Chronic treatment with haloperidol diminishes the phencyclidine-induced sensorimotor gating deficit in rats

Prepulse inhibition is a model in which a weak subthreshold stimulus (prepulse), presented to an individual before a strong stimulus (pulse), inhibits a startle response to the latter. A deficit of prepulse inhibition induced by dopaminomimetics and antagonists of NMDA receptors has been suggested as an animal model of the sensorimotor deficit in schizophrenia. The aim of the present study was to examine the effect of chronic treatment with the classic neuroleptic haloperidol on the disruption of prepulse inhibition induced by the uncompetitive antagonist of NMDA receptors phencyclidine (PCP, 5mg/kg sc). Haloperidol in a dose of 1mg/kg/day was given to rats in drinking water for 3 months. The PCP-induced reduction in prepulse inhibition was not reversed by short-term (4-day) haloperidol administration. In contrast, long-term treatment with haloperidol (6 weeks or 3 months) diminished the PCP-induced effect. The present study suggests that the improvement in sensorimotor gating in the PCP model in rats by prolonged treatment with haloperidol may reflect its antipsychotic action. Received: 13 October 1997 / Accepted: 14 January 1998     

Influence of CGS 21680, a selective adenosine A(2A) agonist,on the phencyclidine-induced sensorimotor gating deficit and motor behaviour in rats

Rationale Recently it has been suggested that adenosine A_2A receptor agonists may be potential antipsychotic drugs. It is, however, not clear whether these compounds may exert their antipsychotic effect without producing extrapyramidal side-effects (e.g. catalepsy, muscle rigidity, ataxia). It is known that such side-effects may be due to overactivation of the GABAergic strio-pallidal pathway, which may be estimated as an increased expression of proenkephalin (PENK) mRNA in the striatum. Objective The aim of this study was to determine whether CGS 21680, a selective adenosine A_2A receptor agonist, can reverse the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by the non-competitive antagonist of NMDA receptors phencyclidine (PCP) without producing motor side-effects in rats. Results Systemic administration of PCP (5 mg/kg) produced profound reduction of the PPI, which was reversed by CGS 21680 (1 mg/kg). CGS 21680 (0.1 and 1 mg/kg) was without effect on catalepsy, muscle rigidity and rotarod performance in rats as well as on the PENK mRNA expression in the striatum estimated by in situ hybridization. Only after the highest dose used (5 mg/kg) were signs of catalepsy (measured using a 9-cm cork test), disturbed balance and a loss of hind limb control (measured in the rotarod test) seen. Moreover, increased muscle resistance during passive extension measured mechanomyographically after this dose of CGS 21680 was observed. Conclusions The present results support the hypothesis that adenosine A_2A receptor agonists may be potentially useful antipsychotic agents with the low incidence of extrapyramidal side-effects.     

Startle and sensorimotor gating in rats lacking CCK-A receptors.

Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the non-competitive NMDA antagonist, dizocilpine (0.1 mg/kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 mg/kg) produced a comparable facilitation of PPI in both groups. In a separate study, OLETF rats were found to be less sensitive to the locomotor stimulating effects of amphetamine. These results suggest that CCK-A receptors play a significant role in the behavioral effects of amphetamine and dizocilpine. The PPI response of OLETF rats to amphetamine and dizocilpine is similar to normal rats pretreated with atypical antipsychotics, suggesting that CCK-A receptors may play an important role in the restoration of drug-disrupted PPI by antipsychotics.     

