The goals of this project are: 1. To isolate and clone the DNA for the cocaine receptor (or dopamine transporter); 2. To isolate and clone the DNA for the Dl dopamine receptor and its variants; 3. To search for variants of the D2 dopamine; and 4. To determine the gene expression responsivity of the above receptors. The receptor for cocaine is the dopamine transporter protein on which cocaine acts to release dopamine. The released dopamine activates the high-affinity states of Dl and D2 dopamine receptors to elicit psychomotor behavior associated with euphoria, self-reward and addiction. Since Dl full agonist drugs are recognized by animals as being cocaine, and since Dl antagonists successfully block the action of cocaine, the Dl receptor is important in mediating the behavioral effects of cocaine. Moreover, since Dl and D2 are biochemically linked, D2 receptors play an additional role in mediating cocaine's actions. The cocaine receptor will be isolated by means of our newly developed [125I]FAPP photoaffinity label which is selective for the dopamine transporter. Serial chromatographic procedures ensure that a single protein will be isolated. Partial peptide sequences from this pure material will permit the preparation of oligonucleotide probes to detect and isolate the complete transporter or receptor for cocaine. The Dl dopamine receptor DNA will be obtained via homology probing by means of the polymerase chain reaction. Preliminary data reveal a clone which may have Dl properties D2 receptor variants will also be sought by such homology probing methods. Finally, we intend to examine the speed of change of synthesis of messenger RNA for the cocaine receptor as well as for the Dl and D2 receptors upon antipsychotic or cocaine administration to rats. The availability of clones for these receptors would facilitate new drug design and provide new markers for disease linkage studies in families.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Drug Abuse Biomedical Research Review Committee (DABR)
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University of Toronto
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M5 1-S8
Hasbi, Ahmed; Perreault, Melissa L; Shen, Maurice Y F et al. (2017) Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and ?FosB. Front Pharmacol 8:924
Perreault, Melissa L; Hasbi, Ahmed; Shen, Maurice Y F et al. (2016) Disruption of a dopamine receptor complex amplifies the actions of cocaine. Eur Neuropsychopharmacol 26:1366-1377
Perreault, M L; Shen, M Y F; Fan, T et al. (2015) Regulation of c-fos expression by the dopamine D1-D2 receptor heteromer. Neuroscience 285:194-203
Shen, Maurice Y F; Perreault, Melissa L; Fan, Theresa et al. (2015) The dopamine D1-D2 receptor heteromer exerts a tonic inhibitory effect on the expression of amphetamine-induced locomotor sensitization. Pharmacol Biochem Behav 128:33-40
Hasbi, Ahmed; Perreault, Melissa L; Shen, Maurice Y F et al. (2014) A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism. FASEB J 28:4806-20
Perreault, Melissa L; Hasbi, Ahmed; O'Dowd, Brian F et al. (2014) Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology 39:156-68
Perreault, Melissa L; Jones-Tabah, Jace; O'Dowd, Brian F et al. (2013) A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex. Int J Neuropsychopharmacol 16:477-83
Perreault, Melissa L; Fan, Theresa; O'Dowd, Brian F et al. (2013) Enhanced brain-derived neurotrophic factor signaling in the nucleus accumbens of juvenile rats. Dev Neurosci 35:384-95
Ting-A-Kee, Ryan; Mercuriano, Laura E; Vargas-Perez, Hector et al. (2013) Dopamine D1 receptors are not critical for opiate reward but can mediate opiate memory retrieval in a state-dependent manner. Behav Brain Res 247:174-177
O'Dowd, Brian F; Nguyen, Tuan; Ji, Xiaodong et al. (2013) D5 dopamine receptor carboxyl tail involved in D5-D2 heteromer formation. Biochem Biophys Res Commun 431:586-9

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