Quantitative analysis of performance on a progressive-ratio schedule: effects of reinforcer type, food deprivation and acute treatment with Δ9-tetrahydrocannabinol (THC).

Rats' performance on a progressive-ratio schedule maintained by sucrose (0.6M, 50 µl) and corn oil (100%, 25 µl) reinforcers was assessed using a model derived from Killeen's (1994) theory of schedule-controlled behaviour, 'Mathematical Principles of Reinforcement'. When the rats were maintained at 80% of their free-feeding body weights, the parameter expressing incentive value, a, was greater for the corn oil than for the sucrose reinforcer; the response-time parameter, δ, did not differ between the reinforcer types, but a parameter derived from the linear waiting principle (T0), indicated that the minimum post-reinforcement pause was longer for corn oil than for sucrose. When the rats were maintained under free-feeding conditions, a was reduced, indicating a reduction of incentive value, but δ was unaltered. Under the food-deprived condition, the CB1 cannabinoid receptor agonist Δ(9)-tetrahydrocannabinol (THC: 0.3, 1 and 3 mg kg(-1)) increased the value of a for sucrose but not for corn oil, suggesting a selective enhancement of the incentive value of sucrose; none of the other parameters was affected by THC. The results provide new information about the sensitivity of the model's parameters to deprivation and reinforcer quality, and suggest that THC selectively enhances the incentive value of sucrose.

Effects of SKF-83566 and haloperidol on performance on progressive ratio schedules maintained by sucrose and corn oil reinforcement: quantitative analysis using a new model derived from the Mathematical Principles of Reinforcement (MPR).

RATIONALE: Mathematical models can assist the interpretation of the effects of interventions on schedule-controlled behaviour and help to differentiate between processes that may be confounded in traditional performance measures such as response rate and the breakpoint in progressive ratio (PR) schedules. OBJECTIVE: The effects of a D1-like dopamine receptor antagonist, 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide (SKF-83566), and a D2-like receptor antagonist, haloperidol, on rats' performance on PR schedules maintained by sucrose and corn oil reinforcers were assessed using a new model derived from Killeen's (Behav Brain Sci 17:105-172, 1994) Mathematical Principles of Reinforcement. METHOD: Separate groups of rats were trained under a PR schedule using sucrose or corn oil reinforcers. SKF-83566 (0.015 and 0.03 mg kg(-1)) and haloperidol (0.05 and 0.1 mg kg(-1)) were administered intraperitoneally (five administrations of each treatment). Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model's parameters were compared between treatments. RESULTS: Haloperidol reduced a (the parameter expressing incentive value) in the case of both reinforcers, but did not affect the parameters related to response time and post-reinforcement pausing. SKF-83566 reduced a and k (the parameter expressing sensitivity of post-reinforcement pausing to the prior inter-reinforcement interval) in the case of sucrose, but did not affect any of the parameters in the case of corn oil. CONCLUSIONS: The results are consistent with the hypothesis that blockade of both D1-like and D2-like receptors reduces the incentive value of sucrose, whereas the incentive value of corn oil is more sensitive to blockade of D2-like than D1-like receptors.

Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule.

It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes.

Effects of threat of electric shock and diazepam on the N1/P2 auditory-evoked potential elicited by low-intensity auditory stimuli.