Chronic haloperidol and clozapine administration increases the number of cortical NMDA receptors in rats

The aim of the present study was to examine the influence of 3-month administration of haloperidol (1 mg/kg per day) and clozapine (30 mg/kg per day) in drinking water on cortical NMDA (N-methyl-d-aspartate) receptors in rats. On day 5 of withdrawal, the animals were killed and their brains were removed. The binding of [³H]MK-801 ([³H](5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine) and [³H]CGP 39653 ([³H]d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) to NMDA receptors in different cortical areas, as well as the binding of [³H]spiperone to dopamine D₂ receptors in the striatum, were analysed by quantitative autoradiography. Haloperidol increased the binding of [³H]CGP 39653 in frontal, insular and parietal cortices. Clozapine increased the binding of [³H]CGP 39653 in insular and parietal cortices. Haloperidol, but not clozapine, increased the binding of [³H]spiperone in the striatum. None of the neuroleptics influenced the binding of [³H]MK-801 to cortical NMDA receptors. An additional assay revealed an increase in the B _max value, with no significant changes in the K _D of [³H]CGP 39653 binding in parieto-insular cortical homo-genates as a result of haloperidol and clozapine administration. The present results suggest that long-term treatments with haloperidol and clozapine increase the number of NMDA receptors in different cortical regions. Received: 15 September 1998 / Accepted: 25 January 1999     

Effects of NMDA receptor ligands on sensorimotor gating in the rat.

Pre-pulse inhibition of the acoustic startle response is a model of reflex modification which is thought to reflect sensorimotor gating mechanisms and is sensitive to disruption by non-competitive N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine. The effects of two competitive antagonists, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) (3-30 mg/kg) and cis-4-phosphonomethyl-2-piperidine-carboxylate (CGS 19755) (1-10 mg/kg), the non-competitive NMDA antagonist dizocilpine (0.5 mg/kg), and NMDA itself (1-30 mg/kg) were studied in the pre-pulse inhibition model. Rats were exposed to sessions in which 122 dB[A] startle-eliciting stimuli were presented either alone or preceded by weak 80 dB[A] prepulses with durations of 3, 10 and 30 ms, which under control conditions reduced the magnitude of the startle response. Neither NPC 12626 nor CGS 19755 produced disruption of pre-pulse inhibition as normally observed with phencyclidine-like drugs. NMDA also did not affect pre-pulse inhibition. As in previous experiments, dizocilpine produced a significant disruption of pre-pulse inhibition at all pre-pulse durations. These data suggest that actions at the phencyclidine binding site, and not the NMDA site, are responsible for the disruption of pre-pulse inhibition by phencyclidine-like drugs, and support reports of differences in the behavioral effects of competitive and noncompetitive NMDA antagonists. The effects of phencyclidine-like drugs on pre-pulse inhibition may represent a useful pharmacological model of schizophrenia-like cognitive deficits.     

Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats

Rationale Acutely administered N-methyl-D-asparate (NMDA) antagonists are used to model schizophrenia, as measured by impairments in sensorimotor gating reflected in decreases in prepulse inhibition of the startle response (PPI). Aspects of acute NMDA receptor antagonism limit the applications of these models.Objective The aim of this paper is to determine the long-term effects of developmental phencyclidine (PCP) treatment on sensorimotor gating in both male and female rats.Materials and methods Male and female Sprague Dawley rats were injected with PCP (10 mg/kg s.c.) on postnatal days (PN) 7, 9, and 11 and were tested for PPI on PN 32—34. The groups were then divided and some of the animals received a single dose of PCP (10 mg/kg s.c.) on PN 45. The animals were tested again for PPI at approximately 1, 4, and 6 weeks after the treatment.Results There were no significant effects of neonatal-only treatment. One week after the PN 45 treatment, animals that were treated as neonates and as adolescents (PCP/PCP) were significantly impaired in PPI in both sexes. Male and female PCP/PCP rats also had significant increases in acoustic startle response 4 weeks posttreatment, which subsequently declined. PPI impairments in both sexes recovered over time and the adolescent-only treated females showed significant increases (improvement) in PPI approximately 6 weeks posttreatment.Conclusion These data suggest that treatment with an NMDA receptor antagonist during adolescence or early adulthood can produce a relatively long-term impairment of PPI (approximately 1 week) and that this effect is more pronounced in male animals.     

"Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits.

Both dopamine (DA) agonists and NMDA antagonists produce prepulse inhibition (PPI) deficits in rats that model PPI deficits in schizophrenia patients. While DA agonist effects on PPI are reversed by acute treatment with either "typical" high-potency D2 DA antagonists or "atypical" antipsychotics, PPI deficits produced by phencyclidine (PCP) are preferentially reversed by acute treatment with "atypical" antipsychotics. Acute effects of antipsychotics may not accurately model the more clinically relevant effects of these drugs that emerge after several weeks of continuous treatment. In the present study, sustained treatment with haloperidol via subcutaneous minipumps blocked the PPI-disruptive effects of apomorphine and attenuated the PCP-induced disruption of PPI. Restoration of PPI in apomorphine-treated rats was evident within the first week of sustained haloperidol administration. A partial reversal of PCP effects on PPI did not develop until the second week of sustained haloperidol treatment, followed a fluctuating course, but remained significant into the seventh week of sustained haloperidol administration. The delayed emergence of anti-PCP effects of haloperidol suggests that the brain substrates responsible for the DAergic and NMDA regulation of PPI are differentially sensitive to acute and chronic effects of antipsychotics.     

The role of NMDA receptor upregulation in phencyclidine-induced cortical apoptosis in organotypic culture

Phencyclidine (PCP) is an N-methyl-D-aspartate receptor (NMDAR) antagonist known to cause selective neurotoxicity in the cortex following subchronic administration. The purpose of this study was to test the hypothesis that upregulation of the NMDAR plays a role in PCP-induced apoptotic cell death. Corticostriatal slice cultures were used to determine the effects of NMDAR subunit antisense oligodeoxynucleotides (ODNs) on PCP-induced apoptosis and NMDAR upregulation. NR1, NR2A or NR2B antisense ODNs were incubated alone or with PCP for 48h. One day following washout, it was observed that PCP treatment caused an increase in NR1, NR2A and Bax polypeptides in the cortex, but had no effect on Bcl-xL. These increases were associated with an increase in cortical histone-associated DNA fragments. Co-incubation of PCP with either NR1 or NR2A antisense significantly reduced PCP-induced apoptosis, while neither NR2B antisense ODN nor NR1 sense ODN used as a control had an effect. This effect was exactly correlated with the ability of the antisense ODNs to prevent PCP-induced upregulation of NR subunit proteins and the pro-apoptotic protein, Bax. That is, western analysis showed that antisense ODNs directed against either NR1 or NR2A prevented PCP-induced increases in Bax in addition to preventing the upregulation of the respective receptor proteins. On the other hand, the NR2B antisense ODN had no effect on either NR2B protein or on Bax. These data suggest that NR1 and NR2A antisense ODNs offer neuroprotection from apoptosis, and that upregulation of the NR1 and NR2A subunits following PCP administration is at least partly responsible for the observed apoptotic DNA fragmentation.     

Effects of sustained phencyclidine exposure on sensorimotor gating of startle in rats.

Phencyclidine (PCP), a non-competitive NMDA antagonist with actions at multiple other central nervous system receptors, can cause both acute and lasting psychoses in humans, and has also been used in cross-species models of psychosis. Acute exposure to PCP in rats produces behavioral changes, including a loss of prepulse inhibition (PPI) of the startle reflex, which parallels the loss of PPI observed in schizophrenia patients. Sustained exposure to PCP in rats produces neuropathological changes in several limbic regions and prolonged behavioral abnormalities that may parallel neuropsychological deficits in schizophrenia. It is unclear whether sustained PCP exposure will also produce a loss of prepulse inhibition which parallels the decrease observed in schizophrenia patients. In the present study, we examined changes in PPI during and after sustained PCP administration, using 5-day PCP exposure via subcutaneous osmotic minipumps, or 14-day PCP exposure via repeated intraperitoneal injections. In both forms of drug delivery, PPI was disrupted during, but not after, sustained drug exposure. PPI does not appear to be sensitive to neuropathological effects of sustained PCP exposure.     

