THE NEUROKININ(1) RECEPTOR ANTAGONIST CP-99,994 REDUCES CATALEPSY PRODUCED BY THE DOPAMINE-D-2 RECEPTOR ANTAGONIST RACLOPRIDE - CORRELATIONWITH EXTRACELLULAR ACETYLCHOLINE LEVELS IN STRIATUM

The ability of the substance P (NK1) receptor antagonist CP-99,994 to alter catalepsy induced by a dopamine D-1 or D-2 receptor antagonist a nd the ability of CP-99,944 to influence acetylcholine (ACh) release i n the striatum were investigated in rats. Catalepsy produced by the D- 1 antagonist SCH 23390 (0.5 mg/kg s.c.) was not altered by CP-94,994 ( 0.5, 2.5, or 10 mg/kg s.c.). In contrast, catalepsy induced by the D-2 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 wh en given alone. The less active enantiomer of CP-99,994, CP-I 00,263 ( 10 mg/kg) did not alter raclopride-induced catalepsy. Both systemic ad ministration and intrastriatal perfusion of CP-99,994 alone decreased striatal ACh release. Bilateral intrastriatal perfusion of CP-99,994 ( 40 and 100 mu M) reduced catalepsy produced by raclopride and attenuat ed raclopride-induced increases in striatal ACh release. The reduction s in the duration of catalepsy and decreases in striatal ACh release a ssociated with CP-99,994 perfusion were positively correlated. These f indings suggest that blockade of striatal NK1 receptors reduces catale psy induced by a dopamine D-2 antagonist, an effect mediated, at least in part, by reducing striatal ACh release. Striatal NK1 receptors, th erefore, may be a new therapeutic target for developing drugs that all eviate motor side effects associated with antipsychotic treatment.