Mood stabilizers increase prepulse inhibition in DBA/2NCrl mice

Rationale  Lithium and several antiepileptic drugs have mood-stabilizing effects in bipolar disorder and schizophrenia. Both disorders are characterized by deficits in prepulse inhibition (PPI) of the acoustic startle response. Objectives  Using the DBA/2 model of naturally low PPI, which is reliably increased by antipsychotics, five mood stabilizers in clinical use were tested to determine whether they would also increase PPI in this model. All drugs were administered intraperitoneally (i.p.) 30 min before testing. Results  Lithium chloride (30 mg/kg), topiramate (100 and 300 mg/kg), carbamazepine (30, 60, and 100 mg/kg), valproic acid (178 and 316 mg/kg), and lamotrigine (3, 10, and 30 mg/kg) increased percent PPI. The antiepileptic drugs carbamazepine, valproic acid, and lamotrigine at high doses also decreased no-stimulus amplitudes and increased startle amplitudes. At high doses of carbamazepine, valproic acid, and lamotrigine, increases in percent PPI were independent of the increases in startle amplitude. Conclusions  The demonstrated efficacy of five mood stabilizers in the DBA/2 model of naturally low PPI points to the translational value of this model in predicting therapeutic activity in schizophrenia and bipolar disorder of compounds with diverse mechanisms of action.     

Galantamine and donepezil attenuate pharmacologically induced deficits in prepulse inhibition in rats

Acetylcholinesterase inhibitors (AChEIs) are currently being evaluated as adjunctive therapy for the cognitive dysfunction of schizophrenia. This core symptom of schizophrenia has often been attributed to impaired attention and abnormal sensory motor gating, features that are also found in Huntington's Disease, autism, and several other psychiatric and neurological disorders. The ability to improve prepulse inhibition (PPI) of the acoustic startle response may predict the efficacy of compounds as cognitive enhancers. In this study, PPI was disrupted in Wistar rats in three pharmacologic models: dopamine receptor agonism by apomorphine, NMDA receptor antagonism by MK801, or muscarinic acetylcholine receptor antagonism by scopolamine. We then evaluated the commonly used AChEIs, donepezil (0.5, 1.0, or 2.0mg/kg) and galantamine (0.3, 1.0, or 3.0mg/kg) for the capacity to improve PPI in each model. Under vehicle conditions, the prepulse stimuli (75, 80 and 85dB) inhibited the startle response to a 120dB auditory stimulus in a graded fashion. Galantamine (depending on dose) improved PPI deficits in all three PPI disruption models, whereas donepezil ameliorated PPI deficits induced by scopolamine and apomorphine, but was not effective in the MK801 model. These results indicate that some AChEIs may have the potential to improve cognition in schizophrenia by improving auditory sensory gating.     

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 SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity

5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.     

Quinelorane,a dopamine D3/D2 receptor agonist,reduces prepulse inhibition of startle and ventral pallidal GABA efflux: Time course studies

Startle is inhibited when the startling stimulus is preceded 30–300 ms by a weak prepulse. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients, and reduced in rats and humans by dopamine agonists. The neural basis for the PPI-disruptive effects of dopamine agonists in rats is studied to understand neural circuitry regulating PPI and its deficits in schizophrenia. Existing data suggest that ventral pallidal (VP) GABAergic transmission regulates PPI and its disruption by dopamine agonists. We measured changes in VP GABA efflux and PPI in rats in response to the D2/D3 agonist, quinelorane. Wistar rats were administered quinelorane (vehicle, 0.003 or 0.01 mg/kg). In some rats, VP dialysate was analyzed for GABA content. In others, PPI was assessed using 120 dB(A) startle pulses and prepulses 10 dB over a 70 dB(A) background. Quinelorane reduced GABA efflux, with significant effects for 0.01 but not 0.003 mg/kg, persisting for at least 100 min. Quinelorane reduced PPI for 50 min, an effect significant for both the 0.003 (p < 0.05) and 0.01 mg/kg doses (p < 0.015). Differences in time course and dose sensitivity of quinelorane effects on VP GABA efflux and PPI are discussed.     

