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Prepulse inhibition of acoustic startle is the normal reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Previous studies have shown that several neuroanatomical structures and pathways in the brain are involved in the modulation of prepulse inhibition. In the present study, the functional importance of the medial geniculate body (MG) in the modulation of prepulse inhibition was investigated. To this end, in vivo brain microdialysis probes were used to infuse drugs locally into the MG of awake, freely moving rats simultaneously with startle response and prepulse inhibition measurements in the same animals. Intrageniculate infusion of the sodium channel blocker, tetrodotoxin, significantly reduced prepulse inhibition without affecting baseline startle amplitude. A similar effect was obtained after intrageniculate infusion of the GABA(B) receptor agonist, baclofen. In addition, intrageniculate infusion of muscimol, an agonist at the GABA(A) receptor complex, reduced prepulse inhibition, although this effect was obtained at a higher concentration of the drug compared to that of baclofen. These studies suggest that the MG is involved in the modulation of prepulse inhibition and that auditory signals relayed via the MG may be subjected to inhibitory control at this level, involving GABA neurotransmission.

The ability of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to block the behavioural effects of the potent psychotomimetic, phencyclidine, was tested in rats using two different behavioural models. L-NAME was found to block both phencyclidine-induced disruption of prepulse inhibition of acoustic startle and phencyclidine-induced stimulation of locomotor activity. A selective action of L-NAME on the effects of phencyclidine was indicated, since L-NAME did not alter the effects of amphetamine, another potent psychotomimetic, in these behavioural models. These observations suggest that a nitric oxide-dependent mechanism may be involved in the effects of phencyclidine in the central nervous system.

The effect of various typical (haloperidol) and atypical (clozapine, raclopride, remoxipride) antipsychotics on phencyclidine (PCP)-induced disruption of sensorimotor gating was tested in rats using an acoustic startle paradigm. Clozapine (4-40 mumol/kg), haloperidol (1-5 mumol/kg) and raclopride (1-12 mumol/kg) failed to reverse PCP-induced disruption of prepulse inhibition (PPI) of the acoustic startle response. In contrast, remoxipride (12-60 mumol/kg) caused a dose-dependent block of this effect. PCP-induced disruption of PPI is a widely accepted animal model of a corresponding behavioural deficit observed in schizophrenia although little evidence has been presented that it is in fact sensitive to antipsychotic agents. The present results indicate that remoxipride behaves in a unique way in this model compared to clozapine, haloperidol and raclopride.

The psychotomimetic drug, phencyclidine, induces schizophrenia-like behavioural changes in both humans and animals. Phencyclidine-induced disruption of sensory motor gating mechanisms, as assessed by prepulse inhibition of the acoustic startle, is widely used in research animals as a screening model for antipsychotic properties in general and may predict effects on negative and cognitive deficits in particular. Dopamine (DA) stabilizers comprise a new generation of antipsychotics characterized by a partial DA receptor agonist or antagonist action and have been suggested to have a more favourable clinical profile.The aim of the present study was to investigate the ability of first, second and third generation antipsychotics to interfere with the disruptive effect of phencyclidine on prepulse inhibition in mice.Aripiprazole blocked the phencyclidine-induced disruption of prepulse inhibition. The atypical antipsychotic clozapine was less effective, whereas olanzapine, and the typical antipsychotic haloperidol, failed to alter the effects of phencyclidine on prepulse inhibition.The somewhat superior efficacy of clozapine compared to haloperidol may be explained by its lower affinity and faster dissociation rate for DA D2 receptors possibly combined with an interaction with other receptor systems. Aripiprazole was found to be more effective than clozapine or olanzapine, which may be explained by a partial agonist activity of aripiprazole at DA D2 receptors. In conclusion, the present findings suggest that partial DA agonism leading to DA stabilizing properties may have favourable effects on sensorimotor gating and thus tentatively on cognitive dysfunctions in schizophrenia.

