j.1460-9568.2005.04353.x.pdfVIP

Deletion of dopamine D1 and D3 receptors differentially affects spontaneous behaviour and cocaine-induced locomotor activity, reward and CREB phosphorylation Joanna M. Karasinska,1 Susan R. George1,2,3 Regina Cheng1,3 and Brian F. O’Dowd1,3 1Department of Pharmacology, University of Toronto, Medical Sciences Building, Room 4358, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada 2Department of Medicine, University of Toronto, Toronto, Ontario, Canada 3Centre for Addiction and Mental Health, Toronto, Ontario, Canada Keywords: cocaine reward, dopamine receptor, gene knockout mice, locomotor activity, phosphorylated CREB Abstract Co-localization of dopamine D1 and D3 receptors in striatal neurons suggests that these two receptors interact at a cellular level in mediating dopaminergic function including psychostimulant-induced behaviour. To study D1 and D3 receptor interactions in cocaine- mediated effects, cocaine-induced locomotion and reward in mice lacking either D1, D3 or both receptors were analysed. Spontaneous locomotor activity was increased in D1– ? – and D1– ? –D3– ? – mice and D1– ? –D3– ? – mice did not exhibit habituation of spontaneous rearing activity. Cocaine (20 mg ? kg) increased locomotor activity in wild-type and D3– ? – mice, failed to stimulate activity in D1– ? – mice and reduced activity in D1– ? –D3– ? – mice. In the conditioned place preference, all groups exhibited reward at 5, 10 and 20 mg ? kg of cocaine. D1– ? –D3– ? – mice did not demonstrate preference at 2.5 mg ? kg of cocaine although preference was observed in wild-type, D1– ? – and D3– ? – mice. The transcription factor cAMP-responsive element binding protein (CREB) is activated by phosphorylation in striatal regions following dopamine receptor activation. Striatal pCREB levels following acute cocaine were increased in wild-type and D3– ? – mice and decreased in D1– ? – and D1– ? –D3– ? – mice. After repeated administration of 2.5 mg ? kg of cocaine, D1– ? – mice had lower pCREB le