The neurokinin1 receptor antagonist CP-99,994 reduces catalepsy produced by the dopamine D2 receptor antagonist raclopride: correlation with extracellular acetylcholine levels in striatum.
The ability of the substance P (NK1) receptor antagonist CP-99,994 to alter catalepsy induced by a dopamine D1 or D2 receptor antagonist and the ability of CP-99,994 to influence acetylcholine (ACh) release in the striatum were investigated in rats. Catalepsy produced by the D1 antagonist SCH 23390 (0.5 mg/kg s.c.) was not altered by CP-99,994 (0.5, 2.5, or 10 mg/kg s.c.). In contrast, catalepsy induced by the D2 antagonist raclopride (2.5 mg/kg i.p.) was attenuated by CP-99,994 (2.5 and 10 mg/kg). CP-99,994 (10 mg/kg) did not stimulate locomotion when given alone. The less active enantiomer of CP-99,994, CP-100,263 (10 mg/kg), did not alter raclopride-induced catalepsy. Both systemic administration and intrastriatal perfusion of CP-99,994 alone decreased striatal ACh release. Bilateral intrastriatal perfusion of CP-99,994 (40 and 100 microM) reduced catalepsy produced by raclopride and attenuated raclopride-induced increases in striatal ACh release. The reductions in the duration of catalepsy and decreases in striatal ACh release associated with CP-99,994 perfusion were positively correlated. These findings suggest that blockade of striatal NK1 receptors reduces catalepsy induced by a dopamine D2 antagonist, an effect mediated, at least in part, by reducing striatal ACh release. Striatal NK1 receptors, therefore, may be a new therapeutic target for developing drugs that alleviate motor side effects associated with antipsychotic treatment.
Anderson
J J
JJ
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Randall
S
S
Chase
T N
TN
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000494:pharmacology*
D001552:Benzazepines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D012457:Salicylamides; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D020891:Raclopride; D000109:Acetylcholine