Yohimbine — facilitated acoustic startle reflex in humans

Preclinical studies have suggested the acoustic startle reflex (ASR) may be a useful animal model to investigate the neurochemical basis of anxiety and fear states. This work has revealed that the anxiogenic alpha-2 receptor antagonist, yohimbine, increases the amplitude of the ASR in laboratory animals. The present investigation evaluated the effects of yohimbine on the ASR in healthy subjects. Seven healthy subjects received IV yohimbine (0.4 mg/kg) or saline placebo on two separate days in a randomized double blind placebo control design. A trial of 2 tone frequencies with varied intensity (90, 96, 102, 108, 114 dB) white noise, instantaneous rise time, was delivered binaurally through headphones. Tones were delivered every 25–60 sec, for a 30 ms duration. Startle testing was done 80 minutes post infusion and lasted 15–20 minutes. Sign rank testing indicated yohimbine caused an overall increase in startle amplitude, as well as significant augmentation of startle amplitude at 96, 102, 108, 114 decibels but not at the 90 dB intensity. Sign rank tests indicated a significant reduction of startle latency by yohimbine at only the 96 dB intensity. Significant correlations were observed between startle and peak anxiety, startle and plasma MHPG, peak anxiety and plasma MHPG. This study demonstrates in healthy human subjects an excitatory effect of yohimbine on the mangnitude of the ASR and a decrease in its latency. In the context of the key role of this reflex in the alarm response, this finding adds to the array of documented behavioral, biochemical and cardiovascular effects of yohimbine in humans which support the relationship between increased noradrenergic function and anxiety states.     

Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine

Brain noradrenergic systems have been shown to be altered in opioid dependence and to mediate aspects of opioid withdrawal. Pre-clinical and clinical studies by others have shown that yohimbine, which increases noradrenergic activity, also increases both baseline and fear enhancement of the magnitude of the acoustic startle response (ASR). In a separate report from this experiment, it was shown that yohimbine produced opioid withdrawal-like symptoms, including anxiety, in clinically stable methadone-maintained patients and also produced elevations in the norepinepherine (NE) metabolite, 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol serum levels. The current study reports the effects of intravenous yohimbine hydrochloride, 0.4 mg/kg versus saline (double-blind), on ASR magnitude, plasma MHPG, and cortisol levels in eight methadone-maintained patients and 13 healthy subjects in a double-blind fashion. Yohimbine increased startle magnitude in both groups. There was no basal (placebo day) difference between the startle response of the two groups, but methadone patients had a larger startle magnitude increase in response to yohimbine than healthy controls. Methadone-maintained patients had lower baseline plasma levels of MHPG and similar baseline plasma cortisol levels compared with normal subjects. Yohimbine caused significant elevation in cortisol and MHPG in both groups. Methadone-maintained subjects had higher elevations in cortisol levels and MHPG (methadone main effect) levels in response to yohimbine. However, when MHPG levels were corrected for baseline differences by analysis of covariance (ANCOVA), the yohimbine effect, but not the methadone effect remained statistically significant. These results are consistent with the previous report and support the hypothesis that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and of noradrenergic mechanisms of stress response persist in opioid-agonist maintenance. The ASR effect extends the previous report and provides an additional objective measure for perturbation of noradrenergic and stress responses in these patients.     

Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-Chlorophenylpiperazine (mCPP)

