Haloperidol and reduced haloperidol-induced exacerbation of the dystonia produced by the kappa opioid U50,488H in guinea-pigs is associated with inhibition of sigma binding sites: behavioural and autoradiographical studies.
A single dose of haloperidol and reduced haloperidol has been found to exacerbate the dystonic response produced by U50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) -cyclohexyl]-benzeacetamide methane sulphonate) in guinea-pigs [8]. The present study sought to correlate the behavioural effect of haloperidol and reduced haloperidol with their effect on inhibition of sigma binding sites in guinea-pig brain using receptor binding and semi-quantitative autoradiography. In the first experiments, groups of guinea-pigs were injected with saline (control, n = 12), haloperidol (0.1 and 1 mg/kg i.p., n = 5) or reduced haloperidol (0.1 and 1 mg/kg i.p., n = 5) 1, 3 and 10 days before, followed by U50,488H (10 mg/kg s.c.) and the effect on the dystonic response rated using a behavioural rating scale [8]. In the second experiments, animals (n = 5) were injected with saline, haloperidol and reduced haloperidol as above and killed 1, 3 and 10 days later, their brains removed, dissected and tissue sections processed for sigma binding site autoradiography using [3H]3-(3-hydroxyphenyl)-N-(n-propyl)piperidine ([3H]-3-PPP). Triplicate tissue sections were wiped using GF/C filters and radioactivity counted. Injection of haloperidol and reduced haloperidol 1, 3 and 10 days earlier exacerbated the dystonic response by decreasing the latency to maximal dystonia and increasing the duration of the response at each dose tested compared with saline-treated animals. These effects of haloperidol and reduced haloperidol on latency and duration were time-related since the effect at 1 > 3 > 10 days. In addition, [3H]-3-PPP binding was inhibited by haloperidol and reduced haloperidol in a dose-and time-related manner. For example, % inhibition of [3H]-3-PPP binding for haloperidol (1 mg/kg) > haloperidol (0.1 mg/kg) and % inhibition of binding (mean +/- SEM) produced by haloperidol (0.1 mg/kg) at 1 (96.1 +/- 2.4) > 3 (74.8 +/- 4.8) > 10 days (36.2 +/- 1.6). Similar results were obtained for haloperidol (1 mg/kg) and reduced haloperidol (0.1 and 1 mg/kg). [3H]-3-PPP autoradiography confirmed these binding data. The results indicate that the exacerbation by sigma ligands of the dystonia produced by U50,488H was associated with the degree of inhibition of [3H]-3-PPP binding.
Brent
P J
PJ
Neuropharmacology Laboratory, Faculty of Medicine, University of Newcastle, Mater Hospital, Waratah, NSW, Australia.
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal; D001665:Binding Sites; D005260:Female; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D013997:Time Factors
D000700:Analgesics; D011759:Pyrrolidines; D012965:Sodium Chloride; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D006220:Haloperidol