Quinelorane, a dopamine D3/D2 receptor agonist, reduces prepulse inhibition of startle and ventral pallidal GABA efflux: time course studies

Startle is inhibited when the startling stimulus is preceded 30–300 ms by a weak prepulse. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients, and reduced in rats and humans by dopamine agonists. The neural basis for the PPI-disruptive effects of dopamine agonists in rats is studied to understand neural circuitry regulating PPI and its deficits in schizophrenia. Existing data suggest that ventral pallidal (VP) GABAergic transmission regulates PPI and its disruption by dopamine agonists. We measured changes in VP GABA efflux and PPI in rats in response to the D2/D3 agonist, quinelorane. Wistar rats were administered quinelorane (vehicle, 0.003 or 0.01 mg/kg). In some rats, VP dialysate was analyzed for GABA content. In others, PPI was assessed using 120 dB(A) startle pulses and prepulses 10 dB over a 70 dB(A) background. Quinelorane reduced GABA efflux, with significant effects for 0.01 but not 0.003 mg/kg, persisting for at least 100 min. Quinelorane reduced PPI for 50 min, an effect significant for both the 0.003 (p < 0.05) and 0.01 mg/kg doses (p < 0.015). Differences in time course and dose sensitivity of quinelorane effects on VP GABA efflux and PPI are discussed.     

Dopamine and nitric oxide interaction on the modulation of prepulse inhibition of the acoustic startle response in the Wistar rat

Rationale The nitric oxide (NO)–arginine pathway is intimately connected to the release of dopamine (DA), a neurotransmitter system that may be dysfunctional in schizophrenia. Both schizophrenic patients and rats treated with DA agonists present deficits in sensorimotor gating measured by prepulse inhibition (PPI). Objective Our aim was to investigate the interaction between a NO synthase inhibitor, N ^G-nitro-l-arginine (l-NOARG), and the DA agonists, amphetamine (Amph), apomorphine (Apo), bromocriptine (BRC), quinpirole (QNP) and SKF38393, on the modulation of the PPI. Methods Male Wistar rats received two injections of either l-NOARG (40 mg/kg, i.p.) or saline, 1 h before the test, and the DA agonists or vehicle. Testing began 5 min after treatment with Amph (2 mg/kg, i.p.), Apo (0.5 mg/kg, s.c.) or QNP (0.3 mg/kg and 1.0 mg/kg, s.c.), 120 min after BRC (1 and 40 mg/kg, i.p.) and 15 min after SKF38393 (10 mg/kg, s.c.). The PPI test consisted of 60 presentations divided into pulse (100 dB), prepulse (65, 70, 75 and/or 80 dB) and prepulse + pulse. Results l-NOARG prevented the PPI disruption caused by Amph (2 mg/kg). Apo, QNP and BRC disrupted PPI, but these effects were not significantly changed by l-NOARG. SKF38393 had no significant effect on PPI whether or not preceded by l-NOARG. Conclusions Our findings show that l-NOARG interacted with Amph, an indirect DA agonist, but not with the direct DA agonists on PPI, suggesting that NO is involved on the dopaminergic modulation of sensorimotor gating, probably by a presynaptic mechanism.     

Clinical and sensorimotor gating effects of ketamine in normals.

