotine produced its expected effects on physiologic and subjective measures within the intended time course. The findings of this study contribute to a growing literature indicating that nicotine differentially affects specific subtypes of cognitive performance in healthy nonsmokers.     

Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic alpha7 receptors

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05-1 mg kg(-1), s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5-5 mg kg(-1), s.c.), an alpha(7) nicotinic receptor antagonist, nor dihydro-beta-erythroidine (0.5-2 mg kg(-1), s.c.), an alpha(4)beta(2) nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01-0.2 mg kg(-1), s.c.) dose-dependently reversed the disruption of PPI induced by apomorphine (1 mg kg(-1), s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg(-1), s.c.). The reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg(-1)) was eliminated by mecamylamine (1 mg kg(-1), i.p.), but not by hexamethonium (10 mg kg(-1), i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine-induced PPI disruption was dose-dependently blocked by methyllycaconitine (1 and 2 mg kg(-1), s.c.). However, dihydro-beta-erythroidine (1 and 2 mg kg(-1), s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine-induced PPI through central alpha(7) nicotinic receptors.     

Smoking withdrawal, nicotine dependence and prepulse inhibition of the acoustic startle reflex

The present study examined the relationship between nicotine dependence as measured by the Fagerstrom Tolerance Questionnaire (FTQ) and prepulse inhibition (PPI) of the acoustic startle reflex measured after overnight smoking withdrawal in a non-clinical population of male smokers with no history of psychiatric disorders or drug/alcohol abuse. It was found that smokers who scored high (>median) on the FTQ showed significantly less PPI as compared to those scoring low (<median) on this scale. This finding further supports a role for nicotine in modulation of PPI, as has previously been found in rats and also in human beings. Received: 26 November 1997/Final version: 8 June 1998     

Effects of amantadine and bromocriptine on startle and sensorimotor gating: parametric studies and cross-species comparisons

Abstract Background. We recently reported that prepulse inhibition (PPI) in humans was increased by the dopamine (DA) agonist/N-methyl-D-aspartate (NMDA) antagonist amantadine (200 mg), but was not significantly altered by the DA agonist bromocriptine (1.25–2.5 mg). PPI-enhancing effects of DA agonists occur in rats under specific stimulus conditions, including short prepulse intervals (<30 ms). We characterized the effects of amantadine and bromocriptine on PPI across species, assessing: (1) dose–response effects on PPI in rats over 10- to 120-ms prepulse intervals; (2) drug effects on PPI in humans, using this same range of prepulse intervals; and (3) drug effects on measures related to PPI, including PPI of perceived stimulus intensity (PPIPSI), and startle habituation. Methods. Drug effects on PPI were assessed in male Sprague Dawley rats (n=90) and humans (n=49); startle habituation and PPIPSI were also studied in humans. Results. Amantadine and bromocriptine exhibited dose- and stimulus-dependent effects on PPI in rats, increasing PPI with short (10–20 ms) prepulse intervals, and decreasing PPI with long (60–120 ms) prepulse intervals. In humans, amantadine increased PPI with both short (20 ms) and long (120 ms) prepulse intervals. Bromocriptine had no significant effect on PPI in humans, but tended to increase PPI at short (20 ms) intervals. Amantadine eliminated PPIPSI. Conclusions. Amantadine modifies prepulse effects on startle in rats and humans, and disrupts prepulse effects on perceived stimulus intensity in humans; bromocriptine has clear effects on PPI in rats, but not in humans. The divergent effects of amantadine on sensorimotor and sensory effects of prepulses may reflect a divergence of brain circuitry regulating these processes. Electronic Publication     

Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.     

