Analysis of the long-lasting antagonistic effect of caerulein on amphetamine hyperactivity in rats

Caerulein (CLN), which is chemically related to cholecystokinin octapeptide (CCK-8) and produces a short-lasting pharmacological effect when administered peripherally, caused a long-lasting antagonistic effect on amphetamine (AMP) hyperactivity in rats when given in combination with haloperidol (HLP). Briefly, rats were treated with a combination of CLN (0.3-40 micrograms/kg, s.c.) and HLP (0.1 mg/kg, s.c.) and exposed to AMP on the first day. The animals became less sensitive to AMP for 24 hr to about 2 weeks depending on the CLN dose, according to measurements of their ambulatory activities in an open field or with an Animex activity meter at low sensitivity. Examination of the properties of this long-lasting effect revealed that: 1) in animals treated with CLN and HLP, but without AMP on the first day, the susceptibility to AMP was not influenced on the next day; 2) in substitution experiments, the antagonistic effect of CLN could be reproduced by higher doses of CCK-8 (160 micrograms/kg) but not by nonsulfated CLN; 3) in the regimen of the treatment schedule, HLP could be replaced by chlorpromazine or sulpiride, but not by alpha-blocking agents like phenoxybenzamine or yohimbine; 4) apomorphine, nomifensine and tranylcypromine could not substitute for AMP. Thus, injection of CLN together with HLP and AMP on the first day might be necessary to produce the long-lasting anti-AMP effect. The possible mechanism of this CLN effect is discussed.