The clinical similarities between PCP psychosis and schizophrenia have contributed importantly to the development of the glutamate hypothesis of schizophrenia. Sensory gating, as measured by prepulse inhibition of the acoustic startle reflex (PPI), is impaired in patients with schizophrenia. In animals, the noncompetitive NMDA antagonists PCP and ketamine disrupt PPI in a way that resembles the defect seen in schizophrenia. The purpose of this work is to investigate the modulation of sensory gating in humans by subanaesthetic doses of ketamine. 16 healthy male subjects received a 60-min infusion of ketamine (0.5 mg/kg) or normal saline on two separate days in a randomized double-blind crossover design. Clinical ratings and PPI were done during the infusion on both days. Ketamine produced robust clinical effects. Dissociative symptoms as measured by the CADSS increased from 0 +/- 0.0 to 29.3 +/- 14.3; negative symptoms (Affect Rating Scale) increased from 17.2 +/- 0.8 to 24.8 +/- 3.1; and total BPRS scores increased from 18.3 +/- 0.8 to 26.4 +/- 5.1. ANOVAs for these ratings were all significant at the p <.000 level, although BPRS increases were not in the range seen in decompensated schizophrenic patients. The amplitudes of the startle responses to pulse-alone stimuli were not significantly different on ketamine and placebo days. Ketamine did not cause disruption in PPI as expected. On the contrary, in the first block of the PPI session ketamine significantly enhanced PPI (ANOVA; F=6.15, p =.026). These results indicate that the clinical effects of ketamine are not coupled with schizophrenic-like disruption of PPI in normal controls.     

Antipsychotics improve Delta9-tetrahydrocannabinol-induced impairment of the prepulse inhibition of the startle reflex in mice

Recently, cannabinoid receptor agonists have been reported to impair prepulse inhibition (PPI) of the startle reflex. In the current study, we examined the effect of Delta9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, on the PPI, and found that THC (10 mg/kg, i.p.) impaired the PPI concomitant with a decrease in the startle response. Antipsychotics such as haloperidol (0.3 mg/kg, i.p.) and risperidone (0.1 mg/kg, i.p.), which are potent dopamine D2 receptor antagonists, and SR141716 (10 mg/kg, i.p.), a CB1 cannabinoid receptor antagonist, reversed these THC-induced PPI deficits. Moreover, THC (10 mg/kg) increased dopamine (DA) release in the nucleus accumbens but not medial prefrontal cortex over a 50-100-min period (time of PPI test) after treatment, and SR141716 (10 mg/kg) reversed this increase in DA release induced by THC. These results suggest that dopaminergic hyperfunction in the nucleus accumbens may be involved in THC-induced PPI deficits.     

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.     

The DBA/2J strain and prepulse inhibition of startle: a model system to test antipsychotics?

RATIONALE: Prepulse inhibition (PPI) of the startle response in mice is increasingly used as a paradigm of sensory gating with potential predictive and construct validity towards schizophrenia. OBJECTIVES: Establishment of a mouse PPI paradigm in which typical and atypical antipsychotic drugs directly improve a low performance PPI. METHODS: Three strains of mice--C57Bl/6J, 129S6/SvEvTac and DBA/2J--were tested in a startle paradigm with three prepulse intensities, 2, 4 and 8 dB above background. RESULTS: Under these conditions, risperidone (0, 0.25, 0.5 and 1 mg/kg i.p.) and clozapine (0, 1, 3 and 9 mg/kg i.p.) improved PPI in all three strains, with order of effect in DBA/2J > 129S6SvEvTac > C57Bl/6J. The DBA/2J strain showed larger PPI-enhancing effects, without disturbing the basal startle response. Two alpha7 nicotinic receptor agonists, GTS-21 (1-10 mg/kg i.p.) and AR-R17779 (1-10 mg/kg i.p.) were inactive in the PPI procedure in DBA/2J mice. CONCLUSIONS: DBA/2J mice were very sensitive to the antipsychotic-like effects of atypical (clozapine) and typical (risperidone) antipsychotics, and this strain is proposed as a model to directly measure sensory gating properties of drugs. Alpha7 Nicotinergic receptor agonists were ineffective in this PPI paradigm.     

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.     

Actions of novel antipsychotic agents on apomorphine-induced PPI disruption: influence of combined serotonin 5-HT1A receptor activation and dopamine D2 receptor blockade.

The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D2 antagonist property, various levels of 5-HT1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT1A agonist, did not. New generation antipsychotics with marked 5-HT1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D2 and 5-HT1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.     

Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice.

Cannabidiol, a nonpsychoactive constituent of the Cannabis sativa plant, has been reported to act as an agonist of the vanilloid 1 channel in the transient receptor potential family (TRPV1) and also to inhibit the hydrolysis and cellular uptake of the endogenous cannabinoid anandamide. Cannabidiol has also been reported to have potential as an antipsychotic. We investigated the effect of cannabidiol on sensorimotor gating deficits in mice induced by the noncompetitive NMDA receptor antagonist, MK-801. Sensorimotor gating is deficient in psychotic disorders such as schizophrenia and may be reliably measured by prepulse inhibition (PPI) of the startle response in rodents and humans. MK-801 (0.3-1 mg/kg i.p.) dose dependently disrupted PPI while cannabidiol (1-15 mg/kg i.p.), when administered with vehicle, had no effect on PPI. Cannabidiol (5 mg/kg i.p.) successfully reversed disruptions in PPI induced by MK-801 (1 mg/kg i.p.), as did the atypical antipsychotic clozapine (4 mg/kg i.p.). Pretreatment with capsazepine (20 mg/kg i.p.) prevented the reversal of MK-801-induced disruption of PPI by cannabidiol, providing preliminary evidence that TRPV1 receptors are involved in the reversal of MK-801-induced sensorimotor gating deficits by cannabidiol.     

Antipsychotic effects on prepulse inhibition in normal 'low gating' humans and rats.

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg p.o.) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.     

Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function

Rationale Reduced N-methyl d-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. Objectives The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1−/−) mice would be affected by antipsychotic drug treatment. Methods Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli. Results Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1−/− mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1−/− or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice. Conclusions The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.     

Differential effects of apomorphine on prepulse inhibition of acoustic startle reflex in two rat strains

Apomorphine disruption of prepulse inhibition (PPI) has been proposed as an animal model of sensorimotor gating deficits exhibited by schizophrenics. The effects of apomorphine on PPI of the acoustic startle reflex in male rats of Wistar and CD (Sprague-Dawley derived) strains were compared under identical test conditions. In Wistar rats, subcutaneous administration of 0.25–1.0 mg/kg apomorphine blocked PPI without affecting startle amplitude. In CD rats, apomorphine (0.3–3.0 mg/kg, SC) had no effect on PPI, but increased startle amplitude. Therefore, choice of rat strain is an important factor in the design of experiments studying apomorphine effects on PPI.     

Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone

Ziprasidone, an antipsychotic with efficacy against core symptoms of schizophrenia and schizoaffective disorder, has a low incidence of extrapyramidal syndrome (EPS). Because of its high 5-HT(2A)/D(2) binding-affinity ratio and low EPS liability, ziprasidone is considered to belong to the newer class of "novel" antipsychotics typified by clozapine. Its unique pharmacological profile, however, distinguishes it from other novel agents. We evaluated ziprasidone in the prepulse inhibition (PPI) model, which is sensitive to clinically active antipsychotics. Male Wistar rats were tested in acoustic startle sessions in which some startle-eliciting stimuli were presented alone, and others were preceded by a weak prepulse. Administration of the dopamine agonist apomorphine (1 mg/kg) or the N-methyl-D-aspartate (NMDA) antagonist ketamine (10 mg/kg) significantly disrupted PPI. When coadministered with either of these compounds, clozapine (1-5.6 mg/kg sc) and ziprasidone (5.6-17.8 mg/kg po) significantly attenuated the declines in PPI. Haloperidol (0.03-0.56 mg/kg) also attenuated drug-induced deficits in PPI but to a lesser extent (and at higher doses) with ketamine than with apomorphine. Together, these data confirm that ziprasidone shares common effects in PPI models with other novel antipsychotics. Ziprasidone's affinity for non-D(2) receptors in the central nervous system may partly account for its attenuation of ketamine's effect.     

