Distinct changes in the behavioural effects of morphine and naloxone in CCK2 receptor-deficient mice

• Published in: Behavioural brain research 2003-09, Vol.144 (1-2), p.125-135
• Main Authors: Rünkorg, Kertu, Veraksits, Alar, Kurrikoff, Kaido, Luuk, Hendrik, Raud, Sirli, Abramov, Urho, Matsui, Toshimitsu, Bourin, Michel, Kõks, Sulev, Vasar, Eero
• Format: Article
• Language: English
• Subjects: Animals; Avoidance Learning - drug effects; Behavior, Animal - drug effects; Brain - anatomy & histology; Brain - diagnostic imaging; Conditioning (Psychology) - drug effects; Diprenorphine - pharmacokinetics; Exploratory Behavior - drug effects; Homozygote; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine - pharmacology; Motor Activity - drug effects; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics - pharmacology; Radioligand Assay; Radionuclide Imaging; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - deficiency; Receptors, Cholecystokinin - genetics; Receptors, Cholecystokinin - metabolism; Time Factors; Tritium - pharmacokinetics
• ISSN: 0166-4328
• DOI: 10.1016/S0166-4328(03)00070-6

The effects of morphine, mu-opioid receptor agonist, and naloxone, a non-selective opioid receptor antagonist, in the locomotor activity and place conditioning tests were studied in the CCK(2) receptor-deficient male mice. The exposure of mice to the motility boxes for 3 consecutive days induced a significant inhibition of locomotor activity in the wild-type (+/+) mice compared to homozygous (-/-) animals. The administration of naloxone (10 mg/kg i.p.) to animals, adapted to the motility boxes, induced a significant reduction of locomotor activity in the homozygous (-/-), but not in the wild-type (+/+) mice. Treatment of habituated mice with morphine (10 mg/kg i.p.) caused a stronger increase of locomotor activity in the wild-type (+/+) mice compared to the homozygous (-/-) littermates. In the place preference test the pairing of the preferred side with naloxone (1 and 10 mg/kg i.p.) induced a dose-dependent place aversion in the wild-type (+/+) mice. The treatment with naloxone was less effective in the homozygous (-/-) mice, because the high dose of naloxone (10 mg/kg) tended to shift the preference. The pairing of morphine (3 mg/kg i.p.) injections with the non-preferred side induced a significant place preference both in the wild-type (+/+) and homozygous (-/-) mice. The increased density of opioid receptors was established in the striatum of homozygous (-/-) mice, but not in the other forebrain structures. In conclusion, the targeted invalidation of CCK(2) receptors induces a dissociation of behavioural effects of morphine and naloxone. Morphine-induced place preference remained unchanged, whereas hyper-locomotion was less pronounced in the mutant mice compared to the wild-type (+/+) littermates. By contrast, naloxone-induced place aversion was weaker, but naloxone caused a stronger inhibition of locomotor activity in the homozygous (-/-) mice than in the wild-type (+/+) animals. These behavioural alterations can be explained in the light of data that the targeted mutation of CCK(2) receptors induces distinct changes in the properties of opioid receptors in various brain structures.