Preclinical studies suggest that acoustic startle amplitude is increased during ethanol withdrawal. The current study evaluated the effects of intravenous infusion of the α₂-adrenergic antagonist, yohimbine (0.4 mg/kg), the serotonin partial agonist m-chlorophenylpiperazine (mCPP, 0.1 mg/kg), and placebo administered to 22 male patients meeting DSM-III-R criteria for alcohol dependence and 13 male healthy subjects. Patients and healthy subjects completed 3 test days under double-blind conditions in a randomized order. Patients were sober for 12–26 days prior to testing. On each test day, participants completed startle testing 80 min following drug infusion. Stimuli with varying intensities (90, 96, 102, 108, 114 dB) were presented in a randomized order balanced across four blocks. Stimuli consisted of 40-ms bursts of white noise administered every 45–60 s for 15–20 min through headphones. Analyses indicated that patients exhibited elevated acoustic startle magnitudes on the placebo day relative to healthy subjects. In patients, the magnitude of startle amplitudes elicited at 90 dB, but not 114 dB, correlated significantly with the number of previous alcohol detoxifications. Yohimbine increased startle magnitudes and reduced startle latencies relative to placebo and mCPP in both patients and healthy subjects. mCPP did not alter startle magnitude in either group. Yohimbine also increased the probability that a 90-dB stimulus produced a startle response in healthy subjects, but not in patients. Blunting of yohimbine effects on startle probability may reflect the baseline elevations in startle probability levels in patients, but may also be consistent with other evidence of reduced postsynaptic, but not presynaptic, noradrenergic function in these same patients. These data replicate and extend previous reports indicating that yohimbine facilitates the acoustic startle response in humans. They also further implicate the number of episodes of ethanol withdrawal as a factor influencing subsequent neurobiological responsivity in chronic alcoholic patients. Based on the current data, future research should explore whether measurement of the acoustic startle response provides an objective quantitative severity measure of ethanol withdrawal. Received: 31 August 1995 /Final version: 4 October 1996     

The effects of pimozide and phenoxybenzamine pretreatments on amphetamine and apomorphine potentiation of the acoustic startle response in rats

A series of three experiments investigated the individual roles of neurons containing dopamine (DA) and norepinephrine (NE) in modulating the amplitude of the acoustic startle response (ASR) in rats. Experiment I investigated the effects of 0.1, 0.5, and 2.5 mg/kg pimozide or 5, 10, and 20 mg/kg phenoxybenzamine alone on startle amplitude. Experiments II–III investigated the effects of pretreatment with either 2.5 mg/kg pimozide or 10 mg/kg phenoxybenzamine on the potentiation of startleamplitude by either d-amphetamine (8 mg/kg), l-amphetamine (32 mg/kg), or apomorphine (3 mg/kg). Treatment with pimozide (2.5 mg/kg given 85 min before testing) and phenoxybenzamine (10 mg/kg, given 25 min before testing) resulted in a significant reduction in startle amplitude, supporting the conclusion that neurons containing NE and DA both tonically facilitate the ASR. The startlepotentiating effect of d- and l-amphetamine and apomorphine were totally blocked by pretreatment with pimozide (2.5 mg/kg, injected 2 h before these drugs), which supports the hypothesis that these agents potentiate startle at least in part by acting through dopaminergic neural systems. Phenoxybenzamine pretreatment (10 mg/kg, given 0.5 h before) also blocked the startle-potentiating effects of l-amphetamine and apomorphine, which suggests that noradrenergic neural systems are also involved in the potentiation of ASR by these agents, possibly through the interaction of dopaminergic and noradrenergic neural systems. The potentiating effect of d-amphetamine on ASR magnitude was not attenuated by phenoxybenzamine.     

Exogenous cortisol exerts effects on the startle reflex independent of emotional modulation

Exogenous cortisol's modulation of the acoustic startle reflex (ASR) was tested alone and during exposure to affectively valenced photographs in healthy men and women. During nonmodulated startle, oral hydrocortisone had a biphasic dose effect, with 5 mg increasing and 20 mg decreasing, eyeblink reflex magnitude compared to placebo. During emotion modulation, 20 mg of hydrocortisone reduced reflex magnitude without affecting the usual pattern of modulation across positive, neutral, and negatively affective slides. Gender differences were not found in either relationship. These findings illustrate dose-dependent effects of cortisol on the startle pathway independent of emotional state and consistent across genders.     

Effect of clonidine on the human acoustic startle reflex

The present study investigated in healthy human volunteers whether clonidine reduced the amplitude of the acoustic startle reflex and whether this effect, if found, was due to an accelerated rate of habituation. Subjects were presented with startleeliciting noise-bursts after intravenous (iv) infusion of clonidine (1.5 µg/kg) and saline on separate days. Clonidine significantly reduced the amplitude of the acoustic startle reflex (as indexed by the eyeblink component) relative to the saline treated condition. This effect was neither due to an accelerated rate of habituation of the startle reflex nor to the sedative effect of clonidine. These findings complement an earlier report (Morgan et al. 1993) that yohimbine augments the amplitude of the startle reflex in man. Taken together, the two reports indicate a new model for the clinical investigation of central alpha₂ adrenoceptor function in humans.     

The differential effects of prenatal stress in rats on the acoustic startle reflex under baseline conditions and in response to anxiogenic drugs

RATIONALE: The prenatal stress syndrome (PS) is characterized by exaggerated behavioral and physiological responses to stressful stimuli and anxiogenic agents. OBJECTIVES: To characterize the behavioral effects of PS on the acoustic startle reflex (ASR) and to determine the possible role of PS-induced alterations in noradrenergic control of ASR by determining the effects of the alpha2-adrenoceptor antagonists, yohimbine, idazoxan, and RS79948-197. METHODS: PS was induced by exposing pregnant dams to a mild stressor of handling and saline injection (0.1 ml, s.c.) from gestational days 14 to 21. Control dams were left undisturbed throughout pregnancy. Using adult male offspring, all ASR studies consisted of either a 30- or 60-min testing period containing 60 or 120 acoustic startle stimuli trials (95 dB, 50 ms noise burst) at a fixed intertrial interval of 30 s after a 5-min acclimation period. For drug studies, a 3-day repeated measures design was implemented. RESULTS: With the exception of the response to the first startle stimulus on the first day of testing, there were no significant differences in baseline ASR between control and PS offspring. Low doses of yohimbine, idazoxan, and RS79948-197 were anxiogenic in the ASR test in both control and PS offspring. PS offspring were less responsive to higher doses of yohimbine (5 mg/kg) and idazoxan (8 mg/kg) but did not differ from control in their responses to any dose of RS79948-197. CONCLUSIONS: Anxiogenic effects of yohimbine, idazoxan, and RS79978-197, likely mediated via alpha2-adrenoceptor blockade, are similar in control and PS rats. Differences between control and PS rats occurred in the response to higher doses of yohimbine and idazoxan. Non-specific effects of these drugs, such as actions at 5HT1A receptors, may cause their behavioral profile to be altered by PS, and to differ from the highly selective RS79948-197.     

Effects of CCK-4 infusion on the acoustic eye-blink startle and psychophysiological measures in healthy volunteers

The acoustic startle response (ASR) and a range of psychophysiological parameters were evaluated during a continuous intravenous administration of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Subjects (n=28) were randomly assigned to double-blind infusion of either CCK-4 (0.5 mg/60 min) or placebo. The ASR sessions were performed prior to infusion and at 20 min and 50 min after the onset of infusion by recording eye-blink response to a series of acoustic stimuli (110 dB, 40 ms). An effect of CCK-4 on the eye-blink startle was observed in the first half of infusion. CCK-4 produced an increase of eye-blink startle amplitude from baseline values in contrast to the decrease observed at this time point with placebo. A mild increase in anxiety and heart rate followed by fatigue was reported with CCK-4. Administration of CCK-4 produced increases in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and growth hormone. The results of this study show that a prolonged intravenous administration of CCK-4 may be a useful challenge method for further studies on the role of CCK system in the modulation of human anxiety and stress response.     

Luteal-phase accentuation of acoustic startle response in women with premenstrual dysphoric disorder.

Alterations in central nervous system response to menstrual cycle-related fluctuations in neuroactive steroids are thought to underlie the emergence of negative affect in the luteal phase of the menstrual cycle in women with premenstrual dysphoric disorder (PMDD). Such changes in the neuroendocrine milieu may lead to heightened arousal and response to stress in women with PMDD. Using the acoustic startle paradigm, we sought to determine whether women with PMDD have an accentuated physiologic response to a mildly aversive stimulus during the luteal compared to follicular phase. Further, we also examined the impact of visual affective stimuli on acoustic startle response (ASR) magnitude. During the follicular and luteal phases of the menstrual cycle, acoustic stimuli (103 dB) were delivered to 15 women with PMDD and 14 healthy menstruating women of similar age. After obtaining baseline ASR, the procedure was repeated when subjects viewed pleasant, neutral and unpleasant pictures. There was a significant group by menstrual cycle phase interaction for baseline ASR magnitude, which can be attributed to the heightened startle magnitude in women with PMDD compared to healthy women during the luteal relative to the follicular phase. The direction and degree to which picture viewing modulated the startle magnitude did not vary by group or menstrual cycle phase. These data suggest that menstrual cycle phase has a powerful modulatory effect on physiologic reactivity in women with PMDD but not in healthy women. Physiologic response to affective stimuli appears to be intact in women with PMDD across the menstrual cycle.     