Effects of nicotine on novelty detection and memory recognition performance: double-blind, placebo-controlled studies of smokers and nonsmokers

Rationale  Dependent smokers exhibit deficits in attentional and memory processes when smoking abstinent as compared to when satiated. While nicotine replacement therapy improves attention during abstinence, it is unclear whether this is due to the alleviation of withdrawal-related deficits or inherent beneficial effects of nicotine. Objectives  The primary aim of these studies was to test whether nicotine exerts a beneficial effect on novelty detection and whether such effects occur in nonsmokers as well as habitual smokers. Materials and methods  In two parallel, double-blind, placebo-controlled studies, 24 smokers (study 1) and 24 nonsmokers (study 2) were tested in two counterbalanced sessions: once while wearing a nicotine patch (smokers = 14 mg; nonsmokers = 7 mg) and once while wearing a placebo patch. On each day, participants performed three content-specific oddball tasks (perceptual, semantic, and emotional) that required them to press a button whenever they saw a novel target (20% of stimuli) embedded in a stream of common nontarget stimuli (80% of stimuli). Recognition memory for targets was subsequently tested. Reports of mood, smoking withdrawal, patch side effects, and blind success were collected in each session. Results  Among smokers, compared to placebo, nicotine decreased target reaction time during all oddball tasks. Among nonsmokers, nicotine increased target detection accuracy and subsequent memory recognition. Nicotine’s enhancement on each respective measure was not task-content specific in either sample. Conclusions  These data suggest that acute nicotine administration may exert direct beneficial effects on novelty detection and subsequent memory recognition in both smokers and nonsmokers. Moreover, these effects are not content-specific.     

Startle response during smoking and 24 h after withdrawal predicts successful smoking cessation

RATIONALE: The startle response is thought to reflect changes in attentional processes in humans. The startle response shows a number of forms of plasticity, of which prepulse inhibition (PPI) refers to the attenuation of the startle response to a strong sensory stimulus (pulse), when such a pulse is preceded by a stimulus of lower intensity (prepulse). Recent studies have shown that nicotine modulates startle and PPI of the startle reflex in humans and animals. The present study examined individual differences in cognitive benefits obtained from smoking as indexed by startle response and PPI. OBJECTIVES: We investigated, using a within-subjects design, the effects of cigarette smoking via a comparison of baseline and withdrawal measures of startle and PPI in 18 subjects wishing to quit cigarette smoking. The relapse of five of these subjects enabled a between-group comparison of these measures with the successful quitters. METHODS: Startle and PPI were measured on three separate occasions: before quitting, 24 h after quitting and 1 month after quitting. RESULTS: The presence of a high startle response amplitude while subjects were still engaged in their normal smoking patterns (baseline) and the occurrence of a significant drop of startle amplitude in withdrawal relative to baseline factors were found to be predictive of an individual's ability to quit smoking. Changes in PPI were found to reflect these changes in startle amplitude. CONCLUSIONS: The observed response patterns are discussed in terms of individual differences in commitment to quitting and self-dosing to manipulate attentional mechanisms as measured by the acoustic startle response. Furthermore, it is suggested that these specific response profiles may be predictive of the ability to quit smoking.     

The effects of transdermal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controls.

Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia (n=28) and healthy controls (n=32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebo-controlled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia.     

Transdermal nicotine effects on attention

Nicotine has been shown to improve attentiveness in smokers and attenuate attentional deficits in Alzheimer’s disease patients, schizophrenics and adults with attention-deficit/hyperactivity disorder (ADHD). The current study was conducted to determine whether nicotine administered via transdermal patches would improve attentiveness in non-smoking adults without attentional deficits. The subjects underwent the nicotine and placebo exposure in a counterbalanced double-blind manner. Measures of treatment effect included the Profile of Mood States (POMS), Conners’ computerized Continuous Performance Test (CPT) of attentiveness and a computerized interval-timing task. The subjects were administered a 7 mg/day nicotine transdermal patch for 4.5 h during a morning session. Nicotine significantly increased self-perceived vigor as measured by the POMS test. On the CPT, nicotine significantly decreased the number of errors of omission without causing increases in either errors of commission or correct hit reaction time. Nicotine also significantly decreased the variance of hit reaction time and the composite measure of attentiveness. This study shows that, in addition to reducing attentional impairment, nicotine administered via transdermal patches can improve attentiveness in normal adult nonsmokers. Received: 11 June 1997/Final version: 13 March 1998     

