Dopaminergic stimulation disrupts sensorimotor gating in the rat

Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125–4.0 mg/kg) and d-amphetamine (0.5–4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.     

D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia

The amplitude of the acoustic startle response is decreased if the startle stimulus is preceded by a nonstartle eliciting stimulus. This sensorimotor gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the dopamine agonist apomorphine disrupts prepulse inhibition and this disruption is reversed by classical and atypical antipsychotics. Furthermore, the ability of antipsychotics to reverse the apomorphine disruption is correlated with clinical potency and D₂ receptor affinity. In the present study, the role of the D₁ receptor in prepulse inhibition of the acoustic startle response was studied; the effects of the D₁ receptor antagonist SCH 23390 were examined and compared to the effects of the D₂ receptor antagonist eticlopride. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB noise bursts presented alone or preceded by a 75 dB noise burst. Trials consisting of no stimulus and the 75 dB prepulse stimulus alone were also included. These six trial types (ten each) were randomly presented within a 35-min session. Rats treated with 2.0 mg/kg apomorphine (SC) demonstrated a significant disruption of prepulse inhibition compared to vehicle controls. Pretreatment with the D₁ antagonist SCH 23390 (0.01, 0.05, 0.1 mg/kg SC) or the D₂ antagonist eticlopride (0.01, 0.05, 0.1 mg/kg SC) attenuated the disruptive effects of apomorphine. These results indicate that selective blockade of either the D₁ or D₂ receptor subtype is sufficient in reversing the sensorimotor gating deficits produced by apomorphine. The effects of eticlopride and SCH 23390 on prepulse inhibition in saline-treated rats were also examined. Each antagonist produced a dose-related facilitation of prepulse inhibition, suggesting that endogenous DA acting at either receptor subtype plays a role in the tonic modulation of sensorimotor gating.     

Cocaine: Excitatory effects on sensorimotor reactivity measured with acoustic startle

Cocaine (2.5–10 mg/kg) caused a dose-related increase in the amplitude of the acoustic startle reflex in rats. In contrast, procaine (5–40 mg/kg) caused a dose-related decrease in startle, indicating that the effects of cocaine could not be ascribed to its local anesthetic effects. Cocaine's excitatory effects were blocked by pretreatment with haloperidol (0.5 mg/kg) but not by cyproheptadine or prazosin. The excitatory effects of cocaine (10 mg/kg) were markedly attenuated by pretreatment with reserpine (5 mg/kg 24 and 18 h earlier) but not by -methyl-p-tyrosine (100 mg/kg 1 h earlier). In contrast, comparably sized excitatory effects of d-amphetamine were blocked by -methyl-p-tyrosine and greatly enhanced by pretreatment with reserpine. Neither pretreatment blocked excitatory effects of apomorphine on startle. The data indicate that cocaine increases startle by acting through reserpine-sensitive pools of dopamine and provide further support for the conclusion that acoustic startle is enhanced by activation of dopamine receptors.     

Effects of d- and l-amphetamine on habituation and sensitization of the acoustic startle response in rats

In a series of 3 experiments the effects of 2, 4, 8, or 16 mg/kg d-amphetamine and 4, 8, 16, or 32 mg/kg l-amphetamine on acoustic startle amplitude in the rat were investigated. d-Amphetamine was 4–5 times as potent as l-amphetamine in augmenting startle amplitude. Startle potentiation was associated with vigorous stereotypies but the resultant cage movement could not account for the change in startle. Pretreatment with -methyl-p-tyrosine (100 mg/kg, 1 hr before) had only a slight depressant effect on startle but essentially eliminated augmentation of startle by either d-amphetamine (8 mg/kg) or l-amphetamine (32 mg/kg). d-Amphetamine did not have a direct effect on startle but instead enhanced sensitization produced by the startle stimuli without altering sensitization produced by background white noise or habituation. The results suggest that startle sensitization is enhanced by increased availability of catecholamines and, by virtue of the different potencies of the d- and l-isomers, that dopamine and norepinephrine may affect startle differently.     

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.     

