Haloperidol and Cerebral Metabolism in the Conscious Rat: Relation to Pharmacokinetics

Abstract

The time course and distribution of alterations in cerebral metabolic activity after haloperidol administration were evaluated in relation to the pharmacokinetics of haloperidol and the topography of the dopaminergic system in the brain. Local cerebral glucose utilization was measured, using the 2-deoxyglucose technique, in awake rats after i.p. administration of the dopamine antagonist haloperidol (0.5 or 1 mg/kg). Haloperidol significantly reduced glucose utilization in 60% of 59 brain regions examined, but produced a large increase in the lateral habenula. The regional distribution of changes in glucose utilization was not closely related to the known anatomy of the brain dopaminergic system. The time course of the effect of haloperidol on cerebral metabolism was different for the two doses studied (0.5 and 1 mg/kg), and was not simply related to estimated brain concentrations of haloperidol. However, a linear relation between the metabolic effect and the time-integrated brain concentration was demonstrated. These results show that haloperidol has an effect on CNS metabolic activity that is more widespread than would be predicted from the topography of the dopaminergic system; this may be due to indirect propagation of the primary effects of haloperidol. The metabolic response to haloperidol depends on brain concentration and duration of exposure to the drug.

Patterns of Brain Glucose Metabolism Induced by Phosphodiesterase 10A Inhibitors in the Mouse: A Potential Translational Biomarker

“…Moreover, the doses required for the induction of specific 2-DG changes by the PDE10A inhibitors were also in line with doses generally needed for efficacy in behavioral assays (Siuciak et al, 2006a;Grauer et al, 2009). It is noteworthy that haloperidol, in agreement with previous studies (Pizzolato et al, 1984;Duncan et al, 1998), induced an increase in 2-DG uptake in the lateral habenula, the MED corresponding with 100% D 2 receptor occupancy (Natesan et al, 2005). PDE10A inhibitors, on the other hand, were already effectively inducing 2-DG changes at 10 to 40% occupancy of the PDE10A enzyme (in-house data).…”

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“…The studies which have been published, most of which use 2 deoxyglucose autoradiography, consistently show altered regional metabolic activity in medial thalamic nuclei (McCulloch et al 1982;Pizzolato et al 1984Pizzolato et al , 1987Tarazi et al 1992).…”

Effects of Dopamine Receptor Blockade on Cerebral Blood Flow Response to Somatosensory Stimulation in the Unanesthetized Rat

“…All of the haloperidol-treated rats exhibited dose-dependent signs of catalepsy. The degree of catalepsy was evaluated according to the scale described by Pizzolato et al (1984), which ranges from 0 (no effect) to 4 (completely cataleptic) on the basis of the following features: presence and intensity of reduced spontaneous movements of head and forelimbs; hypertonic-akinetic posture with kyphotic trunk, extended head, broad-based support, and rigid up-turned tail; resistance to imposed horizontal displacement of forequarters; and ptosis. Rats given the low dose of haloperidol fell in the 1 to 2 range, and those given the high dose fell within the 3 to 4 range.…”

“…Bonferroni statistics, however, are notoriously conservative and prone to type II errors, which might possibly have obscured a tendency for small selective local effects on CBF by haloperidol. For example, in the six structures outside the whisker-to-barrel cortex pathway in which the uncorrected t tests showed statistically significant lowering of CBF by the high dose of haloperidol, jpet.aspetjournals.org all but the inferior olive had been reported to exhibit significant reductions in local glucose utilization after administration of the same dose of haloperidol; glucose utilization in the VPM thalamic nucleus was not reported but found to be reduced in other parts of the thalamus (McCulloch et al, 1980(McCulloch et al, , 1982Pizzolato et al, 1984Pizzolato et al, , 1985. There were a few discrepancies.…”

“…For example, haloperidol was reported to reduce glucose utilization in the parietal cortex, medial geniculate, and hypothalamus (McCulloch et al, 1980(McCulloch et al, , 1982Pizzolato et al, 1984Pizzolato et al, , 1985, but even by the uncorrected t tests, it had no statistically significant effects on CBF in these structures. Also, the lateral habenula and the nucleus accumbens are two of the very few reported to show increased glucose utilization in response to 1.0 mg/kg haloperidol (McCulloch et al, 1980(McCulloch et al, , 1982Pizzolato et al, 1984Pizzolato et al, , 1985, and both showed increases in CBF in the present study, although the lateral habenula was the only structure in which the uncorrected t test showed haloperidol to cause a statistically significant increase in CBF. This tendency for corresponding changes in both CBF and glucose metabolism in a number of structures suggests that haloperidol might have some effects on local CBF, but they are likely to be secondary to changes in energy metabolism rather than to inhibition of direct vasoactive actions of dopamine at the level of dopamine receptors on the cerebral blood vessels.…”