The cognitive and attentional deficits observed in schizophrenic patients are now considered central to the pathophysiology of the disorder. These deficits include an inability to filter sensory input as measured by, e.g., prepulse inhibition (PPI) reflex. Administration of phencyclidine (PCP), a drug that can induce a schizophrenia-like psychosis in humans, disrupts PPI in experimental animals. In rodents, this PCP-induced deficit can be blocked by pretreatment with nitric oxide (NO) synthase inhibitors. This suggests that some of the behavioral effects of PCP are mediated via NO. The substrate for in vivo NO production is l-arginine, and active transport of l-arginine via the cationic amino acid transporter may serve as a regulatory mechanism in NO production. The aim of the present study was to study the effects of l-arginine transport inhibition, using acute and repeated l-lysine treatment, on PCP-induced disruption of PPI in mice. Subchronic, and to some extent acute, pretreatment with l-lysine blocked a PCP-induced deficit in PPI without affecting basal PPI. l-lysine has been shown to block l-arginine transport in vitro, most likely via a competitive blockade and down regulation of cationic amino acid transporters. However, the importance of l-arginine transport as a regulatory mechanism in NO production in vivo is still not clear. The present results lend further support to the notion that some of the effects of PCP in the central nervous system are mediated via NO and that l-arginine transport may play a role in the regulation of NO production in the brain.

Schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP.The aim of the present study was to investigate the effects of PCP on cAMP production in the ventral hippocampus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in cAMP levels in the ventral hippocampus.Significant increases in cAMP levels were observed in the ventral hippocampus following both local infusion (10(-4) mol/l and 10(-3) mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in cAMP levels in the hippocampus. Furthermore, systemic administration of the NO synthase inhibitor, L: -NAME (10 mg/kg), blocked both the changes in cAMP levels and the behavioural responses induced by PCP.These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in cAMP levels in the ventral hippocampus, and that this change in cAMP response may be linked to the production of NO.

A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP. The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation. PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801. The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.

Rationale: Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like syndromes can be induced in humans by phencyclidine (PCP), a drug with marked psychomimetic properties. Recent studies show that the behavioural and biochemical effects of PCP in rats are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in the pharmacological effects of PCP. Objective: The aim of this study was to investigate if PCP-induced disruption of prepulse inhibition of acoustic startle could be blocked by the NOS inhibitor, L-NAME, in mice. Results: The present study shows that PCP readily disrupts prepulse inhibition in mice normally without affecting pulse-alone trials. Furthermore, L-NAME blocked the PCP-induced disruption of prepulse inhibition in a dose-related manner. Conclusions: The PCP-induced disruption of prepulse inhibition and the ability of L-NAME to block this effect in both rats and mice suggest that this is a general and not a species-specific effect. The results of the present study further suggest that PCP exerts at least some of its actions in the central nervous system by a NO-dependent mechanism.

Rationale: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Objective: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. Results: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. Conclusions: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.

Male Sprague-Dawley rats were repeatedly treated with amphetamine (AMP, 1 mg/kg, SC) at 3- day intervals for 15 days and tested for prepulse inhibition of acoustic startle after each treatment. This treatment regimen induced sensitisation in the animals as evidenced by a progressive increase in the disruptive effect of AMP on prepulse inhibition. Persistent changes in brain function was indicated, since an increase in disruptive effect was observed in sensitised animals also after a 22-day-long drug- and test-free period. The development of sensitisation was blocked by pretreatment with haloperidol (HPD, 0.1 mg/kg, SC), which suggests that sensitisation to the disruptive effect of AMP was dependent on dopamine (DA) D2 receptor activation. Furthermore, the development of sensitisation was blocked by adrenalectomy, which suggests that sensitisation was dependent also on circulating adrenal hormones. Increased DA-ergic activity has been implicated in the pathophysiology of schizophrenia and AMP-induced sensitisation to the neuronal functions that modulate prepulse inhibition may be an experimental model to investigate this hypothesis.