PHNO, a selective dopamine D2 receptor agonist, does not reduce prepulse inhibition of the startle reflex in rats

RATIONALE: Dopamine agonists nonselective for dopamine receptor subtypes, such as apomorphine, reduce prepulse inhibition of the startle reflex. It has been suggested that either D2 or D3 dopamine receptors mediate this action of apomorphine. OBJECTIVE: The present study investigated whether a selective D2 agonist with relatively low affinity for D3 receptors can reduce prepulse inhibition. METHODS: Rats (n=48) were treated with vehicle or one of three doses ( 15, 30 or 60 microg/kg, s.c.) of the specific dopamine D2 receptor agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) for 11 days. On days 1, 6 and 11 of treatment, the rats (n=12 in each group) were tested for their acoustic startle reflexes (105-dB, 40-ms white noise) and for prepulse inhibition (5-kHz tone, 5 dB above a 65 dB background white noise). Prepulses were presented with a range of stimulus onset asynchronies (SOAs: 5-160 ms) or lead times between the onset of the prepulse and the onset of the startle stimulus. In a second experiment, two groups of rats (n=10 in each group) were tested in a similar manner after vehicle or apomorphine (0.8 mg/kg, s.c.) to verify the sensitivity of the present procedure to agonist-induced reductions in prepulse inhibition. RESULTS: At doses that increased motor activity, PHNO increased prepulse inhibition at SOAs less than 80 ms and had no effect on prepulse inhibition at SOAs of 80 ms or above. However, all doses decreased startle amplitudes on trials in which only the startle-eliciting stimulus was presented. Apomorphine reduced prepulse inhibition under the same conditions. CONCLUSIONS: These findings with PHNO are in contrast to the less-specific D2 agonist, quinpirole, which has been reported to decrease prepulse inhibition. It is concluded that activation of D2 dopamine receptors alone is not sufficient to attenuate prepulse inhibition of the startle reflex.     

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats

 This study assessed whether repeated injections of d-amphetamine or apomorphine could induce sensitization to the disruptive effects of these psychomotor stimulants on sensorimotor gating in rats. In the first experiment, rats were given six pre-exposures to either 2.0 mg/kg d-amphetamine or saline before being tested for the effects of d-amphetamine (0.0, 0.5, 1.0, 2.0 or 4.0 mg/kg, IP) on prepulse inhibition of acoustic startle (PPI) and locomotor activity. The tests for PPI confirmed that sensorimotor gating could be disrupted by a high dose of d-amphetamine (4.0 mg/kg). However, comparison of the dose-response curves for the drug and saline pre-exposed groups did not reveal evidence for sensitization to this d-amphetamine effect in drug-pre-exposed rats, despite indications that sensitization had developed to the locomotor stimulant effects of d-amphetamine. A similar pattern of results was obtained in a second experiment that examined the effects of apomorphine (0.0, 0.1, 0.2, 0.4 and 0.8 mg/kg, SC) on PPI and locomotion in rats pre-exposed to 2.0 mg/kg of this drug or its vehicle. These findings demonstrate that treatments which induce sensitization to the behavioral activating effects of psychomotor stimulants do not necessarily produce sensitization to the disruptive effects of stimulants on sensorimotor gating. The implications of these results for hypotheses linking sensitization-like processes to the etiology of schizophrenia are discussed. Received: 15 May 1997/Final version: 7 July 1997     

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.     

Effects of scopolamine in comparison with apomorphine and phencyclidine on prepulse inhibition in rats

The potential involvement of the muscarinic cholinergic system in the underlying mechanisms of prepulse inhibition of the acoustic startle reflex was evaluated in male Sprague-Dawley rats under conditions of varying dose, prepulse intensity, and interstimulus interval. The effects of scopolamine on prepulse inhibition were also directly compared with the effects observed using apomorphine and phencyclidine under the same test parameters. Scopolamine (0. 03-1.0 mg/kg) produced a significant dose-dependent decrease in prepulse inhibition, but had no effect on startle amplitude over the dose range tested. Apomorphine (0.03-1.0 mg/kg) and phencyclidine (0. 1-5.6 mg/kg) produced significant dose-dependent decreases in prepulse inhibition and changes in startle amplitude. The scopolamine-induced decrease in prepulse inhibition varied with prepulse intensity in that the changes produced by scopolamine became smaller in magnitude as the prepulse intensity was increased from 9 to 30 dB above background. On the other hand, apomorphine and phencyclidine decreased prepulse inhibition to approximately the same magnitude across all prepulse intensities tested. The observed decreases in prepulse inhibition produced by scopolamine, apomorphine, and phencyclidine were also dependent on interstimulus interval duration. Scopolamine produced marked decreases in prepulse inhibition at the 100- and 300-ms interstimulus interval durations, but had little or no effect on prepulse inhibition at the 30- and 1000-ms interstimulus interval durations. In contrast, apomorphine decreased prepulse inhibition across all interstimulus interval durations while phencyclidine decreased prepulse inhibition across the 30- to 300-ms interstimulus interval durations. The present findings support the hypothesis that the muscarinic cholinergic system, like the dopaminergic and glutamatergic systems, is directly involved in the mechanisms of prepulse inhibition. However, these three neurotransmitter systems appear to modulate different aspects of prepulse inhibition.     

