The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat

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Title: The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat
Authors: Goutier, W.
O'Connor, J. J.
Lowry, John P.
McCreary, Andrew C.
Permanent link: http://hdl.handle.net/10197/6525
Date: 2015
Abstract: Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a wide range of psychostimulants. The mechanism underlying this phenomenon is putatively involved in many neuropsychiatric disorders (incl. drug addiction) and therefore, understanding of its mechanism is of great importance. Although these different drugs have diverse molecular targets located across the brain, they share the ability to increase the release of dopamine. The aim of the present study is to investigate the effect of the dopamine D1 ligands on nicotine induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically intermittent (5 days) treated with vehicle or nicotine (0.4 mg/kg; s.c.) and locomotor activity was measured. After the establishment of sensitization, rats were withdrawn for a period of 5 days followed by administration of a nicotine challenge, with or without a pre-challenge of SCH-23390 (0.03 mg/kg; i.p., a dopamine D1 antagonist) given 30 min prior to the nicotine. Either 45 min or 24 h post-challenge, the dorsal striatum was isolated and used to assess the effect of forskolin, dopamine, and dopamine D1 ligands on intracellular cAMP accumulation ex vivo. The cAMP levels were measured using LC-MS/MS. Acute nicotine administration significantly increased locomotor activity and subsequent chronic nicotine administration induced the development of locomotor sensitization. Moreover, following the 5 days withdrawal period, a nicotine challenge produced a robust sensitized response (i.e. expression of sensitization) and was antagonized by SCH-23390. Nicotine induced sensitization had no effect on forskolin stimulated cAMP accumulation however, it increased the efficacy of dopamine for the dopamine D1 receptor, and decreased the potency of D1 agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. Moreover, a time dependent effect was observed between tissue taken at 45 min and 24 h post-challenge. In conclusion, the present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the dopamine D1 receptor. Therefore D1 signaling in the dorsal striatum may play an important role in the underlying mechanism of the expression of nicotine induced behavioral sensitization.
Type of material: Journal Article
Publisher: Elsevier
Copyright (published version): 2015 Elsevier
Keywords: Dopamine D1;Nicotine;Behavioral sensitization;cAMP;SCH-23390;Receptor binding
DOI: 10.1016/j.euroneuro.2015.02.008
Language: en
Status of Item: Peer reviewed
Appears in Collections:Biomolecular and Biomedical Science Research Collection

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