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The possible effect of different cholecystokinin (CCK) receptor antagonists (MK-329 and L-365260) on the maintenance and reactivation of morphine conditioned place preference (CPP) were investigated in rats, respectively. The results show that the maintenance of morphine CPP could be induced by injection of morphine (10 mg/kg, s.c.) once for 3 days and this effects were significantly attenuated by pretreatment with 1 but not by 0.1 mg/kg L-365260. Furthermore, following a 28-day extinction, the morphine CPP disappeared and then reactivated again by a single injection of morphine (10 mg/kg). Pretreatment with L-365260 (1 and 0.1 mg/kg) significantly blocked this reactivation of morphine CPP. In contrast, pretreatment of MK-329 (1 and 0.1 mg/kg) failed to do so. The present study demonstrated that CCK-B receptor but not CCK-A receptor is involved in the maintenance and reactivation of morphine CPP. These findings suggest that CCK-B receptor antagonists might be of some value in the treatment and prevention of relapse to drug dependence long after detoxification.

The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (Nalpha-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 microCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 microCi each). Rats were decapitated 12s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/l4C for sample)]/[(3H/14C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean+/-s.e.m.) was 1.6+/-0.3 for [3H]mannitol (n=5), 90.6+/-4.1 for [3H]devazepide (n=7, P<0.001 compared with mannitol) and 3.5+/-0.7 for [3H]A-65186 (n=4, P > 0.05 compared with mannitol, P < 0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.