Reversal of isolation-rearing-induced PPI deficits by an α7 nicotinic receptor agonist

Rationale The α7 subtype of the nicotinic receptor plays an important role in auditory sensory gating. Schizophrenics show deficient sensory gating and abnormalities in the number and regulation of nicotinic receptors. Prepulse inhibition (PPI) deficits exhibited by isolation-reared rats are thought to model the sensorimotor gating deficits seen in schizophrenia. Objective To examine the role of nicotinic α7 receptors in the isolation-rearing rat model, we tested whether the selective α7 receptor agonist (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A) could reverse isolation-rearing-induced PPI deficits, and investigated α7 receptor RNA expression in the hippocampus, prefrontal cortex, cerebellum, nucleus accumbens and thalamus, and α7 receptor protein expression in the hippocampus of isolation- and group-reared rats. Method Rats reared in isolation or groups of five from weaning were tested in the PPI paradigm under conditions of variable inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse=75 dB/30 ms; ISI=30, 100 and 300 ms) 30 min following administration of compound A (3.2–10 mg/kg i.p.). α7 Receptor expression was measured by TaqMan RT-PCR (total RNA) and autoradiography (protein). Results Isolation-rearing-induced PPI deficits were attenuated by both doses of compound A at 100-ms ISI and by 10 mg/kg at 300-ms ISI. Expression of α7 receptor RNA and protein was unaltered in isolation-reared rats. Conclusion Although altered α7 receptor expression may not underlie the phenotype of isolation-reared rats, the activation of these receptors may be of benefit in re-establishing efficient gating function.     

Clozapine enhances disruption of prepulse inhibition after sub-chronic dizocilpine- or phencyclidine-treatment in Wistar rats

Sensitisation (i.e. progressive enhancement) of behavioural abnormalities induced by repeated treatment with non-competitive NMDA receptor antagonists in animals is considered an animal model for schizophrenia. Here, male Wistar rats were treated for 11 days with either dizocilpine (0.1 mg/kg), phencyclidine (PCP, 2 mg/kg), or saline and tested for prepulse inhibition (PPI) of the acoustic startle response (ASR). The aims of this study were twofold: First, we tested whether sensitisation of PPI deficits previously found in Sprague-Dawley rats were also found in Wistar rats, and, second, whether these effects can be ameliorated by the atypical antipsychotic clozapine. PPI is a paradigm for the assessment of sensorimotor gating (and its deficits) and is impaired in schizophrenic patients. After the sub-chronic treatment the rats were tested drug-free (day 12), and on the following days after drug challenge by PCP (2 mg/kg), combinations of PCP (2 mg/kg) and clozapine (5 and 10 mg/kg), or clozapine (5 mg/kg) alone. PPI was significantly reduced by both NMDA receptor antagonists. This effect was not further enhanced by the daily treatment. Startle magnitude was increased after eight days of dizocilpine-treatment only, indicating sensitisation of startle-potentiation by this drug. Testing the rats drug-free on day 12 revealed enhanced PPI and reduced startle (compared to the matching test on day 0) irrespective of previous treatment. Drug challenge with PCP (2 mg/kg) again reduced PPI in all groups. Clozapine (5 and 10 mg/kg) failed to antagonise the PPI-disruptive effects of PCP and even enhanced the PCP-induced PPI-deficits in rats pretreated with PCP or dizocilpine. These findings suggest: (1) that PPI and startle are influenced differently by non-competitive NMDA receptor antagonists, (2) that PCP and dizocilpine reduce PPI in Wistar rats, but do not lead to a sensitisation of this effect; and (3) that under the present schedule of treatments, the antipsychotic compound clozapine does not antagonise but rather enhances PPI-disruptive effects of non-competitive NMDA receptor antagonists, pointing towards a complex interaction of the brain processes underlying the action of psychotomimetic and atypical antipsychotic drugs.