Effects of d-amphetamine and apomorphine in a new animal model of petit mal epilepsy

d-Amphetamine is effective in controlling seizures in petit mal epilepsy. The flash-evoked afterdischarge (FEAD) in rats has been proposed as a model of the petit mal seizure. The experiments reported here investigated the dose response relationship for the suppression of FEAD by d-amphetamine, and compared its effects with those of the dopamine-mimetic, apomorphine. Significant suppression of FEAD was observed at doses of d-amphetamine greater than 0.2 mg/kg. A maximum decrease of 60% occurred at 1.2 mg/kg. Higher doses did not result in any further suppression. In contrast, apomorphine had no effect on the FEAD event at doses that induced intense stereotypic behavior. In other experiments, administration of either the dopamine antagonist pimozide or the -adrenergic antagonist phenoxybenzamine exacerbated FEAD and also prevented the suppression of FEAD by d-amphetamine. The results of these experiments support the hypothesis that the FEAD is a valid model of the petit mal seizure. Furthermore, they provide evidence that norepinephrine is necessary for the seizuresuppressant action of d-amphetamine.     

Effects of cannabinoid receptor ligands on psychosis-relevant behavior models in the rat

Abstract Rationale. Marijuana is known to have psychotropic effects in humans. In this study, we used rat models of sensorimotor gating, hyperactivity and stereotypy to explore whether CB₁ receptor stimulation or blockade induces behavioral changes consistent with psychotomimetic or antipsychotic agents, respectively. Objectives. We determined whether (a) the cannabinoid agonist CP 55940 decreased pre-pulse inhibition (PPI) as might be expected from a psychotomimetic agent, and (b) the selective CB₁ receptor antagonist, SR 141716A, had any effect on PPI on its own or following disruptions by psychotomimetic agents. In addition, we investigated the effects of SR 141716A on elevated levels of hyperactivity and stereotypy elicited by d-amphetamine. Methods. These studies were conducted in rats using standard methodologies for determination of PPI following acoustic stimuli, and d-amphetamine-induced hyperactivity and stereotypies. Results. Decreased startle responses to 120 dB stimuli were observed in rats treated with CP 55940 (0.1 mg/kg IP) in the absence and presence of a 73 dB pre-pulse. These effects were reversed by SR 141716A (5 and 10 mg/kg, respectively). SR 141716A (0.1, 5, 10 mg/kg) had no effect on PPI on its own or following disruptions by apomorphine, d-amphetamine or MK-801. Conversely, in separate experiments different antipsychotic agents reversed disruptions in PPI induced by d-amphetamine (haloperidol), apomorphine (haloperidol or clozapine) or MK-801 (clozapine or olanzapine). In addition, unlike haloperidol, SR 141716A (5 mg/kg) did not reverse d-amphetamine-mediated increases in hyperactivity or stereotypy. Conclusions. The CP 55940-mediated decreases in startle amplitude confound assessment of the effects of CB₁ receptor activation on PPI. The failure of SR 141716A to reverse disruptions in PPI, hyperactivity or stereotypy induced by non-cannabinoid psychotomimetic agents suggests that blockade of the CB₁ receptor on its own is not sufficient for antipsychotic therapy. Electronic Publication     

5-HT6 receptor antagonist reversal of emotional learning and prepulse inhibition deficits induced by apomorphine or scopolamine

