Long-Term Application of Haloperidol: Effects on Dopamine and Acetylcholine Receptors

Abstract

Rats were injected daily with haloperidol, 0.5 mg/kg i.p., or pimozide, 2 mg/kg i.p., for a period of 8 or 16 days, respectively. 24 h after the last injection of haloperidol, these rats were challenged with gamma-butyrolactone (GBL) in doses of 200- 750 mg/kg i.p. In haloperidol-treated rats, higher doses of GBL are needed in order to increase the rate of dopa accumulation. This finding demonstrates the development of supersensitivity of dopamine (DA) autoreceptors towards endogenously released DA. Pimozide had no effect on the increased rate of dopa accumulation induced by increasing doses of GBL. From this data it is concluded that pimozide in our model is mainly active on postsynaptic DA receptors and haloperidol is active on pre- and postsynaptic DA receptors. In rats treated chronically with daily injections of haloperidol, benztropine, in a dose of 50 mg/kg, induced a decrease in dopa accumulation which was more marked than the decrease seen with benztropine, 50 mg/kg in animals treated with a single injection of haloperidol only. The opiate antagonist, naloxone at a dose of 10 mg/kg, had no effect on these results. Benztropine, 50 mg/kg i.p., had no effect on the increased rate of dopa accumulation induced by GBL, 400 mg/kg. The data support the hypothesis that in parallel to the development of supersensitive postsynaptic DA receptors, there is a development of subsensitivity in cholinergic receptors within the nigro-neostriatal system. Further the results show that a new DA-acetylcholine equilibrium is reached during long-term haloperidol treatment. The implications of these findings in regard to extrapyramidal side effects during long-term neuroleptic treatment are briefly discussed.

Neurobiological Basis of Dyskinetic Effects Induced by Antipsychotics: the Contribution of Animal Models

“…Striatal ACh release is tonically inhibited by DA activation of D2 receptors [139] [140], and HAL treatment increases ACh release [137]. Chronic HAL treatment leads to reduced numbers of choline acetyl transferase (ChAT)-positive neurons in the striatum [55], increased synaptic protein expression in these neurons [47] and increased sensitivity of ACh receptors [114]. However, this latter finding has not been replicated in all studies, and may depend on ligand specificity and receptor subtype [141] [142].…”