The acoustic startle response includes rapid muscular contractions elicited by loud sounds; it may be measured in humans as the electromyographic response of the orbicularis oculi muscle. Enhancement of this response during exposure to threat of electric shock (fear- potentiated startle) is a widely used model of human anxiety. A problem with the use of the startle reflex in studies of human anxiety is the aversiveness of startle-eliciting sounds, which may, in some subjects, exceed the aversiveness of the electric shock itself. We have recently found that the long-latency N1/P2 auditory-evoked potential elicited by loud sounds is subject to fear potentiation. However, it is not known whether N1/P2 potentials elicited by low-intensity sounds, which do not elicit the startle response, are also subject to fear potentiation. This study examined the susceptibility of the N1/P2 potential elicited by low-intensity sounds to fear potentiation, and the effect of the anxiolytic diazepam on the N1/P2 potential in the absence and presence of threat of electric shock. Fifteen male volunteers (18-43 years) participated in three sessions in which they received placebo, diazepam 5 mg and diazepam 10 mg according to a double-blind protocol. Sixty minutes after treatment, auditory-evoked potentials were elicited by 40 ms 1 kHz tones 5, 10, 15, 20 and 25 dB[A] above a background of 70 dB[A]. Recording sessions consisted of eight alternating 2 min THREAT and SAFE blocks; unpredictable shocks (1.8 mA, 50 ms) were delivered to the subject's wrist in THREAT blocks (1-4 shocks per block). The amplitude of the N1/P2 potential increased monotonically as a function of stimulus intensity. The responses were significantly greater during THREAT blocks than during SAFE blocks (fear potentiation). Diazepam attenuated the responses in both the SAFE and THREAT conditions. Fear potentiation of the N1/P2 potential was significantly reduced by diazepam. Diazepam reduced subjective alertness and lowered critical flicker fusion frequency, a measure of arousal. The results suggest that fear potentiation of the N1/P2 potential is not simply a manifestation of the fear-potentiated startle response. The use of low-intensity stimuli may be advantageous in studies of fear potentiation in humans.

Sensitivity of late-latency auditory and somatosensory evoked potentials to threat of electric shock and the sedative drugs diazepam and diphenhydramine in human volunteers.

Late-latency auditory and somatosensory evoked potentials are sensitive to some centrally acting drugs and to certain psychological interventions. In this experiment we compared the effects of acute doses of a benzodiazepine, diazepam and an H(1) histamine receptor-blocking sedative, diphenhydramine, on auditory and somatosensory evoked potentials within the latency range 100-500 ms in a fear conditioning paradigm. Twelve healthy males (18-30 years) participated in three sessions at weekly intervals in which they received diazepam 10mg, diphenhydramine 75 mg and placebo in a balanced, double-blind, crossover protocol. One hundred and twenty min after diphenhydramine or 60 min after diazepam, they underwent an 8 min recording period in which auditory evoked potentials elicited by 40 ms, 95 dB[A], 1 kHz tones, and somatosensory evoked potentials elicited by a mildly painful electric shock (1.8 mA, 50 ms) were recorded at Cz (vertex). Each session consisted of four blocks of trials in which either the sound pulse or the shock was presented. Alternate blocks were designated SAFE or THREAT ('context' conditions); in THREAT blocks subjects were warned that shocks would be delivered via electrodes placed on the wrist (electrodes were removed during SAFE blocks). In one SAFE and one THREAT block, the sound stimuli and shocks (shocks were delivered only in the THREAT block) were preceded by a 2 s conditioned stimulus (CS: a red light) ('cue' condition). Diazepam, but not diphenhydramine, reduced the amplitude of the P2 auditory evoked potential. The THREAT context was associated with increased N1 and reduced N2 potential amplitudes. The CS had no effect on the amplitudes, but markedly reduced the latencies of the N1, P2 and N2 potentials under the THREAT condition. Diazepam reduced the amplitudes of the somatosensory potential evoked by the shock; the CS shortened the latencies of the later components of the response. Diazepam and diphenhydramine were approximately equi-sedative in the doses used in this experiment, as judged by visual analogue self-rating scales. The results indicate that the suppression of late-latency auditory and somatosensory evoked potentials by diazepam is not simply a reflection of sedation. Late-latency evoked potentials can be modified by an aversive CS, but the components that are sensitive to the CS are different from those that are sensitive to diazepam.

Diazepam suppresses the acquisition but not the expression of 'fear-potentiation' of the acoustic startle response in man.

