title: Adenosine (A)(2A)receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach.
abstract: Preclinical evidence indicates an important role of adenosine (A)(2A) receptors in drug addiction while their therapeutic relevance is still a matter of debate. We examined the influence of the A(2A) receptor agonist CGS 21680 and the antagonist KW 6002 on nicotine sensitization and conditioned locomotor activity in adult (8-week old) male Sprague-Dawley rats (WT). Moreover, behavioral responses to nicotine were studied in rats overexpressing A(2A) receptors under the control of the neuronal specific enolase (NSE) promotor. Changes in the levels of dopamine, glutamate and γ-aminobutyric acid in wild type (WT) and NSEA(2A) rats were determined with using LC-MS. KW 6002 significantly enhanced expression of nicotine sensitization and conditioned locomotion, while CGS 21680 reduced all these effects in WT rats. A reduction of the expression of nicotine-evoked conditioned locomotor activity was also observed in the NSEA(2A) animals. The transgenic rats displayed a reduced basal tissue level of glutamate in the prefrontal cortex and hippocampus while dopamine basal levels in the nucleus accumbens were raised. Chronic nicotine treatment caused a significant reduction in the glutamate tissue level in the dorsal and ventral striatum, prefrontal cortex and cerebellum in wild type rats. In NSEA(2A) animals the same drug treatment instead produced a rise of glutamate levels in the hippocampus and dorsal striatum. Taken together, A(2A) receptor signaling in the rat brain can counteract locomotor sensitization and conditioned locomotion to nicotine which are related to nicotine reward-learning. It is suggested that treatment with A(2A) receptor agonists can help counteract the abuse actions of nicotine.
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jastrzębska
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Nowak
authors.affiliation: Department of Toxicology, Faculty of Pharmacy, Jagiellonian University, Kraków, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Smaga
authors.affiliation: Department of Toxicology, Faculty of Pharmacy, Jagiellonian University, Kraków, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Bystrowska
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Frankowska
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland; Department of Toxicology, Faculty of Pharmacy, Jagiellonian University, Kraków, Poland. Electronic address: mal.fil@if-pan.krakow.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Filip
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006948:Hyperkinesis / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D018722:Nicotinic Agonists; D010627:Phenethylamines; D011687:Purines; D043705:Receptor, Adenosine A2A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C111599:istradefylline; D009538:Nicotine; D010751:Phosphopyruvate Hydratase; D000241:Adenosine
keywords: A(2A) receptors; Conditioned locomotion; Neurochemical analyses; Nicotine locomotor sensitization; Transgenic rats