Do Central Antiadrenergic Actions Contribute to the Atypical Properties of Clozapine?

Abstract

Full neuropharmacological understanding of the atypical antipsychotic agent clozapine remains elusive. Antidopaminergic actions of most neuroleptics probably contribute to their antipsychotic benefits, but also to neurological side-effects. Clinical evidence of abnormalities of dopamine (DA) and serotonin (5-HT) in psychotic disorders is inconsistent, but there is substantial metabolic and post-mortem evidence for hyperactivity of noradrenalin (NA). Clozapine is only weakly antidopaminergic but is a potent antagonist at brain α1-adrenergic, 5-HT2-serotonergic, and muscarinic receptors. Its apparent limbic-over-extrapyramidal neuro-physiological selectivity can be mimicked by combining a typical neuroleptic with a central α1 antagonist. Clozapine strongly upregulates α1, but not DA, receptor abundance, and may supersensitise α1 but not DA receptors in rat brain. Clozapine also selectively increases activity of NA neurons and metabolic turnover in NA more than DA areas of rat brain, and also increases NA, but not DA or 5-HT, metabolites in human CSF. Potential psychotropic effects of selective central antiadrenergic agents may deserve reconsideration.

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

“…Clozapine binds with high affinity to D4, 5-HT 1A, 2A , a1 adrenergic, histamine H1 and muscarinic receptors, and with lower affinity for D1, D2, D3 and D5 receptors. [58][59][60][61][62] While the significant effect of haloperidol upon PPI, independent of genotype, is consistent with previous studies, 63 clozapine mediated a complete rescue of PPI deficits in the KO mice. Thus, at the level of PPI behavior, environmental enrichment is acting in a parallel manner to clozapine, an atypical antipsychotic drug with clinical efficiency.…”

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

“…In fact, some have proposed that the noradrenergic system may be an important component in the therapeutic actions of certain antipsychotic medications (Baldessarini et al, 1992;Breier, 1994;Cohen and Lipinski, 1986;Prinssen et al, 1994;Svensson et al, 1995). Several disorders with deficient sensorimotor gating, such as ADHD and PTSD have hypothesized pathology within the NE system (AstonJones et al, 1999;Southwick et al, 1999), and there is some evidence that administration of clonidine, which decreases noradrenergic transmission from the LC, improves conduct symptoms in patients with ADHD and global symptoms in patients with PTSD (Hazell and Stuart, 2003;Kinzie and Leung, 1989;Porter and Bell, 1999).…”

Increase of Dialysate Dopamine in the Bed Nucleus of Stria Terminalis by Clozapine and Related Neuroleptics

“…Also devoid of (Leysen et al 1985), (0.5 and 1.5 mg/kg IP), (Figure 10) and the adrenergic ␣ 1 antagonist prazosin (Baldessarini et al 1992), (0.91 and 2.73 mg/kg IP), (Fig. 11).…”