The beta-adrenoceptor antagonist as well as serotonin 5-HT1 receptor antagonist, (-)alprenolol, was found to potentiate the disrupting effect of the noncompetitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (-)alprenolol. (-)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective beta-adrenoceptor antagonist property of (-)alprenolol, since combined pretreatment with the beta1- and beta2-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT2 selective receptor antagonist, MDL 100907, significantly reduced the (-)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT3 selective receptor antagonist, ondansetron, failed to do that. Finally, the (-)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D2 receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.

The effect of local injection of pertussis toxin (PTX) into the ventral tegmental area (VTA) on acoustic startle in rats was investigated. The PTX treatment caused only minor effects of its own on the acoustic startle response (ASR) or prepulse inhibition (PPI) of acoustic startle. However, systemic treatment with the indirect DA receptor agonist, amphetamine (2 mg/kg, SC) caused a significant increase in ASR magnitude and a significant disruption of PPI in PTX-treated rats while no such effects were observed in sham-treated rats. Treatment with the direct DA receptor agonist, apomorphine (2 mg/kg, SC), caused a significant disruption of PPI, an effect that was observed in both PTX- and sham-treated rats. Treatment with the 5-HT1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, SC), did not affect PPI in either group but caused a marked increase in ASR magnitude in sham-treated rats. Interestingly, this effect was blocked in PTX-treated rats. The present results suggest that local injection of PTX into the VTA causes an increased sensitivity to the behavioural effects of psychostimulants on acoustic startle and may also suggest that intact midbrain 5-HT1A receptors are essential for the effect of 5-HT1A agonists on acoustic startle.

The effect of diazepam on spontaneous and tail-pinch-induced behaviour was monitored together with the measurement of extracellular ascorbate using constant potential voltammetry with carbon paste electrodes. Diazepam (3 mg/kg) was followed by eating during the 1st hour after administration in non-food-deprived rats and a reduction in the behaviour triggered by a mild tail-pinch 90 min after drug administration. There was no change in ascorbate concentration in parallel with the spontaneous eating; however, the brisk increase in ascorbate concentration in striatum, nucleus accumbens and hippocampus, which accompanies the tail-pinch, was decreased in size and duration after diazepam. This effect was blocked by the central benzodiazepine receptor antagonist Ro15 1788 (5 mg/kg).

Five ergot-related compounds were examined for their effects on the acoustic startle response in the rat. The startle amplitude and the startle latency were registered. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.5–8 mg/kg) and lisuride (0.05–0.8 mg/kg) were found to enhance the startle amplitude, while the mainly DA receptor active ergot derivatives pergolide (0.2–0.8 mg/kg), bromocriptine (5–20 mg/kg) and LY 141865 (5–20 mg/kg) had no, or even the reverse, effect. All five compounds caused a prolongation of the startle latency. The increased startle amplitude caused by 8-OH-DPAT (2 mg/kg) and lisuride (0.2 mg/kg) was successfully antagonized by the 5-HT receptor antagonist methiothepin (0.1 mg/kg) but not by metergoline (1 mg/kg). 5-Hydroxy-L-tryptophan (L-5-HTP; 12.5–50 mg/kg), administered to pargyline- and benserazide-pretreated animals, was included for comparison. The serotonin precursor caused a marked increase in the startle amplitude and a shortening of the startle latency.

The 5-hydroxytryptamine (5-HT) reuptake inhibitors zimelidine (10 mg/kg IP 1.5 h pretest) or alaproclate (20 mg/kg IP 1.5 h pretest) produced a prolongation of the ejaculation latency and of the post-ejaculatory interval in male rats treated with a subthreshold dose of 5-hydroxytryptophan (5-HTP) (12.5 mg/kg IP 1 h pretest). The 5-HTP-induced (50 mg/kg IP 1 h pretest) prolongation of ejaculatory latency was effectively counteracted by administration of the 5-HT receptor blocking agent metergoline (1 mg/kg IP 1.5 h pretest). All animals were treated with an inhibitor of peripheral aromatic amino acid decarboxylase, indicating that the effects are of central origin. The results support the contention that central 5-HT plays an inhibitory role in male rat sexual behavior.