Sudden auditory stimuli elicit a short-latency muscular response (acoustic startle response) which is enhanced during presentation of a Pavlovian conditioned stimulus (CS) that has previously been paired with an aversive unconditioned stimulus (US) ('fear-potentiation'). In rodents, acute treatment with benzodiazepines blocks both the acquisition of fear-potentiation and the expression of fear-potentiation induced by prior exposure to CS/US pairing. We examined the effect of diazepam on the acquisition and expression of fear-potentiation of the acoustic startle response in man. Forty-six male volunteers (18-30 years) participated in two sessions separated by 7 days. In session 1, they were exposed to 20 2-s presentations of a light (CS), 50% of which terminated with an electric shock to the wrist (1.8 mA, 50 ms: US). Somatosensory potentials evoked by the US were recorded from the scalp at Cz, and skin conductance responses from electrodes taped to the second and fourth fingers. In session 2, the CS was presented 20 times without the US; a random 50% of CS presentations terminated with a sound pulse (40-ms 115-dB 1-kHz); an equal number of sound pulses was presented without the CS. Electromyographic responses of the orbicularis oculi muscle to the acoustic stimuli were recorded from electrodes placed on the lower eyelid, late-latency auditory evoked potentials were recorded at Cz, and skin conductance responses from electrodes taped to the second and fourth fingers. In each session, alertness was measured using visual analogue self-rating scales and critical flicker fusion frequency. Subjects received placebo or diazepam 10mg in the two sessions in a double-blind protocol: group 1 (n 12) placebo/placebo; group 2 (n 11) placebo/diazepam; group 3 (n 12) diazepam/placebo; group 4 (n 11) diazepam/diazepam. Diazepam reduced alertness as measured by visual-analogue self-rating scales and critical flicker fusion frequency. In session 1, diazepam reduced the amplitude of the somatosensory potentials and skin conductance responses evoked by the CS. In session 2, the acoustic startle response, the N1/P2 auditory evoked response and the skin conductance response evoked by the sound stimuli were enhanced in the presence of the CS. This fear-potentiation was attenuated in subjects who received diazepam in session 1, but was not affected by the treatment given in session 2. The results indicate that diazepam blocks the acquisition of fear-potentiation of startle responses in man, as in animals, but does not prevent the expression of a previously learned response.

Effects of lorazepam on fear-potentiated startle responses in man.

Sudden intense sensory stimuli elicit a cascade of involuntary responses, including a short-latency skeletal muscular response ('eyeblink startle response') and longer-latency autonomic responses. These responses are enhanced when subjects anticipate an aversive event compared to periods when subjects are resting ('fear potentiation'). It has been reported previously that the anxiolytic diazepam can suppress fear-potentiation of the eyeblink startle response in human volunteers. The present experiment aimed to confirm and extend these observations by examining the effect of another benzodiazepine, lorazepam, on the eyeblink and skin conductance components of the acoustic startle, and on fear-potentiation of these responses. Eighteen male volunteers participated in three weekly sessions in which they received oral treatment with placebo, lorazepam (1 mg) and lorazepam (2 mg), according to a balanced three-period, crossover, double-blind design. Two hours after ingestion of the treatments, electromyographic responses of the orbicularis oculi muscle and skin conductance responses were evoked by sound pulses during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with significant increase in the amplitude of the electromyographic (EMG) and skin conductance responses; there were also increases in baseline skin conductance, the number and amplitude of 'spontaneous' skin conductance fluctuations and self-rated anxiety. Lorazepam attenuated the effect of THREAT on self-rated anxiety and on the amplitude of the EMG response, but had no significant effect on fear-potentiation of the skin conductance responses. These results extend previous findings of the effect of diazepam on the fear-potentiated eyeblink startle response to lorazepam, and suggest that fear-potentiation of the later autonomic component of the startle response may be less sensitive to benzodiazepines than the fear-potentiated eyeblink response and self-rated anxiety.

Effects of quetiapine and haloperidol on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (PPI). Here, we report the effects of the 'atypical' antipsychotic drug quetiapine and the 'conventional' antipsychotic haloperidol on these responses. Sixteen males (aged 19-38 years) participated in four sessions at 7-day intervals, in which they received quetiapine 12.5 mg, quetiapine 25 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 2 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage PPI was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Quetiapine 12.5 mg and 25 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses; haloperidol had no effect on EMG response amplitude or PPI. Neither drug affected N1/P2 amplitude or PPI of this response. Quetiapine, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not quetiapine, elevated serum prolactin level. The ability of quetiapine to attenuate the startle response may reflect its sedative action.

