Dose-dependent effects of haloperidol (2.66 nmollkg to 79.8 mmollkg, IP) on levels of dopamine, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were assessed in the corpus striatum, nucleus accumbens, and medial prefrontal cortex (PFCTX) of 18-, 30-, and 110-day-old rats. Eighteen-day-old rats were 35% and 63% more sensitive than adults to the effects of haloperidol on striatal and accumbens turnover and had steeper dose-response curves. The dose-response function in the PFCTX was similar to striatum at 18 days, but KEY WORDS: Haloperidol; Dopamine; Corpus striatum; Nucleus accumbens; Prefrontal cortex; DevelopmentHaloperidol is a prototypical neuroleptic agent that has value throughout the lifespan in the treatment of psy chotic disorders and behavioral agitation (e.g., Baldes sarini, 1985). Some clinical data are available to guide dosing with this or other antipsychotic agents in adults (Baldessarini et al. 1989), but much less is known about optimal dosing in childhood or adolescence (Teicher and Glod 1989). A rational initial approach is to ascer tain whether there are important developmental differ ences in the behavior and neuropharmacologic effects became shallower and nonsigmoidal with age. Maximally effective doses of haloperidol produced, at all ages, a comparable percent rise in DOPAC levels in all regions. With maturation, the percent rise in HV A progressively outstripped DOPAC response in nucleus accumbens and striatum. Overall, prominent developmental differences emerged in these regions in their sensitivity and response to haloperidol, which are consistent with previously reported differences in behavioral sensitivity.INeuropsychopharmacology 9:147-156, 1993J of this representative agent on laboratory animals. Studies by Campbell and Baldessarini and colleagues (Campbell and Baldessarini 1981;Campbell et al. 1988) found that developing rats are much more sensitive to the acute behavioral effects of neuroleptics than adults. The EDso for haloperidol-induced catalepsy, sedation (ptosis), and bradykinesia, respectively, was 16-, 60-, and 75-fold lower in 1-month-old rats than in 18-month old rats (Campbell and Baldessarini 1981). These differ ences were not accounted for by drug disposition fac tors. First, similar age differences occurred in response to a chemically dissimilar neuroleptic, perphenazine (Campbell et al. 1988). Even more signifIcantly, paral lel age differences in dose response to haloperidol and perphenazine were obtained following direct intracere broventricular administration, which bypassed the effects of peripheral metabolism, distribution, and blood-brain barrier penetration (Campbell et al. 1988). These observations strongly suggest that there are im portant pharmacodynamic differences across age in sen sitivity to neuroleptic agents. Supporting these fIndings
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.
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