SCH 23390 in the prefrontal cortex enhances the effect of apomorphine on prepulse inhibition of rats

Abstract

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.1 mg/kg subcutaneously, s.c.) and MK-801 (0.03 mg/kg s.c.) were obtained from preliminary dose-response studies. Intracerebral injection of 0.5 μg/side of the dopamine D1 receptor antagonist, SCH 23390, significantly enhanced the disruptive effect of apomorphine on PPI, but had no effect on its own or on startle amplitude or habituation. Furthermore, the effect of SCH 23390 on PPI was not seen with a lower dose (0.2 μg/side) or in combination with the NMDA receptor antagonist, MK-801. These data confirm and extend previous reports on the importance of dopaminergic innervation of the prefrontal cortex in the regulation of PPI. It is suggested that apomorphine treatment directly or indirectly activates dopamine D1 receptors in the prefrontal cortex to inhibit its own action on PPI elsewhere in the brain, presumably in the nucleus accumbens. Antagonism of this inhibitory component by SCH 23390 therefore leads to a larger disruption of PPI.

Introduction

The observation that all clinically effective antipsychotic drugs are capable of blocking dopamine D2 receptors and the fact that dopamine releasing agents like amphetamine can produce a paranoid psychosis, have led to the concept that schizophrenia reflects a state of dopaminergic hyperactivity (Carlsson et al., 2001, Joyce, 1993). This theory, known as the ‘dopamine hypothesis of schizophrenia’ can best explain the ‘positive symptoms’ of schizophrenia that are thought to involve enhancement of functions that are normally present but have been disinhibited. The ‘negative symptoms’ on the other hand, are suggestive of a loss of dopaminergic function in other brain regions, particularly the prefrontal cortex (PFC). As an extension of the original hypothesis, it is therefore now widely recognized that in addition to subcortical dopaminergic hyperactivity in schizophrenia, there is likely to be a functional deficit in dopamine neurotransmission in the PFC (Carlsson et al., 2001, Okubo et al., 1997). In addition, it is clear that other neurotransmitters, particularly glutamate, are involved in the pathogenesis of schizophrenia (Carlsson et al., 2001).

There is considerable evidence that several aspects of cognitive function depend directly upon the integrity of the PFC. Patients with schizophrenia perform poorer on tests of attention and working memory, tasks that have been linked in human and non-human primate studies with prefrontal function (Andreasen et al., 1992, Goldberg et al., 2004). The PFC receives a major dopaminergic innervation arising from the ventral tegmental area (Emson and Koob, 1978, Lindvall et al., 1978) and there is considerable evidence that dopamine in the PFC subserves critical cognitive abilities in humans, non-human primates and rodents (Brozoski et al., 1979, Seamans et al., 1998). Within the PFC, dopaminergic fibres form contacts with pyramidal cells, either directly or indirectly via GABA-ergic interneurons, and inhibit their firing. The pyramidal cells form the primary efferents of the PFC and send excitatory glutamatergic projections back to the ventral tegmental area and subcortical regions such as the nucleus accumbens and the striatum. In the nucleus accumbens, these glutamatergic projections synapse on, or in proximity of, dopamine terminals that arise from the ventral tegmental area and stimulate their activity (Carr et al., 1999, Goldman-Rakic et al., 1992, Gulledge and Jaffe, 1998).

Dopamine D1 receptors are 10–20 times more abundant throughout the cortex than dopamine D2 receptors (Lidow et al., 1998). Furthermore, a PET study has shown that schizophrenic patients have reduced dopamine D1 receptor binding sites in the PFC, a reduction which is related to the severity of the negative symptoms and to poor performance in the Wisconsin Card Sorting Test (Okubo et al., 1997). Systemic administration of a combined D1/D2 receptor agonist, but not a D2 receptor agonist only, facilitates working memory processes in humans (Muller et al., 1998). Local application of the dopamine D1 receptor antagonist, SCH 23390, to the PFC of rats has been found to reduce the accuracy of attentional performance (Granon et al., 2000) and to disrupt the performance on delayed tasks which require short-term memory (Seamans et al., 1998). In both studies, the dopamine D2 receptor antagonist, sulpiride, was without effect.

Prepulse inhibition of startle is the reduction of the startle response to sudden, high intensity sensory stimuli when these stimuli are preceded by a weak prepulse. It has been hypothesized that deficient PPI reflects the loss of the ability to gate out irrelevant sensory information (sensorimotor gating) which leads to sensory flooding and cognitive fragmentation (Braff and Geyer, 1989, Swerdlow and Geyer, 1998). Multiple studies have shown that patients with schizophrenia do not adequately gate sensory stimuli and therefore show deficiencies in PPI (Braff et al., 2001, Grillon et al., 1992, Kumari et al., 2000). In rats, PPI can be disrupted by systemic administration of direct and indirect dopamine receptor agonists, such as apomorphine and glutamate receptor antagonists, or by surgical manipulations of brain regions such as the medial PFC, the nucleus accumbens, the ventral hippocampus and the amygdala (Geyer et al., 2001, Van den Buuse et al., 2003). The role of dopaminergic activity in the PFC is unclear. Some previous studies suggested no effect on PPI of dopamine receptor blockade in this area (Bast et al., 2002, Lacroix et al., 2000) while in others, intra-PFC injection of a dopamine D1 receptor antagonist caused a disruption of PPI (Ellenbroek et al., 1996). Similarly, reduction of dopaminergic activity in the PFC by local 6-hydroxydopamine-induced dopamine depletion was shown to cause a reduction of PPI (Bubser and Koch, 1994).

To re-evaluate the effects of dopaminergic hypofunction in the PFC on PPI, the present study was aimed at investigating the effect of local micro-injection of a dopamine D1 receptor antagonist in the medial PFC of the rat. The medial PFC in the rat is the equivalent of the dorsolateral PFC in humans, the part of the PFC which appears most affected in glucose utilization and rCBF studies in schizophrenics. Furthermore, the medial section of the PFC contains the highest density of dopamine innervation (Emson and Koob, 1978). Rats were injected into the PFC and tested in the PPI model not only in the unstimulated condition, but also after subcutaneous administration of the dopamine receptor agonist, apomorphine, and the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, causing hyperdopaminergic and hypoglutamatergic states, respectively. It was hypothesized that dopamine D1 receptor blockade in the PFC would render animals more vulnerable to enhanced dopaminergic or decreased glutamatergic activity in subcortical structures.