Increasing attention is being directed towards the role of the serotonergic system in the neurochemistry of schizophrenia and antipsychotic drug treatment. This review considers the 5-HT1A receptor in this context. In patients with schizophrenia, the majority of post-mortem studies have reported increases in 5-HT1A receptor density in the prefrontal cortex in the approximate range 15-80%. Although the pathophysiological significance of this finding is unclear, given the location of a major proportion of these receptors on pyramidal cells, it may reflect an abnormal glutamatergic network. In terms of drug treatment, 5-HT1A agonists clearly display anticataleptic activity in rats. In addition, 5-HT1A agonists consistently increase dopamine release in the prefrontal cortex in rodents, which is an effect that might be predicted to improve negative symptoms. 5-HT1A agonists augment classical neuroleptics in some rat models of antipsychotic action and may be capable of modulating the glutamatergic network therapeutically. Despite the encouraging preclinical data, there is a paucity of clinical studies of 5-HT1A agonist augmentation of neuroleptics in the treatment of schizophrenia. However, the clinical relevance may be clarified by the atypical antipsychotic drugs clozapine, quetiapine and ziprasidone which combine D2 receptor antagonism and 5-HT1A agonism. In conclusion, given the increased prefrontal 5-HT1A receptor density in the illness, and the anticataleptic activity of 5-HT1A agonists combined with their ability to evoke prefrontal dopamine release, there is now a sufficient rationale to examine thoroughly the role of the 5-HT1A receptor in schizophrenia and antipsychotic drug treatment.

There is now substantial evidence from animal studies showing modulation of cognitive performance after administration of dopaminergic agents. Previous studies have focused on cognitive functions such as working memory (WM), with particular reference to spatial processing. However, to date, studies in normal human volunteers have proved inconsistent. We have therefore tested the effects of the dopamine D2 receptor antagonist sulpiride (400 mg) on WM and learning tasks, including those using auditory, spatial or non-spatial stimuli. A further aim was to explore a broader role of the dopaminergic system in mnemonic function by examining long-term and emotional memory. Eighteen healthy male participants were given a battery of cognitive tests after oral sulpiride or placebo, using the cross-over design. WM was assessed using a spatial searching task, and a task of auditory counting with distraction. Tasks that did not emphasize WM were spatial and non-spatial trial-and-error learning, long-term spatial memory and emotional memory. After dopamine D2 receptor blockade, performance was not impaired on the spatial WM (SWM) task, but was impaired on the auditory counting task with distraction. Sulpiride did not impair, but rather appeared to enhance trial-and-error learning overall. Thus, we were unable to support the notion that dopaminergic modulation preferentially influences spatial over non-spatial processing during learning. In addition, recognition was impaired in the emotional memory task after encoding on drug compared to placebo. These findings question the precise role of dopamine D2 receptor modulation on WM, and highlight the need for sensitive tests to study dopaminergic modulation of emotional processing.

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

5-HT1A receptor agonists consistently reduce neuroleptic induced catalepsy in rats. A serotonin-dopamine interaction has been proposed to underlie this effect. Specifically, 5-HT1A receptor agonists may reduce the activity of serotonergic projections that inhibit dopaminergic nigrostriatal neurones, therefore increasing dorsal striatal dopamine levels and partially overcoming the neuroleptic blockade of D2 receptors. We tested the hypothesis that 5-HT1A receptor agonists increase striatal dopamine release in man using PET scanning with the selective D2 receptor radioligand [11C]raclopride, which is sensitive to endogenous dopamine levels. Six healthy volunteers received two PET scans, one after placebo, the other after 1 mg flesinoxan, a selective 5-HT1A receptor agonist. Binding potential values for striatal subdivisions were determined using a simplified reference tissue model. We did not find any difference in striatal [11C]raclopride binding between conditions, even though flesinoxan lead to typical 5-HT1A receptor agonist side effects and produced elevation of growth hormone in five of the six subjects. Our results suggest that the anticataleptic effect of 5-HT1A receptor agonists is not mediated by striatal dopamine release, and indicates a need for further research with other suitable 5-HT1A receptor agonists.

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