5-HT6 receptors have been implicated in consolidation of visuospatial and reward-based learning tasks. Since 5-HT6 receptors may be important in modulation of sensory gating which is often affected in schizophrenic patients, we tested whether Ro 4368554, a 5-HT6 selective antagonist at a dose of 10 mg/kg, could reverse the loss of prepulse inhibition from apomorphine or scopolamine. In addition, we also tested whether Ro 4368554 altered fear conditioning using fear potentiated startle, a model for emotional learning. Prepulse inhibition of startle was disrupted by apomorphine (0.5 mg/kg) when prepulse emissions were 5 dB above background but not above 15 dB, while scopolamine (0.5 mg/kg) caused disruption at both prepulse levels. Scopolamine-mediated disruption was not reversed by Ro 4368854 but apomorphine-mediated disruption was significantly ameliorated by 5-HT6 inhibition. For fear potentiated startle, scopolamine and/or Ro 4368554 were administered before two daily fear conditioning sessions; rats were tested on the following day. Rats that received scopolamine displayed no fear potentiated startle but Ro 4368554 reversed this scopolamine deficit. Additionally, we mapped Fos induction in rats treated with scopolamine and/or Ro 4368554; scopolamine increased Fos expression in the central nucleus of the amygdala and this was attenuated by Ro 4368554. In summary, we have demonstrated the efficacy of 5-HT6 antagonists in modulating sensory gating and fear conditioning, and thus may be of therapeutic use for schizophrenia-related disorders.     

Both corticotropin-releasing factor and apomorphine reduce prepulse inhibition following repeated central infusion of corticotropin-releasing factor

The neuropeptide, corticotropin-releasing factor (CRF) has been shown to disrupt prepulse inhibition of the acoustic startle response in rodents. Prepulse inhibition is deficient in a number of psychiatric disorders. In Experiment 1, we examined whether repeated central infusion of CRF alters the reduction in prepulse inhibition caused by subsequent CRF infusion or apomorphine injection. Repeated intracerebroventricular infusion of CRF (0.3 micro g) did not cause tolerance to the effect of CRF on prepulse inhibition. Additionally, repeated CRF did not alter the effect of apomorphine (0.25 mg/kg, i.p.) on prepulse inhibition. In contrast to other reported results, both CRF and apomorphine reduced baseline startle amplitude in the Brown Norway rats, which show low prepulse inhibition. In Experiment 2, we showed that a CRF-induced change in baseline startle amplitude does not contribute to the CRF-induced decrease in percent prepulse inhibition. In Experiment 3, we found that methylphenidate (20.0 mg/kg, i.p.) increased baseline startle amplitude in Brown Norway rats, yet it also decreased percent prepulse inhibition. These results suggest that CRF can be administered repeatedly without diminution of its effects on prepulse inhibition, and that in Brown Norway rats, compounds that either increase or decrease baseline startle amplitude can reduce percent prepulse inhibition independently of the effects on baseline startle.     

α1- and α2-Adrenoreceptor antagonists differentially influence locomotor and stereotyped behaviour induced byd-amphetamine and apomorphine in the rat

The importance of dopamine (DA) in mediating locomotor, exploratory and stereotyped behaviour in rodents is well established. Evidence also indicates a modulatory role for noradrenaline (NA) although, due to non-specificity of previously available agents, a precise role remains undefined. The effects of the specific and selective -adrenoreceptor antagonists idazoxan (₂) and prazosin (₁) on behaviour induced by amphetamine and apomorphine have been investigated in the rat.d-Amphetamine (2 mg/kg) induced hyperactive locomotion and exploration. Pretreatment with prazosin (1 mg/kg) markedly reduced these responses. In contrast, pretreatment with idazoxan (20 mg/kg) only marginally alteredd-amphetamine hyperactivity. Apomorphine (0.5 mg/kg) induced biphasic locomotor and exploratory activity. Neither -antagonist affected the initial burst of activity (60 min), although prazosin inhibited whereas idazoxan potentiated the secondary phase (90–180 min). At higher dosage, amphetamine (6 mg/kg) and apomorphine (2 mg/kg) induced stereotyped behaviours. Prazosin pretreatment enhanced stereotyped gnawing and decreased sniffing and locomotion, whereas idazoxan increased locomotion and decreased amphetamine-induced mouth movements. These data indicate that DA-induced locomotor and stereotyped behaviours are differentially influenced (in opposite directions) by both ₁- and ₂-adrenoreceptor antagonists. NA may thus modulate the expression and character of behaviour by influencing DA function in certain brain areas.     

Does sensitization occur to prepulse inhibition of the startle reflex effects of repeated apomorphine treatments in rats?

