The potency and efficacy of anticholinergics to inhibit haloperidol-induced catalepsy in rats correlates with their rank order of affinities for the muscarinic receptor subtypes.

Autor: Erosa-Rivero HB; Departamento de Neurociencias, Centro de Investigaciones Regionales 'Dr. Hideyo Noguchi', Universidad Autónoma de Yucatán, CIR-UADY, Avenida Itzáes No. 490 × 59, Mérida, Yucatán 97000, Mexico., Bata-García JL; Departamento de Neurociencias, Centro de Investigaciones Regionales 'Dr. Hideyo Noguchi', Universidad Autónoma de Yucatán, CIR-UADY, Avenida Itzáes No. 490 × 59, Mérida, Yucatán 97000, Mexico., Alvarez-Cervera FJ; Departamento de Neurociencias, Centro de Investigaciones Regionales 'Dr. Hideyo Noguchi', Universidad Autónoma de Yucatán, CIR-UADY, Avenida Itzáes No. 490 × 59, Mérida, Yucatán 97000, Mexico., Heredia-López FJ; Departamento de Neurociencias, Centro de Investigaciones Regionales 'Dr. Hideyo Noguchi', Universidad Autónoma de Yucatán, CIR-UADY, Avenida Itzáes No. 490 × 59, Mérida, Yucatán 97000, Mexico., Góngora-Alfaro JL; Departamento de Neurociencias, Centro de Investigaciones Regionales 'Dr. Hideyo Noguchi', Universidad Autónoma de Yucatán, CIR-UADY, Avenida Itzáes No. 490 × 59, Mérida, Yucatán 97000, Mexico. Electronic address: jlgongoralf@gmail.com.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2014 Jun; Vol. 81, pp. 176-87. Date of Electronic Publication: 2014 Feb 15.
DOI: 10.1016/j.neuropharm.2014.02.005
Abstrakt: Extrapyramidal syndromes (EPS) caused by antipsychotic therapy are currently treated with anticholinergics that lack selectivity for the five muscarinic receptor subtypes. Since these receptors are heterogeneously expressed among the different classes of striatal neurons and their afferents, it can be expected that their simultaneous blockade will cause distinct, sometimes opposed, effects within the striatal circuitry. In order to test the hypothesis that the differential blockade of the muscarinic receptor subtypes would influence their potency and efficacy to prevent EPS, here we tested four anticholinergics with varying order of affinities for the muscarinic receptor subtypes, and compared their dose-response curves to inhibit haloperidol-induced catalepsy in male rats. Drugs were applied into the lateral ventricle 15 min before haloperidol (2 mg/kg, s.c.). Catalepsy was measured in the bar test at 15 min intervals during 5 h. The preferential M1/M4 antagonist pirenzepine (3, 10, 30, 100, and 300 nmol) caused a dose-dependent inhibition of catalepsy intensity: ED50 = 5.6 nmol [95% CI, 3.9-8.1], and latency: ED50 = 5.6 nmol [95% CI, 3.7-8.6]. Pirenzepine had the steepest dose-response curve, producing maximal inhibition (84 ± 5%) at the dose of 10 nmol, while its effect tended to reverse at higher doses (62 ± 11%). The purported M1/M3 antagonist 4-DAMP (30, 100, and 300 nmol) also caused a dose-dependent inhibition of catalepsy intensity: ED50 = 29.5 nmol [95% CI, 7.0 to 123.0], and latency: ED50 = 28.5 nmol [95% CI, 2.2 to 362.0]. However, the curve for 4-DAMP had a less pronounced slope, reaching its maximal effect (63 ± 14%) at the dose of 300 nmol. The M2/M4 antagonist AF-DX 116 (10, 30, and 300 nmol) only caused a partial inhibition of catalepsy (30 ± 11%) at the dose of 30 nmol, but this changed to a non-significant increment (15 ± 10%) at the dose of 100 nmol. The alleged M4 antagonist tropicamide (30, 100, 300, and 600 nmol) produced a partial inhibition of catalepsy (36 ± 12%) at the dose of 300 nmol, but lacked effect at higher or lower doses. Concurrent treatment with pirenzepine (10 nmol) and tropicamide (300 nmol) produced an effect similar to that of tropicamide alone. The greater potency and efficacy of pirenzepine for catalepsy inhibition could be due to its higher affinity for M1 receptors and, to a lesser extent, for M4 receptors. It is suggested that selective M1 antagonists would be more effective than M2, M3 or M4 antagonists to prevent EPS caused by antipsychotic drugs.
(Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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