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 diazepam (2 mg/kg) or morphine (5 mg/kg) from vehicle, using a two-lever food reinforced technique. In the diazepam drug discrimination, the benzodiazepine-receptor agonist FG8205 (0.063-2 mg/kg) produced dose-related drug associated responding, whereas L-365,260 (0.125-4 mg/kg) treated animals showed vehicle appropriate behaviour. In rats trained to discriminate morphine from saline, L-365,260 (0.063-4 mg/kg) produced saline lever responding. When a dose of 1 mg/kg L-365,260 was administered 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) which shifted the dose-response curve to the right. Another group of rats underwent training to discriminate a dose of 6 mg/kg L-365,260 from vehicle. None of the animals learned the discrimination within 50 daily training sessions. In addition, unlike morphine (3 mg/kg), or changing 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 injections received by rats trained to self administer cocaine (0.25 mg/injection). L-365,260 (0.1-3 mg/kg) produced a dose-related inhibition of pentagastrin-stimulated gastric acid secretion in vivo. When administered dissolved in a mixture of ethanol/propylene glycol/saline, the ID50 was 0.83 mg/kg, and when suspended in an ethanol/carboxymethylcellulose 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 does not extend to the discriminative stimulus properties of morphine; 3) that L-365,260 itself does not produce readily discriminable interoceptive stimuli in rats; and 4) that L-365,260 does not substitute for the reinforcing drug cocaine.
Jackson
A
A
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Tattersall
D
D
Bentley
G
G
Rycroft
W
W
Bourson
A
A
Hargreaves
R
R
Tricklebank
M
M
Iversen
S
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage; D003975:Diazepam / Q000008:administration & dosage; D004192:Discrimination, Psychological / Q000187:drug effects*; D004357:Drug Synergism; D005744:Gastric Acid / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage; D009270:Naloxone / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012646:Self Administration; D012965:Sodium Chloride
D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D009270:Naloxone; C058121:L 365260; D012965:Sodium Chloride; D009020:Morphine; D010418:Pentagastrin; D003042:Cocaine; D003975:Diazepam