GR 127935 reduces basal locomotor activity and prevents RU 24969-, but notD-amphetamine induced hyperlocomotion, in the Wistar-Kyoto Hyperactive (WKHA) rat

The hyperlocomotor effect of the serotonin (5-HT)(1A,B) receptor agonist 5- methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)- 1H-indole (RU 24969) has been r epeatedly reported. However, 5-HT1A receptors, 5-HT1B receptors (or both) h ave been claimed to mediate this effect of RU 24969. These contradictory da ta possibly arise from protocol differences, especially those related to an imal species, drugs, and activity assessment. Herein, the influence of a pr etreatment with the selective 5-HT1B,D receptor antagonist N-[4-methoxy-3-( 4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl) -biphenyl-4-carboxamide (GR 127935; 1, 3.3 and 10 mg/kg IP) on the hyperloc omotor effect of a 5 mg/kg (IP) dose of RU 24969 was studied in Wistar-Kyot o Hyperactive (WKHA) rats. In a first series of experiments, it was confirm ed that RU 24969 (2.5 and 5 mg/kg), administered 10 min after the onset of activity recordings, increases locomotion dose-dependently (cage crossings) . In a second series of experiments, administration of GR 127935 10 min aft er the onset of activity recordings promoted a dose-dependent decrease in b asal activity (and rearings) and prevented (3.3 and 10 mg/kg) RU 24969-elic ited locomotor activity. On the other hand, GR 127935 was ineffective again st RU 24969-induced inhibition of rearings. Lastly, it was observed that 3. 3 mg/kg GR 127935 did not affect the number of cage crossings and rearings displayed by rats administered 1.5 mg/kg D-amphetamine. This study shows th at 5-HT1B receptors play a major role in the hyperlocomotor effect of RU 24 969, at least under our experimental setting. Whether these receptors also play a tonic role in the high locomotor activity displayed by WKHA rats rem ains to be determined.