There are conflicting reports as to whether or not the effects of dopamine agonist effects at reducing prepulse inhibition of the acoustic startle reflex develop sensitization with repeated treatments. In this experiment, rats (12 per each dose group) were treated for 10 days prior to startle-testing on each day with 0 (vehicle), 50, 200 or 800 microg/kg of apomorphine. Startle testing was conducted with each rat receiving no stimulus trials (null trials), startle pulse only trials (40 ms 105 dB white noise), prepulse only trials (20 ms 72 dB 5 kHz tone) and prepulse+pulse trials with a 100 ms stimulus onset asynchrony (SOA, i.e. the lead time from onset of prepulse to onset of pulse). The rats were then challenged after 5-7 days of withdrawal from the treatment regimen with a vehicle and apomorphine (200 microg/kg) injection with the order of injection counterbalanced. A range of SOAs and two different prepulse intensities (68 and 70 dB) were presented to every rat on the challenge tests. Sensitization developed during treatment to the increase in motor activity produced by the two higher doses, and to the increase in an orienting response produced by the prepulse stimulus in the highest dose group, but not to the prepulse inhibition effect of the drugs. The 50 microg/kg inhibitory autoreceptor selective dose decreased responses on the first of three blocks of both null trials and prepulse only trials. The two higher doses dose-dependently increased startle reflex amplitudes on the prepulse+pulse trials (reduced prepulse inhibition), but this effect did not exhibit sensitization during treatment. The lowest dose significantly increased prepulse inhibition relative to the vehicle-treated group on the first block of trials over days. After apomorphine challenge, sensitization to the effects of apomorphine on reducing prepulse inhibition was apparent for some dose groups at some SOAs. Sensitization to the effects of apomorphine on prepulse inhibition can be demonstrated upon a subsequent drug challenge if pretreatments are associated exclusively with the startle testing environment.     

Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor

Rationale Prepulse inhibition (PPI) represents a normal sensorimotor gating response that is typically impaired in schizophrenic patients. It is known that cannabinoid CB1 agonists reduce sensorimotor gating in rats, suggesting that the CB1 receptor and the cannabinoid system are involved in sensorimotor gating.Objective The objective was to study the effects of AM404, an anandamide reuptake and degradation inhibitor, on PPI and startle response in Swiss mice.Methods AM404 was injected either acutely (0, 2.5 and 5 mg/kg i.p.) or chronically (5 mg/kg daily, 7 days). The PPI protocol was based on standard methodologies using acoustic stimuli (pulse 120 dB; prepulses 70 dB and 80 dB). SR141716A, a CB1 antagonist, was employed for further confirmation of the involvement of CB1 receptors.Results Acute AM404 (5 mg/kg) disrupted PPI (70-dB prepulse, P<0.05) and enhanced the startle response after the 2.5-mg/kg dose (P<0.01). Chronic AM404 disrupted PPI after both 70-dB (P<0.01) and 80-dB prepulses (P<0.05). These effects were blocked after SR141716A cotreatment.Conclusions The data indicate that AM404 (5 mg/kg) acts as a psychodysleptic, altering PPI through stimulation of cannabinoid CB1 receptors, pointing to a possible psychosis-like state after enhancement of anandamide bioavailability. The startle response was enhanced only following a lower AM404 dose (2.5 mg/kg), indicating that AM404 induced hyperreactivity at a dose that did not affect PPI, further reinforcing a selective disruption of PPI.     

Genetics, haloperidol-induced catalepsy and haloperidol-induced changes in acoustic startle and prepulse inhibition

The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the effects of haloperidol on the ASR and PPI were examined in C57BL/6J (B6) and DBA/2 (D2) inbred mouse strains and their F₁ and F₂ progeny. The startle stimulus was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms white noise bursts at 56, 68 and 80 dB against a 50-dB background presented 100-ms before the startle pulse. The B6 strain showed modest PPI (25–40%); in contrast, the D2 strain showed on average no PPI and numerous individuals showed prepulse augmentation (PPA). The F₂ progeny showed an intermediate PPI; however, the extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol in dose-dependent fashion, increased PPI in both the B6 and D2 strains; the threshold dose was in the range of 0.1–0.2 mg/kg. Raclopride (0.3 mg/kg), clozapine (2 mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The effects of haloperidol (0.4 mg/kg) on PPI in 140 F₂ progeny were examined. For all prepulse intensities, there were highly significant (r > 0.80) and negative correlations between baseline PPI and the haloperidol-induced change in PPI. Thus, those animals that showed the greatest PPA showed the greatest haloperidol-induced increase in PPI. There was, however, significant variance in the haloperidol response; plots of the regression residuals showed the most and least responsive animals differed by almost 100% in effect on PPI. The F₂ progeny were subsequently phenotyped for haloperidol-induced catalepsy. There was no association between the variation in effects on catalepsy and PPI. However, it was observed that those individuals with the poorest baseline PPI were catalepsy non-responsive. Received: 11 February 1997 /Final version: 20 May 1997     