The fear-inhibited light reflex: importance of the anticipation of an aversive event.

RATIONALE: It has been shown previously that the amplitude of the pupillary light reflex response decreases when subjects anticipate an aversive stimulus (i.e. electric shock), compared to periods when subjects are resting ('fear-inhibited light reflex'). OBJECTIVE: To compare the effects of the anticipation of an electric shock (putative aversive event) and of an acoustic stimulus (putative neutral event) on the light reflex. METHODS: Twelve healthy volunteers participated in a training session and an experimental session. Pupil diameter was monitored with infra-red binocular television pupillometry. The experimental session consisted of 14 blocks of 3 light stimuli. 'Relaxation' (no anticipation) and 'anticipation' (electrical or acoustic stimulus) blocks alternated. Mood and feelings were self-rated on visual analogue scales. RESULTS: The anticipation of the electrical stimulus was associated with increases in initial pupil diameter and subjectively rated 'anxiety' and 'alertness', and a decrease in the amplitude of the pupillary light reflex response, whereas anticipation of the acoustic stimulus was associated with increases in initial pupil diameter and subjective 'alertness' only. CONCLUSIONS: The increase in initial pupil diameter is related to the anticipation of any stimulus, whereas the decrease in the amplitude of the light reflex response is associated with the aversiveness of the anticipated stimulus.

Effects of ketanserin and haloperidol on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the serotonin (5-HT)2 receptor antagonist ketanserin and the D2 dopamine receptor blocking antipsychotic drug haloperidol on these responses. Fifteen males (aged 18-35 years) participated in four sessions at 7-day intervals, in which they received ketanserin 20 mg, ketanserin 40 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after ingestion of haloperidol or 1 h after ingestion of ketanserin. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials), and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Ketanserin 40 mg significantly reduced the amplitude of the EMG response and both doses of ketanserin significantly suppressed prepulse inhibition of the response; haloperidol had no effect on EMG response amplitude or prepulse inhibition. Neither drug affected N1/P2 amplitude or prepulse inhibition of this response. Ketanserin, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not ketanserin, elevated serum prolactin level. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The ability of ketanserin to attenuate the startle response may reflect its sedative action, as other drugs with sedative properties have also been found to attenuate the startle response in man. The ability of ketanserin to suppress prepulse inhibition of the startle response is consistent with previous evidence for the involvement of 5-HTergic mechanisms in the regulation of prepulse inhibition in man.

Effects of clonidine and diazepam on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). We examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on prepulse inhibition of these two responses in healthy volunteers. Fifteen males (aged 18-35 years) participated in three sessions in which they received oral doses of placebo, diazepam 10 mg and clonidine 0.2 mg according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory evoked potentials took place 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Sound stimuli (1 kHz) were presented in 60 trials separated by variable intervals (mean 25 s): (i) 40-ms 115-dB ('pulse alone', 20 trials); (ii) 40-ms 85-dB (20 trials); (iii) 40-ms 85-dB, followed after 120 ms by 40-ms 115-dB ('prepulse/pulse', 20 trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. The amplitude of the EMG response was significantly reduced both by diazepam and by clonidine; neither drug significantly altered prepulse inhibition of the EMG response. Diazepam, but not clonidine, significantly reduced the amplitude of the N1/P2 potential; neither drug significantly affected prepulse inhibition of the N1/P2 potential. Both drugs reduced self-rated alertness and anxiety, and systolic blood pressure; clonidine, but not diazepam reduced diastolic blood pressure and salivation. The results confirm previous findings that sedative drugs can suppress the startle response without affecting prepulse inhibition of this response, and provide new information on the effects of these drugs on the N1/P2 potential and its inhibition by prepulses.

Effects of haloperidol and clozapine on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the 'conventional' antipsychotic drug haloperidol and the 'atypical' antipsychotic clozapine on these responses. Fifteen males (aged 19-54 years) participated in four sessions at 7-day intervals, in which they received clozapine 3 mg, clozapine 6 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Clozapine 6 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses. Clozapine 6 mg did not affect the amplitude of the N1/P2 potential, but significantly attenuated prepulse inhibition of that response. Clozapine 3 mg and haloperidol had no significant effect on either response. Clozapine 3 mg and 6 mg, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Clozapine 6 mg reduced salivation. Haloperidol, but not clozapine, elevated serum prolactin levels. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The abililty of clozapine to attenuate the startle response may reflect its sedative action. The basis of the abililty of clozapine to suppress prepulse inhibition of the N1/P2 potential remains uncertain.