Effects of pergolide on sensorimotor gating of the startle reflex in rats

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders, including schizophrenia. This study was designed to assess the effects of the D2-family agonist pergolide in rats, in anticipation of human studies of the dopaminergic regulation of PPI. METHODS: The effects of pergolide (0.0001-0.5 mg/kg) on PPI of the acoustic startle reflex were studied in rats using a wide range of prepulse intensities [1-15 dB(A) over background] and prepulse intervals (5-100 ms, onset to onset). Studies also examined the effects of the D2 antagonist haloperidol on pergolide-induced changes in PPI. RESULTS: Pergolide exhibited dose- and stimulus-dependent effects on PPI. Pergolide increased PPI when startle stimuli were preceded by weak prepulses [1-5 dB(A) over background] at the longest prepulse interval (100 ms), or intense prepulses [15 dB(A) over background] at short prepulse intervals (5-20 ms). Pergolide (0.5 mg/kg) also decreased PPI elicited by intense prepulses at long intervals (60-100 ms). Both PPI-enhancing and PPI-disruptive effects of pergolide were reversed by the D2 antagonist haloperidol. CONCLUSIONS: These effects of pergolide suggest that D2 substrates mediate opposing influences on PPI under different stimulus conditions. The dopaminergic regulation of sensorimotor gating appears to interact with stimulus characteristics such as relative intensity and temporal separation, allowing for dynamic shifts in both the quantity and quality of "gated" information.     

Effects of acute systemic and intra-cerebral stimulation of cannabinoid receptors on sensorimotor gating,locomotion and spatial memory in rats

RATIONALE: Cannabinoid CB(1) receptors in the brain are targets of both endocannabinoid signalling and the psychoactive compounds of the hemp plant. They mediate neuronal effects of their ligands in various corticolimbic and striatal circuits by presynaptic regulation of transmitter release. OBJECTIVES/METHODS: This study investigates acute systemic effects of the full CB(1) receptor agonist WIN 55,212-2 (WIN) on prepulse inhibition (PPI) of the acoustic startle response (ASR), locomotor activity and spatial memory retrieval in an eight-arm radial-maze task. Furthermore, we tested the effect of local intra-cerebral micro-infusions of WIN into the nucleus accumbens (NAc), ventral tegmental area (VTA), dorsal (dHIP) and ventral (vHIP) hippocampus and medial prefrontal cortex (mPFC). RESULTS: Systemic WIN (1.2 mg/kg) reduced PPI without affecting ASR, had no effect on locomotion in the open field, but impaired retrieval of spatial memory. Infusions of 5 microg/0.3 microl WIN into either NAc (core or shell), dHIP or VTA did not affect PPI and locomotion immediately afterwards. However, PPI was significantly reduced after intra-mPFC and intra-vHIP infusion of WIN. Furthermore, WIN infusion into dHIP increased the number of reference memory errors in the maze, suggesting impairment of memory retrieval. CONCLUSIONS: Our data support the notion that CB(1) receptor stimulation impairs sensorimotor gating most likely by modulation of neurotransmitter release in mPFC and vHIP. The lack of effects of local WIN infusions in NAc and VTA might be due to low receptor abundance in these regions. Additionally, CB(1) receptor activation in dHIP impairs spatial memory retrieval. Taken together, cortico-hippocampal cannabinoid receptors play an essential role in the regulation of cognitive and behavioural processes.     

