Preprodynorphin mediates locomotion and D2 dopamine and mu-opioid receptor changes induced by chronic 'binge' cocaine administration.
Evidence suggests that the kappa-opioid receptor (KOP-r) system plays an important role in cocaine addiction. Indeed, cocaine induces endogenous KOP activity, which is a mechanism that opposes alterations in behaviour and brain function resulting from repeated cocaine use. In this study, we have examined the influence of deletion of preprodynorphin (ppDYN) on cocaine-induced behavioural effects and on hypothalamic-pituitary-adrenal axis activity. Furthermore, we have measured mu-opioid receptor (MOP-r) agonist-stimulated [(35)S]GTPgammaS, dopamine D(1), D(2) receptor and dopamine transporter (DAT) binding. Male wild-type (WT) and ppDYN knockout (KO) mice were injected with saline or cocaine (45 mg/kg/day) in a 'binge' administration paradigm for 14 days. Chronic cocaine produced an enhancement of locomotor sensitisation in KO. No genotype effect was found on stereotypy behaviour. Cocaine-enhanced MOP-r activation in WT but not in KO. There was an overall decrease in D(2) receptor binding in cocaine-treated KO but not in WT mice. No changes were observed in D(1) and DAT binding. Cocaine increased plasma corticosterone levels in WT but not in KO. The data confirms that the endogenous KOP system inhibits dopamine neurotransmission and that ppDYN may mediate the enhancement of MOP-r activity and the activation of the hypothalamic-pituitary-adrenal axis after chronic cocaine treatment.
Bailey
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School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UKDepartment of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
Yoo
J H
JH
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UKDepartment of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
Racz
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School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UKDepartment of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
Zimmer
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School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UKDepartment of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
Kitchen
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School of Biomedical and Molecular Sciences, University of Surrey, Guildford, UKDepartment of Molecular Psychiatry, Life & Brain Center, University of Bonn, Bonn, Germany.
D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003345:Corticosterone / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects; D004334:Drug Administration Schedule; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*
D000701:Analgesics, Opioid; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D011498:Protein Precursors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C036448:pre-prodynorphin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004399:Dynorphins; D003042:Cocaine; D003345:Corticosterone