AN INVESTIGATION INTO THE DISCRIMINATIVE STIMULUS AND REINFORCING PROPERTIES OF THE CCKB-RECEPTOR ANTAGONIST, L-365,260 IN RATS

The discriminative stimulus properties of the selective CCKB-receptor antagonist, L-365,260 were evaluated in rats trained to discriminate d iazepam (2 mg/kg) or morphine (5 mg/kg) from vehicle, using a two-leve r food reinforced technique. In the diazepam drug discrimination, the benzodiazepine-receptor agonist FG8205 (0.063-2 mg/kg) produced dose-r elated drug associated responding, whereas L-365,260 (0.125-4 mg/kg) t reated animals showed vehicle appropriate behaviour. In rats trained t o discriminate morphine from saline, L-365,260 (0.063-4 mg/kg) produce d saline lever responding. When a dose of 1 mg/kg L-365,260 was admini stered in combination with morphine, the dose response curve for drug lever responding was not significantly affected. This was in contrast to the effect produced by the opiate antagonist naloxone (0.3 mg/kg) w hich shifted the dose-response curve to the right. Another group of ra ts underwent training to discriminate a dose of 6 mg/kg L-365,260 from vehicle. None of the animals learned the discrimination within 50 dai ly training sessions. In addition, un like morphine (3 mg/kg), or chan ging the training dose of cocaine, intravenous administration of L-365 ,260 (0.3-10 mg/kg) did not modify lever pressing or the number of inj ections received by rats trained to self administer cocaine (0.25 mg/i njection). L-365,260 (0.1-3 mg/kg) produced a dose-related inhibition of pentagastrin-stimulated gastric acid secretion in vivo. When admini stered dissolved in a mixture of ethanol/propylene glycol/saline, the ID50 was 0.83 mg/kg, and when suspended in an ethanol/carboxymethylcel lulose vehicle, it was 0.7 mg/kg. It was concluded: 1) that L-365,260 does not produce discriminative stimuli similar to either diazepam or morphine; 2) that the potentiation of morphine-induced behaviour by L- 365,260(1,2) does not extend to the discriminative stimulus properties of morphine; 3) that L-365,260 itself does not produce readily discri minable interoceptive stimuli in rats; and 4) that L-365,260 does not substitute for the reinforcing drug cocaine.