Effects of nicotine on quinpirole- and dizocilpine (MK-801)-induced sensorimotor gating impairments in rats

RATIONALE: Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as an index of sensorimotor gating to assess preattentive processes. Impairments in PPI have been observed in many neuropsychiatric disorders, especially schizophrenia. Administration of the glutamate N-methyl-D: -aspartate receptor antagonist dizocilpine (MK-801) or dopamine receptor (D2/D3) agonist quinpirole (QNP) results in impairment (reduction) of PPI in rats. Nicotine, on the other hand, may have beneficial effects on attentional/cognitive functions. OBJECTIVE: The purpose of the current set of experiments was to investigate the effects of acute and chronic nicotine on MK-801- and QNP-induced PPI impairments. MATERIALS AND METHODS: Adult female Sprague-Dawley rats were treated acutely or chronically by various doses of nicotine alone or followed by an acute dose of MK-801 (0.15 mg/kg) or QNP (0.5 mg/kg). All drugs were administered intraperitoneally. Controls received saline in lieu of any drug, and ASR and PPI in each animal was evaluated 10 min after the last injection. RESULTS: Both MK-801 and QNP consistently impaired PPI. Administration of nicotine acutely (0.05-0.4 mg/kg) or chronically (0.2 or 0.4 mg/kg daily for 1 week) did not have any effect of its own on ASR or PPI or on MK-801-induced PPI impairment. Acute administration of 0.2 mg/kg nicotine did not have any effect on QNP-induced reduction in PPI, whereas the higher dose of 0.4 mg/kg significantly attenuated this impairment. Chronic daily administration of either 0.2 or 0.4 mg/kg nicotine for 1 week nearly normalized the QNP-induced impairments in PPI. CONCLUSION: The effect of nicotine on sensorimotor gating is dependent on the procedure as well as the dose of nicotine and appears to be efficacious against dopaminergic rather than glutamatergic disruption of PPI in rats.     

Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice

The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHbetaE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.     

Effects of prepulses and d-amphetamine on performance and event-related potential measures on an auditory discrimination task

Rationale: Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating, that is the processing of the startle stimulus (S2) is inhibited by the interfering processing of a closely preceding prepulse (S1). It has been demonstrated that PPI is disrupted in a variety of mental disorders and that several neurotransmitter systems, including dopamine, participate in the modulation of sensorimotor gating. Previous studies have also shown that a task-relevant S1 enhances PPI in healthy subjects but not in schizophrenic patients. These findings indicate an influence of attentional processes on sensorimotor gating and an impairment of this modulation in schizophrenia. Objective: Assuming a dopamine-mediated suppression of S1 processing as a mechanism of resource management and selective attention, which might be impaired in certain mental disorders, the present study investigated the effects of the indirect dopaminergic agonist d-amphetamine on prepulse-altered S2 discrimination and event related potentials (ERPs). Methods: Twelve healthy volunteers were tested in a double-blind, placebo-controlled experimental design. Here, S2 is the target in a difficult Go/NoGo auditory discrimination task. Results: Confirming our previous results, S2 processing is ”accentuated” by a weak acoustic prepulse in healthy subjects, thus leading to a lower rate of errors of omission but also to more false alarms (i.e. a liberal response bias). This performance change correlated with a prepulse-induced increase in the amplitude of the P3 ERP towards non-targets (”prepulse-induced non-target positivity”; PINTP). In addition, the results of the present study show that under prepulse conditions amphetamine disrupts ”S2 accentuation” associated with a dose-related reduction of the P2 component of the S1 response and a plasma level related reduction of PINTP. Conclusions: These data suggest an involuntary attentional shift towards S1 processing with increasing dopamine-release similar to that observed in patients with schizophrenia or OCD. It is concluded that sensory gating alters selective attention via dopaminergic modulation. Received: 30 March 1998 / Final version: 10 February 1999