Effects of acute tryptophan depletion on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked response in man.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effect of acute tryptophan depletion on prepulse inhibition of these responses. Thirteen males (21-52 years) participated in two sessions separated by 7 days, in which they ingested a drink containing a mixture of amino-acids, which either included (+ TP) or did not include (- TP) tryptophan, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 6 h after ingestion of the mixture. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Plasma tryptophan levels were measured from blood samples taken before and 7 h after each treatment. Under the + TP condition, both the EMG response and the N1/P2 complex showed > 60% prepulse inhibition. The - TP condition was associated with (i) significant suppression of prepulse inhibition of the EMG response, with no significant change in response amplitude and (ii) reduction of the amplitude of the N1/P2 potential, with no significant change in prepulse inhibition of this response. Tryptophan levels rose by 90+/-15% under the + TP condition and fell by 81+/-3% under the - TP condition. The suppression of prepulse inhibition of the acoustic startle response under the - TP condition suggests that central 5-hydroxytryptaminergic mechanisms may be involved in regulating prepulse inhibition of this response. The lack of effect of tryptophan depletion on prepulse inhibition of the N1/P2 potential suggests that different mechanisms are involved in prepulse inhibition of the startle response and the N1/P2 complex.

Comparison of the effects of diazepam on the fear-potentiated startle reflex and the fear-inhibited light reflex in man.

It has been shown previously that the amplitude of the acoustic startle reflex is enhanced, and the amplitude of the light reflex reduced, when subjects anticipate an aversive event, compared to periods when subjects are resting ('fear-potentiated startle reflex' and 'fear-inhibited light reflex'). We examined whether the anxiolytic diazepam would reverse the effects of threat on the startle and pupillary reflexes. Twelve male volunteers participated in three weekly sessions in which they received oral treatment with placebo, diazepam 5 mg and diazepam 10 mg, according to a balanced crossover double-blind design. One hour after ingestion of the treatments, miotic responses to light pulses and electromyographic responses of the orbicularis oculi muscle to sound pulses were elicited during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with a significant increase in the amplitude of the electromyographic (EMG) response, a significant reduction of the miotic response amplitude, and an increase in self-rated anxiety. Diazepam attenuated all these effects of THREAT. Diazepam did not affect the amplitude of the miotic response under the SAFE condition, but did suppress the EMG response under this condition. These results confirm the validity of the fear-potentiated startle reflex and fear-inhibited light reflex as laboratory models of human anxiety, and reveal some differences between the effects of diazepam on the two reflexes.

Effects of bromocriptine and haloperidol on prepulse inhibition: comparison of the acoustic startle eyeblink response and the N1/P2 auditory-evoked response in man.

Experiments with animals have shown that D2 dopamine receptors are involved in regulating prepulse inhibition (PPI) of the acoustic startle reflex (suppression of the reflex response evoked by a loud sound by prior presentation of a low-intensity stimulus). Recently we found that PPI of the human eyeblink startle response could be suppressed by a D2 receptor agonist, bromocriptine, and that this suppression could be reversed by a D2 receptor-blocking neuroleptic, haloperidol. The present work attempted to replicate this finding and to extend it to PPI of the N1/P2 component of the auditory-evoked potential. Eleven healthy males (18-30 years) participated in four sessions in which they received oral doses of placebo, bromocriptine 1.25 mg, haloperidol 3mg and combined treatment with bromocriptine 1.25 mg + haloperidol 3 mg, according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory-evoked potentials took place 120 min after ingestion of haloperidol and/or 90 min after ingestion of bromocriptine. Sound stimuli (1-kHz) were presented in 60 trials separated by variable intervals (mean 25 sec): (i) 40 msec 115 dB ('pulse alone': 20 trials); (ii) 40 msec 85 dB (20 trials); (iii) 40 msec 85 dB, followed after 120 msec by 40 msec 115 dB ('prepulse/ pulse': 20 trials). The amplitudes of the EMG and N1/P2 responses were not altered significantly by any of the treatments. Bromocriptine attenuated PPI of the EMG response significantly, this attenuation being absent following combined haloperidol/bromocriptine treatment. Neither bromocriptine nor haloperidol significantly altered PPI of the N1/P2 complex. Bromocriptine suppressed and haloperidol elevated serum prolactin levels, these changes being absent when the two drugs were given in combination. The results suggest that different mechanisms may be involved in regulating PPI of the eyeblink and the N1/P2 component of the auditory-evoked potential, and that D2 receptors may be involved in the former case, but not the latter.

