Disruption Of Prepulse Inhibition In Rats Research Articles

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

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

Effects of antipsychotics and selective D 3 antagonists on PPI deficits induced by PD 128907 and apomorphine

Rats treated with apomorphine and amphetamine display sensorimotor gating impairments, as measured by prepulse inhibition (PPI), and these impairments can be reversed by antipsychotic treatment. However, it remains unknown whether the dopamine (DA) D 3 receptor plays a role in mediating these effects on PPI, as none of these DA agonists or antipsychotics are exclusively selective at either D 2 or D 3 receptors. To address this question, the current study was designed to investigate whether antipsychotic drugs and selective D 3 antagonists could block the PPI-disruptive effects of PD 128907 (a preferential D 3 agonist) and apomorphine. We found that the effect of PD 128907 on PPI in rats could be antagonized by risperidone, clozapine, and the selective D 3 antagonists SB 277011 and A-691990, but not by raclopride or haloperidol, while the apomorphine-induced PPI deficit could be reversed by risperidone, clozapine and haloperidol, but not by SB 2770111 and A-691990. These results suggest that the D 3 receptor does not mediate apomorphine-induced disruption of PPI in rats, however, given the findings that PD 128907 elicited a PPI-disruptive effect that was blocked by selective D 3 antagonists, a role of D 3 receptor in mediating PPI in rats cannot be ruled out. The possible mechanisms of D 3 receptor involvement in PPI are discussed.

Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by d-amphetamine

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool for validation of a pig model of psychosis, we wished to verify the existence of PPI in landrace pigs and investigate the potential disruption of PPI by d-amphetamine (AMPH) in these animals. PPI of the acoustic startle reflex and its potential disruption by AMPH were investigated using three doses 0.5–1.5 mg/kg with a paradigm including two levels of prepulses (82 and 88 dB) and a prepulse (PP) interval of 60 and 120 ms. We found an average PPI of the startle reflex of 25.6% and both of the investigated PP intensities and PP intervals were equally effective in this PP-inhibitive paradigm. AMPH significantly disrupted PPI and, in spite of only the 0.5 mg/kg dose proved statistically significant, the results indicate this to be dose-related. We have demonstrated the phenomenon of PPI of the startle reflex in landrace pigs and its disruption by d-amphetamine. Studies of sensorimotor gating defects could be a valuable additional tool in assessing pig models of neuropsychiatric disorders.

Effects of σ 1 receptor ligand, MS-377 on apomorphine- or phencyclidine-induced disruption of prepulse inhibition of acoustic startle in rats

To evaluate the antipsychotic property of a σ 1 receptor ligand, ( R)-(+)-1-(4-chlorophenyl)-3-{4-(2-methoxyethyl)piperazin-1-yl}methyl-2-pyrrolidinone- l-tartrate (MS-377), an antagonistic effect of MS-377 on the disruption of prepulse inhibition (PPI) of the acoustic startle by apomorphine or phencyclidine (PCP) was investigated in rats. MS-377 antagonized the PCP-induced disruption of PPI. The ED 50 value of MS-377 for this effect was 0.66 mg/kg. In contrast, apomorphine-induced disruption of PPI was not attenuated by MS-377. These data indicate that the PCP-induced disruption of PPI in rats would be, at least partially, mediated by σ receptors and MS-377 could be a novel anti-psychotic agent with clinical efficacy for the sensorimotor-gating deficit in schizophrenia.

The Effects of M100907 in Pharmacological and Developmental Animal Models of Prepulse Inhibition Deficits in Schizophrenia

Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of the startle response. M100907, a selective 5-HT2A-receptor antagonist that has been developed for clinical testing as an antipsychotic in schizophrenic patients, has been tested in several animal models of the gating deficits in schizophrenia, including PPI. Previous studies have shown that M100907 blocks or reduces the disruptive effects of hallucinogenic 5-HT2 agonists (e.g., DOI) and psychotomimetic NMDA antagonists (e.g., phencyclidine) on PPI. In the present paper, we report the results of three studies conducted to determine the effects of M100907 on apomorphine-induced disruption (one experiment) and isolation rearing-induced disruption of PPI in rats (two experiments). Results showed that M100907 failed to reduce the disruption of PPI caused by the dopamine agonist apomorphine. Nevertheless, M100907 partially reduced the disruption of PPI caused by isolation rearing. Thus, M100907 shows efficacy as a putative antipsychotic in nondopaminergic PPI models of the sensorimotor gating deficits in schizophrenia. [

Differential effects of the strychnine-insensitive glycine site antagonist (+)-HA-966 on the hyperactivity and the disruption of prepulse inhibition induced by phencyclidine in rats

