The role of 5-HT 1D and 5-HT 1A receptors in mediating 5-hydroxytryptophan induced myoclonic jerks in guinea pigs

Abstract

Systemic administration of 5-hydroxytryptophan (5-HTP) to guinea pigs causes species-specific, rhythmic, whole body jerks (myoclonic jerks), the frequency and amplitude of which were measured in an automated apparatus. The brain penetrant 5-HT 1D receptor agonist 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF 99101H) (3–30 mg/kg i.p.) and the selective 5-HT 1A receptor agonist (±)8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) (0.3–3 mg/kg s.c.) dose dependently potentiated the frequency and intensity of myoclonic jerks caused by 5-HTP (100 mg/kg). Cotreatment of guinea pigs with 8-OH-DPAT (3 mg/kg s.c.) and SKF 99101H (30 mg/kg i.p.), which were inactive when given alone, gave a marked myoclonic jerk response. Conversely, the myoclonic jerk response to higher doses of 5-HTP (150 mg/kg i.p.) was dose dependently blocked by the 5-HT 1D receptor antagonist GR 127935 ( N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1′-biphenyl]4-carboxamide oxalate) (ED 50 0.32 mg/kg i.p.) and the selective 5-HT 1A receptor antagonist WAY 100635 ( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride) (ED 50 0.33 mg/kg i.p.). The response to 5-HTP (150 mg/kg i.p.) was also blocked by ritanserin (0.01–0.3 mg/kg i.p). Our data therefore confirm previous reports concerning the effects of 5-HT 2A 2C receptor blockade on 5-HTP induced myoclonic jerks and suggest that both 5-HT 1D and 5-HT 1A receptors play an important role in mediating this behavioural response.