Effects of bromocriptine and haloperidol on prepulse inhibition of the acoustic startle response in man.

Experiments with animals have shown that D2 dopamine (DA) receptors are involved in prepulse inhibition of the acoustic startle reflex (suppression of the reflex response evoked by a loud sound by prior presentation of a low-intensity stimulus). The present experiment attempted to extend this observation to man. Twelve healthy males (18-30 years), screened for normal hearing thresholds, participated in four sessions in which they received oral doses of placebo, bromocriptine 1.25 mg (a D2 receptor agonist), haloperidol 3 mg (a D2 receptor antagonist) and combined treatment with bromocriptine 1.25 mg+haloperidol 3 mg, according to a balanced double-blind protocol. Thirty-minute electromyographic recordings from the orbicularis oculi muscle of the right eye were carried out 120 min after ingestion of haloperidol and/or 90 min after ingestion of bromocriptine. Subjects received 36 40-msec sound pulses (115 dB), separated by variable intervals (mean 25 sec); in 24 of the trials the pulse was preceded by a 40-msec prepulse (75 dB in 12 trials and 85 dB in 12 trials; prepulse-pulse interval, 120 msec). The amplitude of the startle response was not significantly altered by any of the active treatments. Under the placebo condition, both 75- and 85-dB prepulses inhibited the startle response. Bromocriptine significantly attenuated this prepulse inhibition; haloperidol also produced a small but statistically significant attenuation of prepulse inhibition. Haloperidol significantly antagonized the attenuation of prepulse inhibition produced by bromocriptine. Neither drug altered self-rated alertness, physiological finger tremor, systolic or diastolic blood pressure or salivation. Bromocriptine significantly suppressed and haloperidol significantly elevated serum prolactin levels, these changes being absent when the two drugs were given in combination. The results provide evidence for the involvement of D2 DA receptors in prepulse inhibition of the startle reflex in man.

Effects of clonidine and diazepam on the acoustic startle response and on its inhibition by 'prepulses' in man.

This experiment examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on the eyeblink component of the acoustic startle response in healthy volunteers. Twelve males (18-30 years), screened for normal hearing thresholds, participated in three sessions in which they received oral doses of placebo, diazepam 10mg and clonidine 200 microg according to a balanced double-blind protocol. Thirty-minute electromyographic recordings from the orbicularis oculi muscle of the right eye were carried out 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Subjects received 36 40-msec sound pulses (115 dB), separated by variable intervals (mean 25 sec); in 24 of the trials the pulse was preceded by a 40-msec prepulse (75 dB in 12 trials and 85 dB in 12 trials; prepulse-pulse interval, 120 msec). The amplitude of the startle response was significantly reduced both by diazepam (mean+/-SEM: -43.9+/-7.4%) and by clonidine (-75.7+/-4.7%). Under the placebo condition, the 75 and 85dB prepulses inhibited the startle response by 38.6+/-6.5 and 70.3+/-2.9%, respectively. Neither drug significantly altered the degree of prepulse inhibition. Both drugs reduced self-rated alertness; clonidine reduced systolic blood pressure and salivation. The results confirm the suppressant effect of clonidine on the startle response and show a qualitatively similar effect of diazepam; the results also demonstrate the insensitivity of prepulse inhibition of the startle response to doses of sedative drugs that are sufficient to attenuate the startle response itself.