A comparison of the effects of neuroleptics on phencyclidine-induced behaviors in the rat

The dose-response effects of neuroleptic pretreatment on phencyclidine (PCP; 3 or 5 mg/kg)-induced locomotor activity, stereotyped behaviors and ataxia were quantified in groups of male rats using rating scales recently developed in this laboratory. Three butyrophenone neuroleptics consistently produced dose-dependent antagonism of the behavioral effects of PCP administration. Fluphenazine antagonized the behavioral effects produced by 3 mg/kg PCP but not those produced by 5 mg/kg PCP. Each of the other neuroleptics examined (chlorpromazine, thioridazine, mesoridazine, triflupromazine, cis-flupenthixol) had no consistent antagonistic effect or actually enhanced one or more of the behavioral effects of PCP. Some neuroleptics slightly reduced PCP locomotion or stereotypies at high doses, but these effects were probably a non-specific consequence of the synergistic ataxia-producing properties of these drugs. In a second set of experiments, atropine sulfate pretreatment increased PCP-induced locomotor activity and stereotyped behaviors but had no effect on ataxia; pretreatment with physostigmine produced opposite effects. Combined pretreatment with haloperidol and atropine sulfate significantly reduced only haloperidol antagonism of PCP-induced ataxia, thus suggesting that non-dopoaminergic effects of neuroleptics may interfere with their ability to antagonize PCP.     

The reelin receptors VLDLR and ApoER2 regulate sensorimotor gating in mice

Postmortem brain loss of reelin is noted in schizophrenia patients. Accordingly, heterozygous reeler mutant mice have been proposed as a putative model of this disorder. Little is known, however, about the involvement of the two receptors for reelin, Very-Low-Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2), on pre-cognitive processes of relevance to deficits seen in schizophrenia. Thus, we evaluated sensorimotor gating in mutant mice heterozygous or homozygous for the two reelin receptors. Mutant mice lacking one of these reelin receptors were tested for prepulse inhibition (PPI) of the acoustic startle reflex prior to and following puberty, and on a crossmodal PPI task, involving the presentation of acoustic and tactile stimuli. Furthermore, because schizophrenia patients show increased sensitivity to N-methyl-d-aspartate (NMDA) receptor blockade, we assessed the sensitivity of these mice to the PPI-disruptive effects of the NMDA receptor antagonist phencyclidine. The results demonstrated that acoustic PPI did not differ between mutant and wildtype mice. However, VLDLR homozygous mice displayed significant deficits in crossmodal PPI, while ApoER2 heterozygous and homozygous mice displayed significantly increased crossmodal PPI. Both ApoER2 and VLDLR heterozygous and homozygous mice exhibited greater sensitivity to the PPI-disruptive effects of phencyclidine than wildtype mice. These results indicate that partial or complete loss of either one of the reelin receptors results in a complex pattern of alterations in PPI function that includes alterations in crossmodal, but not acoustic, PPI and increased sensitivity to NMDA receptor blockade. Thus, reelin receptor function appears to be critically involved in crossmodal PPI and the modulation of the PPI response by NMDA receptors. These findings have relevance to a range of neuropsychiatric disorders that involve sensorimotor gating deficits, including schizophrenia.     

Effects of sustained cocaine exposure on sensorimotor gating of startle in rats

 Deficient sensorimotor gating, as measured by a relative loss of prepulse inhibition (PPI) of the startle reflex, has been reported in schizophrenia patients and in rats treated acutely with dopamine (DA) agonists or other psychotomimetic agents. For this reason, PPI has been used as a cross-species measure for studying the neurochemistry of specific information processing deficits in schizophrenia. Cocaine is a DA reuptake inhibitor which can precipitate psychosis after sustained use in humans. In rats, sustained exposure to cocaine results in neuropathological and neurochemical changes in several brain regions, and is also associated with specific prolonged behavioral abnormalities. In the present study, we examined the effects of both acute and sustained cocaine administration on PPI and other measures of the startle reflex in rats. Cocaine produced a significant, dose-dependent reduction in PPI, both after acute administration, and after 3 days of sustained administration via implanted subcutaneous pellets. PPI returned to control levels when rats were tested 10 days after sustained (5 day) cocaine administration. The effects of acute cocaine administration on PPI are consistent with those of other DA agonists and psychotomimetics, but PPI does not appear to be sensitive to lasting effects of a method of prolonged cocaine administration associated with neuropathological and neurochemical changes in several brain regions. Received: 22 April 1998 / Final version: 18 August 1998     

Efficacy of 3,5-dibromo-L-phenylalanine in rat models of stroke,seizures and sensorimotor gating deficit

Background and purpose:

Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit.

