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.     

Heritable differences in the dopaminergic regulation of sensorimotor gating

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI disruptive effects of the D₁/D₂ agonist apomorphine in Harlan Sprague-Dawley (SDH) versus Long Evans (LEH) rats. In the present study, we assessed the generational pattern of this phenotypic difference across parental SDH and LEH strains under in- and cross-fostering conditions, offspring (F1) of an SDH×LEH cross, and subsequent offspring (N2) of an SDH×F1 cross. Apomorphine sensitivity followed a gradient across generations that suggested relatively simple additive effects of multiple genes. Cross fostering studies confirmed that SDH>LEH apomorphine sensitivity did not reflect post-natal maternal influences. Generational patterns of PPI apomorphine sensitivity were not associated with albino versus hooded phenotypes per se, but apomorphine sensitivity in hooded N2 rats was strongly related to body surface area of fur pigmentation. The association between pigmentation and PPI apomorphine sensitivity may provide an important clue to specific biochemical and genetic substrates responsible for population differences in the regulation of sensorimotor gating.     

Sensitivity to sensorimotor gating-disruptive effects of apomorphine in two outbred parental rat strains and their F1 and N2 progeny.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague-Dawley (SDH) vs Wistar (WH) rats. In the present study, we assessed the inheritance pattern of this phenotypic difference. Sensitivity to the PPI-disruptive effects of apomorphine was compared across parental SDH and WH strains, offspring (F1) of an SDH x WH cross, and subsequent offspring (N2) of an SDH x F1 cross. Apomorphine sensitivity followed a gradient of SDH>N2>F1>WH. Parental SDH and WH strains exhibited comparable sensitivity to the PPI-disruptive effects of phencyclidine. The nature of this gradient of APO sensitivity suggests relatively simple additive effects of multiple genes on the phenotype of PPI sensitivity.     

Separable noradrenergic and dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and Tourette Syndrome

Introduction Startle inhibition by lead stimuli (prepulse inhibition, “PPI”), and the disruption of this process by dopamine agonists and N-methyl-d-aspartate (NMDA) antagonists, are used in predictive models for antipsychotic development. PPI is also disrupted by the norepinephrine α-1 agonist, cirazoline, and the PPI-disruptive effects of the indirect dopamine agonist amphetamine are opposed by the norepinephrine reuptake inhibitor, desipramine. The hypothesis that PPI may be regulated by norepinephrine, or by interactions between dopamine and norepinephrine substrates, was tested in a series of experiments with the α-2 agonist, clonidine, which is used clinically to treat Tourette Syndrome (TS).Materials and methods PPI was measured in male Sprague–Dawley rats after pretreatment with clonidine or the D2 antagonist haloperidol, and treatment with cirazoline, amphetamine, the D1/D2 agonist apomorphine, or the NMDA antagonist, phencyclidine.Results PPI was disrupted by cirazoline; this effect was prevented by clonidine but not haloperidol. PPI was disrupted by apomorphine; this effect was prevented by haloperidol but not clonidine. Clonidine also failed to oppose the PPI-disruptive effects of amphetamine and augmented the PPI-disruptive effects of phencyclidine. Over a range of prepulse intervals, clonidine enhanced PPI at short intervals and opposed the PPI-disruptive effects of cirazoline at long intervals.Conclusions PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for drugs other than antipsychotics. Clonidine’s failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support the specificity of these PPI models for detecting drugs with antipsychotic properties.     

Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.     

M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats.

In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains.     

Sensitivity to drug effects on prepulse inhibition in inbred and outbred rat strains

Genetic differences in the neurochemical regulation of PPI in rats may help clarify the neural basis of inherited PPI differences in neuropsychiatric disorders. We reported and characterized substantial heritable differences in sensitivity to PPI-disruptive effects of DA agonists in outbred Sprague Dawley (SDH) versus Long-Evans (LEH) rats. Other strains might yield large group separations and facilitate studies of the neural basis for these strain differences; inbred strains might also allow us to map genes associated with differential PPI sensitivity. Sensitivity to the PPI-disruptive effects of the DA agonist apomorphine (APO) and the NMDA antagonist phencyclidine (PCP) were compared across inbred and outbred strains. APO sensitivity was greatest in SDH and buffalo rats, but the effect in buffalo rats was complicated by significant APO-induced startle suppression. PPI APO sensitivity was least in ACI and LEH rats; F344s exhibited intermediate sensitivity and Lewis rats showed a nonlinear dose response (sensitivity at low but not higher doses). PPI APO insensitivity in ACI rats developed over time, with ACI pups exhibiting robust sensitivity. Substantial strain differences were observed in short-interval (10-30 ms) prepulse effects, and APO-induced increases in short-interval PPI occurred in SDH, LEH, and Lewis rats, but not in F344, ACI, or buffalo rats. Sensitivity to PPI-disruptive effects of PCP was generally greater in outbred than inbred rats. These findings identify strains suitable for comparisons of PPI neural circuitry and others for whom such comparisons would be complex and perhaps less informative.     

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.     

The Effects of dizocilpine and phencyclidine on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity in C57BL6 mice.

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle reaction to a startle-eliciting stimulus when it is shortly preceded by a subthreshold prepulse stimulus. Here, we evaluated the possible effects on prepulse-elicited reactivity by dizocilpine (MK-801) and phencyclidine (PCP) in the PPI of acoustic startle paradigm in C57BL6/J mice. The aim was to ascertain whether these two drugs would affect prepulse-elicited reactivity in a manner similar to apomorphine, which enhances prepulse-elicited reactivity at doses that disrupt PPI. In two dose-response studies, we showed that both drugs exhibited a tendency to attenuate prepulse-elicited reaction at higher doses when PPI was severely disrupted. On the other hand, at lower doses when PPI was marginally disrupted, reaction to the prepulse, if anything, tended to increase. It is concluded that PPI disruption induced by noncompetitive NMDA receptor antagonists can be distinguished from apomorphine-induced PPI disruption by their concomitant effects on prepulse-elicited reactivity. Our data support the suggestion that dopamine receptor agonists and NMDA receptor antagonists disrupt PPI via interference with distinct neural pathways or neuronal systems.     

A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating

BACKGROUND: Compared to outbred Sprague Dawley (SD) rats, inbred Brown Norway (BN) rats exhibit less prepulse inhibition of startle (PPI) at long prepulse intervals, and more PPI at short intervals. Sensitivity to dopaminergic drug effects on PPI differs substantially across strains, and is heritable within SD and other outbred strains. To further understand the heritability of PPI and its sensitivity to dopamine agonists, we assessed PPI and apomorphine sensitivity in SD, BN and F1 (SD x BN) rats. METHODS: PPI was measured in BN, SD and F1 rats under a variety of stimulus conditions, and after treatment with apomorphine. RESULTS: Findings confirmed significantly more PPI in BN compared to SD rats at short prepulse intervals, and significantly more PPI in SD compared to BN rats at long intervals. F1s were "supersensitive" to both the PPI-disruptive effects of apomorphine at longer intervals, and the PPI-enhancing effects of apomorphine at shorter intervals, compared to either parental strain. CONCLUSION: Differences in sensorimotor gating between SD and BN rats are robust, time-locked and consistent across studies. Unlike patterns in other strains, heritability of PPI apomorphine sensitivity phenotypes in SD x BN F1s cannot be easily explained by simple additive effects.     

Convergence and divergence in the neurochemical regulation of prepulse inhibition of startle and N40 suppression in rats.

Prepulse inhibition of startle ('PPI'), a cross-species measure of sensorimotor gating, is impaired in schizophrenia patients. Suppression of P50 event-related potentials (ERPs) in response to the second of two clicks ('P50 gating') is also impaired in schizophrenia. Suppression of N40 ERPs to the second of two clicks ('N40 gating') is thought by some to be a rat homolog of human P50 gating. Emerging evidence suggests differences in the neurobiology of deficits detected by PPI vs P50 (or N40) gating. We recorded PPI and N40 gating contemporaneously in rats, to assess convergence and divergence in the neurochemical regulation of these measures. Dose-response studies examined the effects of apomorphine (APO), phencyclidine (PCP) or the 5HT2A agonist DOI on PPI, and on motor responses to stimuli (S1 and S2) that elicit N40 gating. Effects of optimal drug doses on PPI and N40 gating were then assessed in other rats with implanted cortical surface electrodes. APO, PCP and DOI caused dose-dependent disruptions of both PPI and gating of motor responses to N40 stimuli. Reduced PPI reflected diminished prepulse effectiveness, demonstrated by increased startle levels on prepulse+pulse trials. In contrast, reduced gating of motor responses to N40 stimuli reflected a reduced motor response to S1. In separate rats, robust PPI, N40 potentials and N40 gating could be detected within one test. PPI and N40 gating were disrupted by APO, PCP, and DOI. Again, drug effects on PPI reflected increased startle on prepulse+pulse trials, while those on N40 gating reflected reduced ERP responses to S1. In conclusion, when PPI and N40 gating were studied concurrently in rats, drug effects on PPI reflected reduced inhibition of startle by the prepulse, while diminished N40 gating reflected S1 response suppression. Despite similarities in drug sensitivity, these results suggest that distinct neurobiological mechanisms underlie drug-induced deficits in PPI and N40 gating.     

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.     

Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice.

Although substantial literature describes the modulation of prepulse inhibition (PPI) by dopamine (DA) in rats, few reports address the effects of dopaminergic manipulations on PPI in mice. We characterized the effects of subtype-specific DA agonists in the PPI paradigm to further delineate the specific influences of each DA receptor subtype on sensorimotor gating in mice. The mixed D1/D2 agonist apomorphine and the preferential D1-family agonists SKF82958 and dihydrexidine significantly disrupted PPI, with differing or no effects on startle. In contrast to findings in rats, the D2/D3 agonist quinpirole reduced startle but had no effect on PPI. Pergolide, which has affinity for D2/D3 and D1-like receptors, reduced both startle and PPI, but only at the higher, nonspecific doses. In addition, the D1-family receptor antagonist SCH23390 blocked the PPI-disruptive effects of apomorphine on PPI, but the D2-family receptor antagonist raclopride failed to alter the disruptive effect of apomorphine. These studies reveal potential species differences in the DA receptor modulation of PPI between rats and mice, where D1-family receptors may play a more prominent and independent role in the modulation of PPI in mice than in rats. Nevertheless, due to the limited selectivity of DA receptor agonists, further studies using specific receptor knockout mice are warranted to clarify the respective roles of specific DA receptor subtypes in modulating PPI in mice.     

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.     

Heritable differences in the dopaminergic regulation of sensorimotor gating

RATIONALE AND OBJECTIVES: The disruption of prepulse inhibition (PPI) of startle in rats by dopamine agonists has been used in a predictive model for antipsychotics, and more recently, to study the neural basis of strain differences in dopaminergic function. We have previously reported that Sprague-Dawley (SDH) and Long Evans (LEH) rats differed in their sensitivity to the PPI-disruptive effects of the D(1)/D(2) agonist apomorphine (APO) in two distinct ways: 1) compared to LEH rats, SDH rats were more sensitive to the ability of APO to disrupt PPI with relatively long prepulse intervals (60-120 ms), and 2) APO enhanced PPI in LEH rats with 10-30 ms prepulse intervals, but this effect was limited to 10 ms prepulse intervals in SDH rats. METHODS: In the present study, we replicated this temporal profile in SDH versus LEH rats, assessed the role of D(1) versus D(2) substrates in the two components of this strain difference, and assessed the heritability of these temporally distinct processes. RESULTS: Pharmacologic studies revealed that: 1) D(2) blockade prevented the long interval PPI-disruptive effects of APO in both strains, and extended the temporal range of the PPI-enhancing effects of APO from 10 to 30 ms in SDH rats, and 2) D(1) blockade increased PPI and blocked the PPI-enhancing effects of APO at short intervals in both strains. Generational studies in adult F0 (SDH and LEH), F1 (SDHxLEH) and N2 (SDHxF1) rats demonstrated that sensitivity to APO of both short and long interval PPI were inherited in a manner suggestive of relatively simple additive effects of multiple genes. CONCLUSIONS: The present findings demonstrate that inherited differences in the dopaminergic regulation of sensorimotor gating are manifested not only in quantitative shifts (more versus less), but also in qualitative shifts in the temporal properties of sensorimotor gating that appear to be under separate control of D(1) and D(2) substrates.     

Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists

The disruption of prepulse inhibition (PPI) in rats by dopamine (DA) agonists is used to study the neural basis of strain differences in dopaminergic function. We reported that, compared to Long-Evans (LEH) rats, Sprague-Dawley (SDH) rats are more sensitive to the PPI-disruptive effects of the direct D1/D2 agonist apomorphine (APO) and the indirect DA agonist d-amphetamine (AMPH). This strain difference is heritable, with PPI drug sensitivity following a generational pattern (SDH>N2>F1>LEH) suggestive of additive effects of multiple genes. Here, we assessed the neurochemical bases for these heritable strain differences by measuring tissue levels of dopamine, serotonin (5HT) and their respective metabolites in several forebrain regions after vehicle, APO or AMPH administration. SDH rats were more sensitive than LEH rats to the PPI-disruptive effects of both APO (0.5 mg/kg) and AMPH (4.5 mg/kg). Several significant SDH vs. LEH strain differences in regional neurochemical levels were detected, as were drug effects on these chemicals. However, SDH, LEH and F1 rats did not exhibit differential drug sensitivity in any neurochemical indices measures. These findings suggest that inherited differences in the dopaminergic regulation of sensorimotor gating do not likely reflect differences in presynaptic forebrain dopaminergic or serotonergic processes.     

Comparison of apomorphine, amphetamine and dizocilpine disruptions of prepulse inhibition in inbred and outbred mice strains

The dopamine agonist apomorphine robustly disrupts prepulse inhibition of the acoustic startle response in the rat, yet published studies have not demonstrated a robust disruption of prepulse inhibition with apomorphine in the mouse. The aim of these studies was to establish the optimal prepulse conditions (using manipulations to prepulse intensity and inter-stimulus interval) and mouse strain(s) for testing apomorphine, and also the prepulse inhibition disrupting drugs amphetamine, and dizocilpine (MK-801). The effects of these drugs on startle response and prepulse inhibition were tested in outbred CD-1 and Swiss Webster (CFW) strains, and the inbred C57BL/6, 129X1/SvJ, and A/J strains. There were strain differences with baseline startle and prepulse inhibition in that the CD-1, CFW, and C57BL/6 strains exhibited high levels of startle and prepulse inhibition, the 129X1/SvJ strain exhibited low levels of startle but high levels of prepulse inhibition, while the A/J strain exhibited low startle and no prepulse inhibition. Apomorphine disrupted prepulse inhibition in the CFW and C57BL/6 strains and the effect was only evident when using a short 30 ms inter-stimulus interval. Amphetamine disrupted prepulse inhibition in the CFW, C57BL/6, and 129X1/SvJ strains, and dizocilpine disrupted prepulse inhibition in the CD-1, CFW, C57BL/6, and 129X1/SvJ strains. The effects of amphetamine and dizocilpine were independent of the inter-stimulus interval. These studies demonstrated clear strain differences in the startle response and prepulse inhibition, and the pharmacological disruptions of prepulse inhibition, and suggest that inter-stimulus intervals less than 100 ms may be optimal for detecting the effects of apomorphine in mice.     

Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats

Disruption of prepulse inhibition (PPI) induced by NMDA receptor antagonists, such as MK801, has been used as an animal model of positive and negative symptoms of schizophrenia. Previous studies suggested that atypical, but not typical, neuroleptics can selectively restore MK801-induced PPI disruption and that such selectivity may depend on strain differences. The present study re-examined PPI disruption by systemic MK801 in Wistar (WS) and Sprague-Dawley (SD) strains, and addressed the issue whether clozapine (atypical), compared to haloperidol (typical), effectively antagonizes MK801-induced PPI disruption. In addition, we tested the effects of bilateral microinfusion of MK801 into the ventral hippocampus in WS. Systemic MK801 disrupted PPI in both strains. Neither clozapine nor haloperidol antagonized MK801-induced PPI in either strain. Our clozapine data do not agree with previous reports of clozapine's ability to antagonize MK801-induced PPI disruption. Similar to previous results with SD, MK801 infusion into the ventral hippocampus failed to affect PPI in WS. In our view, the selective ability of atypical neuroleptics to restore PPI disruption by NMDA antagonists, and to serve as a tool for identifying possible atypical neuroleptics, requires further examination. PPI disruption with systemic MK801 may be due to the blockade of NMDA receptors in multiple brain sites.     

Heritable differences in the dopaminergic regulation of behavior in rats: relationship to D2-like receptor G-protein function.

We reported heritable differences between Sprague-Dawley (SD) and Long Evans (LE) rats in their sensitivity to the disruption of prepulse inhibition of startle (PPI) by dopamine (DA) agonists, and in their basal levels and turnover of forebrain DA. In an effort to better understand these differences, we assessed strain patterns in the efficacy of D2-like receptor-G-protein coupling using [35S]GTPgammaS binding in brain regions that contribute to the dopaminergic regulation of PPI. Sensitivity to the PPI-disruptive effects of apomorphine (APO) was examined in SD, LE, and F1 (SD x LE) rats. Basal and DA-stimulated [35S]GTPgammaS binding were then assessed in these rats using conditions that preferentially exclude Gs proteins to favor visualization of D2-like receptors. To explore the behavioral specificity of these strain differences, locomotor responses to APO and amphetamine (AMPH) were also assessed in SD, LE, and F1 rats. Strain differences were evident in the PPI-disruptive effects of APO (SD>F1>LE), and in the locomotor responses to AMPH (LE>F1>SD) and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DA-stimulated [35S]GTPgammaS binding in nucleus accumbens and caudatoputamen, while F1 progeny had intermediate levels. In conclusion, SD and LE rats exhibit heritable differences in D2-mediated behavioral and biochemical measures. Conceivably, genes that regulate heritable differences in forebrain D2 function may contribute to heritable differences in PPI in patients with specific neuropsychiatric disorders, including schizophrenia and Tourette Syndrome.     

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.