The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics?

Abstract

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.

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

“…Thus, the present data suggest that in this apomorphine-induced gating deficits model, a narrow window of efficacy exists between DA D 2 receptor blockade and serotonin 5-HT 1A receptor activation. While the latter property is considered to be desirable for attenuating negative, cognitive, and affective symptoms of schizophrenia, as well as neuroleptic-induced EPS (Millan, 2000;Bantick et al, 2001;Kleven et al, 2005), it appears that too pronounced an activation of 5-HT 1A receptors impairs the ability of compounds, such as SLV313 and SSR181507 to reverse apomorphine-induced PPI deficits. Taken together, these data indicate that 5-HT 1A activation can alter the antipsychotic-like effects of DA D 2 receptor antagonists in this model of positive symptoms of schizophrenia.…”

“…As a matter of fact, most atypical antipsychotics are DA D 2 and 5-HT 2 receptors blockers, and it has been proposed that antagonist activity at 5-HT 2 receptors prevents the deleterious effects of DA D 2 receptor blockade, that is, extrapyramidal signs (EPS) (Kapur, 1996;Remington and Kapur, 1999). Besides, there is ample preclinical evidence that activation of 5-HT 1A receptors should also prove beneficial in schizophrenia (Millan, 2000;Bantick et al, 2001;Ichikawa et al, 2001). Hence, it has been repeatedly shown that 5-HT 1A receptor agonists prevent catalepsy (an animal model of EPS) produced by blockade of DA D 2 receptors (Wadenberg and Ahlenius, 1991;Wadenberg et al, 1994;Neal-Beliveau et al, 1993;Prinssen et al, 1998Prinssen et al, , 1999Depoortere et al, 2003;Kleven et al, 2005).…”

Estrogen Prevents 5-HT1A Receptor-Induced Disruptions of Prepulse Inhibition in Healthy Women

“…The present study focused on the interaction of estrogen with central serotonin-1A (5-HT 1A ) receptor function. Evidence for the importance of 5-HT 1A receptors in schizophrenia includes post-mortem research (Burnet et al, 1997;Simpson et al, 1996) and some atypical antipsychotics having high affinity for 5-HT 1A receptors (Bantick et al, 2001).…”

Occupancy of Agonist Drugs at the 5-HT1A Receptor

“…It is an inhibitory G-protein coupled receptor that is located both presynaptically, as autoreceptors in the raphe nuclei, and postsynaptically, as heteroreceptors at highest density in the hippocampus and neocortex. In depression, reductions in 5-HT 1A receptor density have been found in a number of cortical regions using [ 11 C]WAY-100635 PET imaging (Drevets et al, 2000;Sargent et al, 2000), while in schizophrenia increases in receptor density have been found in prefrontal cortical regions using post-mortem techniques (reviewed in Bantick et al, 2001) although not with PET (Lombardo et al, 2002;Tauscher et al, 2002;Bantick et al, 2004).…”

“…This is of interest because 5-HT 1A agonists reduce neuroleptic-induced catalepsy and increase dopamine release in the frontal cortex in animals. In schizophrenia, they may therefore have efficacy against neurolepticinduced extrapyramidal side effects, negative symptoms, and perhaps cognitive impairment (reviewed in Bantick et al, 2001;Millan, 2000;Sharma and Shapiro, 1996). A drug's in vitro affinity for a receptor can be translated into adequate in vivo brain receptor occupancy if it has favorable absorption, metabolism, and passage across the blood-brain barrier.…”