Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats

Background Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal an...

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Published in:Pharmacological reports 2024-04, Vol.76 (2), p.338-347
Main Authors: Frankowska, Małgorzata, Smaga, Irena, Gawlińska, Kinga, Pieniążek, Renata, Filip, Małgorzata
Format: Article
Language:English
Subjects:
Animals
Brain - metabolism
Cocaine - pharmacology
Drug Safety and Pharmacovigilance
Drug-Seeking Behavior
Male
Medicine
Nitric Oxide Synthase Type I - metabolism
Nucleus Accumbens - metabolism
Pharmacotherapy
Pharmacy
Rats
Self Administration
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container_title Pharmacological reports
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creator Frankowska, Małgorzata
Smaga, Irena
Gawlińska, Kinga
Pieniążek, Renata
Filip, Małgorzata
description Background Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N -methyl- d -aspartate (NMDA) receptors or metabotropic receptors’ type 5 (mGlu 5 ) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. Methods In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N -ω-propyl- l -arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. Results Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5–5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. Conclusions Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats. Graphical abstract
doi_str_mv 10.1007/s43440-024-00571-y
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One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N -methyl- d -aspartate (NMDA) receptors or metabotropic receptors’ type 5 (mGlu 5 ) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. Methods In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N -ω-propyl- l -arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. Results Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5–5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. Conclusions Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats. Graphical abstract</description><identifier>ISSN: 1734-1140</identifier><identifier>EISSN: 2299-5684</identifier><identifier>DOI: 10.1007/s43440-024-00571-y</identifier><identifier>PMID: 38480667</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animals ; Brain - metabolism ; Cocaine - pharmacology ; Drug Safety and Pharmacovigilance ; Drug-Seeking Behavior ; Male ; Medicine ; Nitric Oxide Synthase Type I - metabolism ; Nucleus Accumbens - metabolism ; Pharmacotherapy ; Pharmacy ; Rats ; Self Administration</subject><ispartof>Pharmacological reports, 2024-04, Vol.76 (2), p.338-347</ispartof><rights>The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences 2024. 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Methods In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N -ω-propyl- l -arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. Results Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5–5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. Conclusions Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats. 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subjects Animals
Brain - metabolism
Cocaine - pharmacology
Drug Safety and Pharmacovigilance
Drug-Seeking Behavior
Male
Medicine
Nitric Oxide Synthase Type I - metabolism
Nucleus Accumbens - metabolism
Pharmacotherapy
Pharmacy
Rats
Self Administration
title Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats
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