Experimental approach:

3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit).

Key results:

Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801.

Conclusion and implications:

The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.     

Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague-Dawley rats

Prepulse inhibition (PPI) of acoustic startle and locomotor activity are both widely studied in the preclinical development of dopaminergic agents, including those acting at D3 dopamine receptors. In mice, the dopamine D3 receptor-preferential agonist pramipexole (PPX) alters locomotor activity in a biphasic manner at doses that have no effect on PPI. The present study examined the time-course of PPX effects on locomotion and PPI in rats. In adult male Sprague-Dawley rats, PPX (0, 0.1, 0.3, 1.0 mg/kg) was injected prior to measurement of locomotor activity for 90 min in photobeam chambers. Based on disparate early vs. late effects of PPX on locomotion, the effects of PPX (0 vs. 0.3 mg/kg) on PPI were tested 20 and 80 min after injection. All doses of PPX decreased locomotor activity for 30 min compared to vehicle, and the higher doses stimulated hyperlocomotion later in the session; the late hyperlocomotion, but not the early hypolocomotion, was blocked by the D2-selective antagonist, L741626 (1.0 mg/kg sc). In contrast to its locomotor effects, PPX caused a similar reduction in PPI at 20 and 80 min after administration. These findings suggest both a temporal and pharmacological dissociation between PPX effects on locomotor activity and PPI; these two behavioral measures contribute non-redundant information to the investigation of D3-related behavioral pharmacology.     

Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats

Sensorimotor gating of the startle reflex – measured by prepulse inhibition (PPI) – is impaired in schizophrenia patients and in rats treated with either dopamine (DA) agonists or with N-methyl-D-aspartate (NMDA) antagonists. While both typical and atypical antipsychotics restore PPI in DA agonist-treated rats, studies thus far have demonstrated that only atypical antipsychotics restore PPI in rats treated with NMDA antagonists. This model for predicting atypical antipsychotic properties has been studied extensively in rats, and there is interest in moving these studies into humans, where the NMDA antagonist ketamine is also reported to significantly reduce PPI. In anticipation of such studies, and to facilitate the use of this model in humans, we examined the effects of high and low potency typical antipsychotics (haloperidol and chlorpromazine), the atypical antipsychotic clozapine, and the putative atypical antipsychotic, Seroquel, on ketamine-disrupted PPI in rats, across a range of ketamine that produced submaximal, as well as maximal disruptions of PPI. Ketamine dose-dependently reduced PPI, and this effect was significantly opposed by Seroquel, clozapine and chlorpromazine, but not haloperidol. The effects of chlorpromazine on ketamine-disrupted PPI demonstrate that the ability of antipsychotics to restore PPI in NMDA antagonist-treated rats is not specific to clinically atypical antipsychotics. Receptor properties shared by Seroquel, clozapine and chlorpromazine, but not haloperidol, may implicate critical substrates in the NMDA antagonist-induced disruption of PPI. Received: 31 December 1997/Final version: 11 March 1998     

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     

Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats

Rationale

Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague?CDawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia.

Objectives

After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH).

Methods

Startle and PPI were assessed in SD and LE rats administered d-amphetamine (0 vs. 4.5?mg/kg, sc). Two weeks later, brain tissue was processed for comt, nrg1, grid2, and csnk1e expression; blood comt expression was also tested.

Results

Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE?>?SD expression in most genes and regions, and female?>?male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120?ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30?ms PPI and startle magnitude correlated significantly with VH nrg1 and blood comt expression.

Conclusions

Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia.