Hippocampal lesions enhance startle gating-disruptive effects of apomorphine in rats: a parametric assessment.

Prepulse inhibition of the startle reflex is an operational measure of sensorimotor gating that is impaired in schizophrenia patients and dopamine agonist-treated rats. Previous reports demonstrated an enhanced sensitivity to the prepulse inhibition-disruptive effects of the D(1)/D(2) agonist apomorphine in adult rats four weeks after cytotoxic lesions of the hippocampus, but left unanswered several important questions regarding the nature of this apparent lesion-induced dopamine supersensitivity. Because of the potential importance of this model to current theories of the pathophysiology of schizophrenia, studies now assessed specific features of this effect of hippocampus lesions on prepulse inhibition in rats. The enhanced prepulse inhibition-disruptive effects of apomorphine in ventral hippocampus-lesioned rats were unaffected by startle pulse intensity, suggesting an independence of this lesion effect from potential ceiling effects of elevated startle magnitude. These lesion effects were observed four weeks post-lesion, but not two weeks post-lesion, suggesting a delayed development of this phenomenon. No enhancement of apomorphine sensitivity was observed in rats four weeks after lesions restricted to the dorsal hippocampus; in contrast, these lesions significantly increased "no-drug" levels of prepulse inhibition. Ventral hippocampus-lesioned rats exhibited a significant reduction in prepulse inhibition after subthreshold doses of either the selective D(2)-family agonist quinpirole or the partial D(1) agonist SKF 38393, suggesting that activation of either receptor family is adequate for the expression of this effect of ventral hippocampus lesions. This may be an important paradigm for understanding the contribution of ventral hippocampus dysfunction to the neurobiology of impaired sensorimotor gating in neuropsychiatric populations.

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.

Towards a cross-species pharmacology of sensorimotor gating: effects of amantadine, bromocriptine, pergolide and ropinirole on prepulse inhibition of acoustic startle in rats.

Animal models in behavioral pharmacology can be evaluated based on their face, predictive and construct validity. A further level of validity may be achieved if a model is reproduced precisely across species--from laboratory animal to human--using identical conditions and manipulations to elicit identical behavioral changes. Under circumstances in which a model achieves 'homologous' validity, it should be possible to demonstrate that the same pharmacological agents produce parallel changes in the same behavior (as distinct from the clinical condition that the animal behaviors are hypothesized to model), when studied in laboratory animals and in humans. Studies have demonstrated that the disruption of sensorimotor gating of the startle reflex, measured by prepulse inhibition (PPI), in rats by dopamine agonists exhibits face, predictive and construct validity for the relative loss of PPI in schizophrenia patients. To assess the homologous validity of this model, and to expand its utility in understanding the pathophysiology of sensorimotor gating deficits and in developing novel antipsychotic agents to reverse these deficits, it will be important to study PPI across species, comparing response profiles to identical pharmacological manipulations. In the present studies, we report that PPI in rats is reduced in a dose-dependent manner by four dopamine agonists that can be administered with relative ease to humans. We also report that the PPI-disruptive effects of the clinically useful dopamine agonist pergolide are reversed by both typical and atypical antipsychotics. These studies establish a foundation for pursuing human pharmacological studies of PPI, and for extrapolating the substantial neurochemical and neurophysiological information from animal studies of PPI, towards understanding the neural basis for deficient sensorimotor gating in specific neuropsychiatric disorders.

Do D1/D2 interactions regulate prepulse inhibition in rats?

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is reduced in schizophrenia patients and in dopamine (DA)-activated rats. We previously found that PPI is disrupted by systemic administration of the D2 agonist quinpirole, but not by the D1 agonist SKF 38393. In this report we further characterize the D1 and D2 substrates and their potential interactions in the regulation of PPI in rats. PPI is reduced by concomitant administration of the D1 agonist SKF 38393 (5 mg/kg; relative affinity D1:D2 = 50:1) and by a subthreshold dose (0.1 mg/kg) of the D2 agonist quinpirole, but not by either drug given alone at these doses. Pretreatment with the D2 antagonist raclopride (0.05 mg/kg), but not the D1 antagonist SCH 23390 (0.05 mg/kg), blocks the SKF 38393/quinpirole synergistic reduction of PPI. The relative D1 agonist SKF 82958 (5 mg/kg; relative affinity D1:D2 = 10:1) disrupts PPI, and this effect of SKF 82958 is reversed by the D2 antagonist raclopride but not by the D1 antagonist SCH 23390. Consistent with a recent report (Hoffman and Donovan 1994), the PPI-disruptive effects of the D1/D2 agonist apomorphine (0.5 mg/kg) could be blocked by pretreatment with the D1 antagonist SCH 23390. Surprisingly the PPI-disruptive effects of quinpirole are also opposed by pretreatment with SCH 23390. Our present findings confirm that D2 receptors are important for the regulation of PPI in rats, but they also suggest that there exists a synergistic interaction between D1 and D2 substrates in the regulation of PPI. D1 receptors might modulate PPI in a "rate-dependent" manner in which tonic D1 activity is essential for the full manifestation of the D2-mediated modulation of PPI. However, D1 receptors do not appear to participate in the modulatory mechanisms of sensorimotor gating as an independent substrate.

A comparison of the effects of amphetamine, strychnine and caffeine on prepulse inhibition and latent inhibition.

Sensorimotor gating deficits characterize several neuropsychiatric disorders, including schizophrenia. Prepulse inhibition (PPI) and latent inhibition (LI) are measures that are used to assess sensorimotor gating and have been found to be reduced in schizophrenia patients. In PPI, a weak stimulus presented immediately prior to a startling stimulus attenuates the startle response. In LI, pre-exposure to a stimulus retards the subsequent association of that stimulus with a consequence (e.g. footshock). In rats, indirect dopamine (DA) agonists such as amphetamine disrupt both PPI and LI. Amphetamine has also been reported to increase exploratory locomotion at doses that decrease PPI and LI. Such behavioral activation might complicate the interpretation of amphetamine-induced changes in measures of sensorimotor gating. The present study was conducted in order to compare the effects of three behaviorally activating drugs on PPI, LI and locomotor activity. Separate groups of rats were treated with either vehicle, the DA releaser amphetamine (1.5mg/kg), the glycine antagonist strychnine (0.75mg/kg), or the adenosine receptor antagonist caffeine (10mg/kg) and then tested in either startle chambers (for PPI) or an active avoidance chamber (for LI). Locomotion was measured by inter-trial crossing in the avoidance chamber. Amphetamine stimulated locomotion and disrupted both PPI and LI, but did not elevate startle amplitude. In contrast, caffeine increased locomotion, but had no effect on PPI or LI. Strychnine did not increase locomotion significantly, but did increase startle amplitude and disrupt PPI and LI. Hence, neither increased startle amplitude nor locomotor activation are necessary or sufficient conditions for disruption of sensorimotor gating as measured by PPI and LI.

Seroquel (ICI 204,636) restores prepulse inhibition of acoustic startle in apomorphine-treated rats: Similarities to clozapine.

Seroquel (ICI 204,636) is a mixed D2/5HT2 antagonist with a preclinical profile suggestive of potential antipsychotic efficacy. We compared seroquel to clozapine in an animal model of sensorimotor gating deficits in shizophrenic patients. Like schizophrenic patients, rats treated with apomophrine (APO) exhibit deficits in prepulse inhibition (PPI) of acoustic startle. The ability of antipsychotics to restore PPI in APO-treated rats correlates (Rs = 0.991) with their clinical potency. Seroquel and clozapine both restore PPI in APO-treated rats. Seroquel's restoration of PPI in apomorphine-treated rats follows simple monotonic ascending dose-response properties, and is not accompanied by consistent changes in startle reflex amplitude. Seroquel's profile in this PPI model mimics that of other antipsychotics.

Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients.

Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency (rs = .991) and D2-receptor affinity (rs = .893). Antipsychotics that restore PPI in apomorphine-treated rats include "typical" antipsychotics and the "atypical" antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.