Effects of serotonergic and noradrenergic antidepressants on auditory startle response in patients with major depression

Rationale Amplitude, habituation and prepulse inhibition (PPI) of the acoustic startle response (ASR) in rodents and humans are sensitive to psychotropic drugs. Studies with rodents suggest that an increase or decrease in serotonin level in the brain alters several modalities of the ASR. So far, little is known about serotonergic and noradrenergic startle modulation in humans.Objective This study was designed to investigate the effects of the selective serotonin uptake inhibitor sertraline versus the selective noradrenalin uptake inhibitor reboxetine on magnitude, habituation and PPI of ASR in patients with major depression.Methods We studied ASR in 23 patients with the diagnosis of major depression according to DSM-IV who were randomly treated either with sertraline or with reboxetine. Initially, ASR assessment was carried out when patients were drug-free for at least 2 weeks and again after 14 days of treatment.Results The habituation of ASR was strongly attenuated by sertraline and not significantly altered by reboxetine. None of the substances altered the startle reactivity. In addition, PPI was not altered by sertraline, but reboxetine tended to decrease PPI. The startle reactivity at baseline was correlated with improvement of depressive symptoms at the end of the study.Conclusion These results provide the first evidence for different effects of noradrenergic and serotonergic antidepressants on the startle response in depressed patients.     

The effect of nicotine and trauma context on acoustic startle in smokers with and without posttraumatic stress disorder

Rationale  

Exaggerated startle response is a prominent feature of posttraumatic stress disorder (PTSD) although results examining differences in the acoustic startle response (ASR) between those with and without PTSD are mixed. One variable that may affect ASR among persons with PTSD is smoking. Individuals with PTSD are more likely to smoke and have greater difficulty quitting smoking. While smokers with PTSD report that smoking provides significant relief of negative affect and PTSD symptoms, the effects of smoking or nicotine deprivation on startle reactivity among smokers with PTSD are unknown.     

Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats

Chronic nicotine administration has been reported to increase acoustic startle response (ASR) amplitude in rats, which has been offered as evidence that some dosages of nicotine can enhance attention. The present experiments examined effects of acutely administered nicotine on amplitude and pre-pulse inhibition (PPI) of acoustic startle in rats. PPI, the decrease in ASR amplitude by a stimulus preceding the startle-eliciting event, reflects pre-attentive neural processes underlying sensory gating. Nicotine had a biphasic dose effect on startle amplitude, with increases at lower dosages (0.01 mg/kg) and decreases at higher dosages (0.5–5.0 mg/kg SC). Lower dosages of nicotine (0.001–0.01 mg/kg) increased PPI and the increase at 0.001 mg/kg occurred independently of changes in ASR amplitude. These results confirm that increases in PPI are not dependent upon changes in ASR amplitude. Results are consistent with nicotine's enhancements of performance on cognitive tasks in humans and are the first reported use of the PPI paradigm to model such effects. These findings indicate that ASR paradigms are useful to study effects of nicotine.This work was supported by USUHS protocol CO 7223. The views contained herein are the private ones of the authors and do not reflect those of the Uniformed Services University of the Health Sciences, the Department of Defense, or the Food and Drug Administration     

Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD

Rationale Exaggerated acoustic startle is a prominent symptom of post-traumatic stress disorder (PTSD); however, its physiological basis is not well understood, and there are few available treatments. Neurobiological research has suggested that anti-kindling agents and/or glutamate antagonists can attenuate the acoustic startle response (ASR) in animal models. The anticonvulsant topiramate is an AMPA antagonist that also demonstrates potent anti-kindling effects and may, therefore, have promise in treating trauma-enhanced ASR.Objective To evaluate the ability of topiramate to attenuate stress-induced increases in ASR in a previously validated animal model of PTSD.Methods Male Sprague-Dawley rats (n=36) served as controls or received single prolonged stress (SPS). SPS consisted of 2 h restraint, forced swim and ether anesthesia, then a 7-day undisturbed period. Animals then received vehicle, 10 mg/kg or 30 mg/kg of topiramate orally, twice daily for 7 days. ASR was assessed for all animals before and after the study, in light and dark environments.Results SPS produced a sustained increase in the ASR in both environments, an effect that was significantly reduced by topiramate. Meanwhile the ASR of control animals remained unaffected by topiramate.Conclusions The current results provide one of the few demonstrations of a single stress episode producing sustained enhancement of ASR. In addition, topiramate demonstrates promise in treating exaggerated acoustic startle symptoms in PTSD or other stress-related disorders.     

Comparison of the effects of clonidine and yohimbine on pupillary diameter at different illumination levels

AIMS: To evaluate the pupillary effects of single doses of the alpha2-adrenoceptor agonist clonidine and the alpha2-adrenoceptor antagonist yohimbine under several illumination conditions. METHODS: Sixteen healthy male volunteers received clonidine 0.2 mg, yohimbine 22 mg, clonidine 0.2 mg + yohimbine 22 mg in a double-blind placebo-controlled, cross-over study. 2 h post drug ingestion pupil diameter was recorded in darkness, and at luminance levels of 6 Cd m-2, 91 Cd m-2 and 360 Cd m-2. The effects of the active treatments on pupil diameter were also expressed as the differences from the placebo condition ('placebo-corrected' data; mean [95% CI]). RESULTS: Clonidine had little effect on pupil diameter in darkness; however, it caused a significant, light-dependent, miosis when the eye was illuminated. On the other hand yohimbine increased pupil size; this increase was significant at 91 and 360 Cd m-2. There were no significant differences between the effects of the combined treatment (clonidine 0.2 mg + yohimbine 22 mg) and the effect of placebo. CONCLUSIONS: The pupillary effects of clonidine and yohimbine are likely to reflect the interaction of these drugs with inhibitory alpha2-adrenoceptors located on central noradrenergic neurones, which in turn would lead to a decrease and an increase, respectively, in sympathetic outflow to the iris. The light dependence of the pupillary effects of these drugs, however, suggests that the parasympathetic light reflex pathway is also involved, which is known to be under inhibitory control from the central noradrenergic neurones. Modulation of parasympathetic outflow seems to play an important role since both drugs had relatively little effect on pupil diameter in darkness when sympathetic activity predominates.     

Effects of ethanol on the acoustic startle reflex in humans

The effect of ethanol on human sensorimotor reactivity was assessed by examining the acoustic startle response. Twelve healthy normal subjects participated in a startle reflex experiment in which placebo or ethanol were given on separate days. Three types of startle probes were used. They consisted of pulse-alone bursts of white noise at 108 dB(A) and 99 dB(A) to explore startle reactivity, and of a 108 dB(A) pulse preceded by a 85 dB(A) prepulse stimulus (prepulse + pulse) to assess prepulse inhibition. Startle amplitude was larger to the 108 dB(A), compared to the 99 dB(A) pulse-alone probes. The prepulse stimulus significantly reduced the amplitude of the startle reflex elicited by the subsequent 108 dB(A) stimulus. The amplitude of the startle response was dramatically reduced by acute ethanol. The effects of ethanol on prepulse inhibition could not be assessed because the startle response was too small in the ethanol condition.Supported by grant 1 RO1 AA0803-01A1 to Dr. O'Malley     

Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe for drug-related motivational states

RATIONALE: Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation. OBJECTIVE: The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes. METHODS: Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment I examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4-7 days of treatment using IV naloxone. RESULTS: Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect. Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect. CONCLUSIONS: Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.     

Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes

Animals depleted of dopamine (DA) in the neonatal period and tested in adulthood exhibit some similarities to patients with schizophrenia, including increased sensitivity to DA agonists, altered sensitivity to DA receptor antagonists, and abnormalities of the acoustic startle response (ASR). In this study, we examined the contributions of D₁-like and D₂-like DA receptors to ASR measures in animals depleted of DA as neonates. Male rat pups received intracerebroventricular injections of 6-hydroxydopamine (DA depleted) or its vehicle (controls) at 3 days of age. Animals underwent startle testing ad adults (60–75 days of age) after administration of DA antagonists (haloperidol: 0.1 or 0.3 mg/kg, SCH 23390: 0.01 or 0.05 mg/kg) with and without DA agonist administration (apomorphine 0.5 mg/kg). ASR amplitude and prepulse inhibition (PPI: percentage decrease in startle amplitude due to a low intensity prepulse) were measured. DA depleted animals showed increased ASR amplitude and reduced PPI compared to controls. Administration of D₁-like or D₂-like DA antagonists significantly reduced overall ASR and increased PPI in both control and DA depleted animals, with DA depleted animals showing a relatively greater sensitivity to the D₁-like antagonist SCH 23390. Findings are discussed in terms of the role of residual DA in mediating ASR phenomena in depleted animals, differences between D₁/D₂ DA receptor mediation of ASR compared to other behaviors in DA depleted animals, and potential implications for neuropsychiatric syndromes such as schizophrenia.     

Prazosin administered prior to inescapable stressor blocks subsequent exaggeration of acoustic startle response in rats

Exposure to traumatic stress can result in a number of pathophysiological conditions, including post-traumatic stress disorder (PTSD). PTSD is characterized by a number of persistently heightened physiological and behavioral indicators, including increased sensory arousal and increased startle response. Similar effects can be seen in an animal model of PTSD in which stress results from restraint and inescapable tailshocks to rats. The present study used this animal model to investigate the effects of prazosin, an alpha(1) adrenoceptor antagonist, on stress-induced elevation of acoustic startle response (ASR). To investigate this, male Sprague-Dawley rats were injected with 0.5 mg/kg of prazosin 30 min before restraint and inescapable tail shock on three consecutive days. ASR testing was performed 1, 4, 7 and 10 days post-stress and compared to baseline and control values. Results show a significant reduction of ASR hyperarousal in the group treated with prazosin prior to stress compared to vehicle treated stressed animals and controls. Pre-stress treatment with lower levels of prazosin (0.25, 0.1 and 0.05 mg/kg) showed similar results. These findings further implicate an alpha(1) adrenoceptor role in the pathophysiological response to traumatic stress and suggest a potential preventative role for prazosin.     

Chronic cannabis use is associated with attention-modulated reduction in prepulse inhibition of the startle reflex in healthy humans

Regardless of a wide research interest the nature of a relationship between cannabis use and schizophrenia is controversial. One of the physiological abnormalities in schizophrenia is attention-modulated deficit in prepulse inhibition (PPI), which is a normal reduction in the startle reflex magnitude when a non-startling stimulus (prepulse) precedes the startling stimulus (pulse). This experiment was designed to determine whether or not otherwise healthy people using cannabis would exhibit attention-modulated deficit in PPI. The startle reflex was recorded in carefully screened healthy humans attending to and ignoring auditory pulse and prepulse stimuli separated by short (20-200 ms) and long prepulse intervals (1600 ms). In contrast to 12 non-using controls, cannabis use in 16 healthy humans was associated with significant reduction in%PPI while attending to auditory stimuli, but not while ignoring them. The PPI was correlated with the duration of cannabis use but not with the concentration of cannabinoid metabolites in urine and the recency of cannabis use in the preceding 24 hours. Cannabis use was not associated with changes in prepulse facilitation of startle reflex magnitude (%PPF) at long prepulse intervals, prepulse facilitation of startle reflex latency and startle reflex magnitude in the absence of prepulses. These results suggest that chronic, but not acute, use of cannabis is associated with schizophrenia-like disruption in PPI in healthy controls. Such reduction in PPI is attention-dependent and does not reflect a global deficit in sensorimotor gating in cannabis users.     

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