The amplitude of the acoustic startle response is reduced by a preceding weak stimulation which by itself does not elicit the startle response. This phenomenon is named prepulse inhibition (PPI) and is thought to reflect the operation of the sensorimotor gating system, which is deficient in schizophrenic patients. It has been reported that an antagonist at the strychnine-insensitive glycine site has atypical neuroleptic properties in experimental animals. To evaluate the effect of an antagonist at the site on disrupted PPI, we examined whether (+)-HA-966 antagonizes phencyclidine-induced (3 mg/kg s.c.) and apomorphine-induced (1 mg/kg s.c.) disruption of PPI in rats. In addition, its effect on phencyclidine-induced hyperactivity was tested. The effects of (+)-HA-966 were compared with those of haloperidol, a typical neuroleptic. (+)-HA-966 antagonized phencyclidine-induced hyperactivity, but not phencyclidine-induced disruption of PPI, which is thought to be a model of refractory symptoms in schizophrenia. Furthermore, (+)-HA-966 did not improve the deficit in PPI induced by apomorphine. On the other hand, haloperidol antagonized phencyclidine-induced hyperactivity and the disruption of PPI by apomorphine, but not by phencyclidine. The results of this study might mean that (+)-HA-966 antagonizes the behavioral change induced by excessive dopamine release (the increment of locomotor activity due to phencyclidine), but not the effect induced by a direct dopamine agonist or the dopamine-independent effect of phencyclidine (the disruption of PPI). Thus, as regards antagonism of phencyclidine-induced disruption of PPI, (+)-HA-966 does not appear to have an atypical neuroleptic-like effect.

The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5-hydroxytryptamine2A receptor antagonist, in rats.

1. The atypical antipsychotic profile of (R)-(+)-2-amino-4-(4-fluorophenyl)-5-[1-[4-(4-fluorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D4 and 5-hydroxytryptamine (5-HT)2A receptor antagonist, was examined in rats. 2. Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED50 3.7 mg kg-1), haloperidol (ED50 0.1 mg kg-1) and chlorpromazine (ED50 0.9 mg kg-1), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg-1, did not exceed 50%. 3. Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg-1, i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED50 0.4 mg kg-1, i.p., and 0.3 mg kg-1, p.o., respectively), clozapine (ED50 0.3 mg kg-1, i.p. and 0.8 mg kg-1, p.o., respectively), haloperidol (ED50 0.02 mg kg-1, i.p. and 0.1 mg kg-1, p.o., respectively), chlorpromazine (ED50 0.3 mg kg-1, i.p. and 3.3 mg kg-1, p.o., respectively). In contrast, the MAP (3 mg kg-1, i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not affected by NRA0045 or clozapine, at the highest dose given (30 mg kg-1, i.p.). Haloperidol (ED50 0.3 mg kg-1, i.p.) and chlorpromazine (ED50 4.8 mg kg-1, i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4. Extracellular single-unit recording studies demonstrated that MAP (1 mg kg-1, i.v.) decreased the firing rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 0.1 mg kg-1, i.v.), whereas the inhibitory effects of MAP on A9 dopamine neurones were not affected by NRA0045, in doses up to 1 mg kg-1 (i.v.). Clozapine completely reversed the inhibitory effects of MAP on A10 dopamine neurones (ED50 1.9 mg kg-1, i.v.) and on A9 dopamine neurones (ED50 2.5 mg kg-1, i.v.). Haloperidol completely reversed the inhibitory effects of MAP on A10 (ED50 0.03 mg kg-1, i.v.) and on A9 dopamine neurones (0.02 mg kg-1, i.v.). NRA0045, like clozapine, was more potent in reversing the effects of MAP on A10 than A9 dopamine neurones. 5. Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg-1, s.c.) was reversed significantly by NRA0045 (3 mg kg-1, i.p.), clozapine (3 mg kg-1, i.p.) and haloperidol (0.3 mg kg-1, i.p.). 6. Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03-0.3 mg kg-1, i.p.) and clozapine (0.1-1 mg kg-1, i.p.) significantly and dose-dependently shortened the PCP(1.25 mg kg-1, i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (0.01-0.1 mg kg-1, i.p.) did not significantly alter swimming latency. 7. These findings suggest that NRA0045 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.

Adenosine A2a receptors in the nucleus accumbens modulate prepulse inhibition of the startle response.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) was disrupted by systemic administration of apomorphine (APO) (2 mg/kg, i.p.). Microinfusion of the selective adenosine A2a-recceptor agonist CGS21680 (0.05 microgram in 1.0 microliter per side) into the nucleus accumbens (NAc), had no significant effect in animals with systemic vehicle pretreatment, but significantly reversed the disruption of PPI in rats pretreated with APO. Adenosine is, therefore, involved in the control of PPI through its actions on A2a receptors in the NAc. APO-induced disruption of PPI is considered to represent an animal model useful for screening both typical and atypical antipsychotic agents. The present results add further support to the view that A2a-receptor agonists may be potentially useful antipsychotic agents.

Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions in the nucleus accumbens core and shell subregions

The amplitude of the acoustic startle reflex is normally reduced when the startling stimulus is preceded by a weak click or ‘prepulse’. Prepulse inhibition (PPI) of acoustic startle has been used as an operational measure of sensorimotor gating or inhibition, and is reduced in schizophrenia patients and in rats with central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus offer a useful animal model to study impaired sensorimotor gating in schizophrenia. We have previously reported that DA-glutamate interactions in the nucleus accumbens (NAC) regulate PPI. The NAC has at least two major subregions — the core and shell — that have distinct anatomical and neurochemical properties. In this study, we compared changes in PPI after manipulations of DA-glutamate activity in these two NAC subregions. Consistent with previous findings, infusion of the non-NMDA agonist AMPA into the NAC core subregion significantly reduced PPI, and this effect was opposed by systemic administration of the D 2 antagonist haloperidol. Also consistent with previous reports, infusion of the non-NMDA antagonist CNQX into the NAC core subregion did not alter PPI, but its co-infusion with D-amphetamine (AMPH) attenuated the AMPH-disruption of PPI. In contrast, while PPI was reduced after AMPA infusion into the NAC shell subregion, this effect of AMPA could not be blocked by pretreatment with haloperidol. Infusion of either AMPH or CNQX into the NAC shell subregion reduced PPI independently. The PPI-disruptive effects of intra-shell CNQX infusion were not blocked by haloperidol. The present results suggest striking differences between the NAC core and shell subregions in their neurochemical modulation of sensorimotor gating of acoustic startle in the rat.

Presynaptic dopamine-glutamate interactions in the nucleus accumbens regulate sensorimotor gating

Prepulse inhibition (PPI) is the normal reduction in startle reflex that occurs when a startling stimulus is preceded by a weak prepulse. PPI is reduced in patients with schizophrenia and in rats after central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus model some features of impaired sensorimotor gating in schizophrenia. Ascending DAergic and descending glutamatergic fibers converge within the nucleus accumbens (NAC), and interactions at this DA-glutamate interface have been implicated in the pathophysiology of schizophrenia. In this study, we examined the role of NAC DA-glutamate interactions in the regulation of PPI in rats. Intra-NAC infusion of the non-NMDA antagonist, CNQX, attenuated the PPI-disruptive effects of d-amphetamine (AMPH), but CNQX did not affect PPI when injected alone, nor did it reverse the PPI-disruptive effects of the direct D2/D3 agonist quinpirole. Intra-NAC infusion of the non-NMDA agonist AMPA significantly reduced PPI. The PPI-disruptive effects of AMPA were blocked by haloperidol and by 6-hydroxydopamine (6OHDA) lesions of the NAC. These data suggest that the PPI-disruptive effects of AMPH are dependent on tonic non-NMDA receptor activation in the NAC, and that non-NMDA receptor activation in the NAC results in a DA-dependent reduction in PPI. The parsimonious interpretation of these data is that non-NMDA glutamate receptors in the NAC facilitate presynaptic DA function, and that this DA-glutamate interaction is a critical regulatory substrate of sensorimotor gating.

8-OH-DPAT disruption of prepulse inhibition in rats: reversal with (+)WAY 100,135 and localization of site of action

Recent studies have implicated central serotonergic systems in the modulation of prepulse inhibition (PPI), an operational measure of sensorimotor gating, which has been used to identify gating deficits in psychiatric disorders, such as schizophrenia, Huntington's disease, and obsessive compulsive disorder. Both serotonin (5-HT) releasers and agonists at 5-HT1A, 5-HT1B, and 5-HT2 receptors reduce PPI in the rat. The present experiments demonstrate that the disruption of PPI in rats induced by the systemic administration of the 5-HT1A agonist, 8-OH-DPAT (8-hydroxy-2(di-n-propylamino)tetralin; 0.2 mg/kg), can be attenuated by the novel, selective 5-HT1A antagonist (+)WAY 100,135, (20.0 mg/kg), N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenyl-propa namide. Further experiments addressing the central site of action of 8-OH-DPAT revealed that the microinjection of 8-OH-DPAT (5.0 micrograms/0.5 microliter) into either the median raphe nucleus (MR) or dorsal raphe nucleus (DR) disrupts PPI. The reduction in PPI produced by intra-raphe microinjections of 8-OH-DPAT was prevented by a systemic injection of (+)WAY 100,135. These results support the hypothesis that somatodendritic 5-HT1A autoreceptors within the midbrain raphe subserve the PPI-disruptive effects of systemically administered 8-OH-DPAT. The decrement in PPI after intra-raphe infusions of a high dose of 8-OH-DPAT, however, was substantially less than the decrement in PPI after systemic administration of the drug. Hence, sites in addition to the somatodendritic autoreceptors may also play an important role in 8-OH-DPAT-induced disruption of PPI.(ABSTRACT TRUNCATED AT 250 WORDS)

Intra-accumbens infusion of quinpirole impairs sensorimotor gating of acoustic startle in rats.

Prepulse inhibition (PPI) of the startle reflex is reduced by systemic administration of dopamine (DA) agonists. Since PPI is impaired in patients with schizophrenia, the DA agonist-induced disruption of PPI in rats may be a useful model for studying the pathophysiology of impaired sensorimotor gating in schizophrenia. In the present study, we replicated the observation that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. PPI caused by weak [1-5 dB(A)] or more intense [10 dB(A)] prepulses was also disrupted by quinpirole infusion into the nucleus accumbens (NAC). The effects of intraaccumbens quinpirole on PPI were blocked by pretreatment with the D2 antagonist haloperidol. These results support the notion that the reduction of PPI after systemic administration of DA agonists is mediated via stimulation of NAC D2 receptors.