Effects of mood stabilizers on the disruption of prepulse inhibition induced by apomorphine or dizocilpine in mice

The prepulse inhibition of the startle response provides an operational measure of sensorimotor gating in which a weak stimulus presented prior to a startling stimulus reduces the startle response. Prepulse inhibition deficits were observed in patients with several neuropsychiatric disorders, including schizophrenia and acute manic bipolar patients. Valproic acid, carbamazepine and lithium carbonate are frequently used as mood stabilizers in patients with bipolar affective disorder and schizophrenia. However, little is known about the mechanisms of action of mood stabilizers on prepulse inhibition deficits. In this study, we investigated the effects of mood stabilizers on the disruption of prepulse inhibition of the acoustic startle response induced by either apomorphine or dizocilpine in mice. Valproate (30-300 mg/kg, i.p.), carbamazepine (3-30 mg/kg, i.p.) and lithium carbonate (10-100 mg/kg, p.o.) had any effect on prepulse inhibition by itself. Valproate, carbamazepine and lithium carbonate reversed the disruption of prepulse inhibition induced by apomorphine (1 mg/kg, s.c.). Although valproate and carbamazepine had no effect on the disruption of prepulse inhibition induced by dizocilpine (0.3 mg/kg, s.c.), lithium carbonate exacerbated the dizocilpine-induced disruption. These results suggest that valproate, carbamazepine and lithium carbonate reverse the disruption of prepulse inhibition through the dopaminergic system.     

5-HT modulation of auditory and visual sensorimotor gating: I. Effects of 5-HT releasers on sound and light prepulse inhibition in Wistar rats

Increasing evidence suggests an important role for serotonin (5-HT) neurons in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study assessed the general role of 5-HT in modulating auditory and visual prepulse inhibition in Wistar rats. A general overactivation of central serotonerigic pathways was produced pharmacologically by four different agents which all shared the common property of releasing 5-HT, i.e.,p-chloroamphetamine, 3,4-methylenedioxymethamphetamine,N-ethyl-3,4-methylenedioxymethamphetamine, or fenfluramine. Within each test session, both sound and light prepulses were used to obtain a cross-modal assessment of auditory and visual sensory gating processes. All four 5-HT releasing agents produced dose-related disruptions of auditory and visual prepulse inhibition, withp-chloroamphetamine being the most potent. The releasers depressed baseline to varying degrees. The ₂-adrenergic agonist clonidine decreased baseline startle without substantially disrupting prepulse inhibition, demonstrating that the two effects were dissociable. Using fenfluramine as the most selective 5-HT releaser, two approaches were used to demonstrate 5-HT mediation of its disruptive effect on prepulse inhibition. In the first approach, the selective 5-HT uptake blocker MDL 28,618A was used to prevent fenfluramine-induced 5-HT release. In the second approach, prior exposure to a neurotoxic dose ofp-chloroamphetamine (10 mg/kg) was used to produce a substantial, sustained depletion of cortical 5-HT, presumably reflecting the loss of 5-HT terminals. Both approaches reduced the disruptive effect of fenfluramine on auditory and visual prepulse inhibition, thereby demonstrating 5-HT mediation of these effects. Neither manipulation significantly affected the depressant effect of fenfluramine on startle baseline, demonstrating that the baseline-reducing and prepulse inhibition-reducing effects of fenfluramine could be dissociated. MDL 28,618A alone did not affect prepulse inhibition or basal startle levels, demonstrating an important functional difference between pharmacologically induced 5-HT uptake blockade and 5-HT release. In summary, these data indicate that serotonergic overactivation can disrupt auditory and visual sensorimotor gating as measured using sound and light prepulse inhibition in rats. These data support a potential role of excessive 5-HT activity as a contributing factor to disrupted sensory gating processes seen in schizophrenia and possibly other neuropsychiatric disorders.     

Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats

Rationale Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity.Objective The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague–Dawley rats.Materials and methods The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus).Results Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects.Conclusion These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating.