title: Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine.
abstract: Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná , Curitiba 81.530-980, PR, Brazil.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gomez-A
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná , Curitiba 81.530-980, PR, Brazil.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Fiorenza
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná , Curitiba 81.530-980, PR, Brazil.|Institute of Biophysics Carlos Chagas Filho and Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil.
authors.forename: Suelen L
authors.initials: SL
authors.lastname: Boschen
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná , Curitiba 81.530-980, PR, Brazil.
authors.forename: Adam H
authors.initials: AH
authors.lastname: Sugi
authors.affiliation: Institute of Biophysics Carlos Chagas Filho and Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Beckman
authors.affiliation: Institute of Biophysics Carlos Chagas Filho and Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil.
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic , Rochester, Minnesota 55905, United States.
authors.forename: Kendall
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic , Rochester, Minnesota 55905, United States.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blaha
authors.affiliation: Departamento de Farmacologia, Universidade Federal do Paraná , Curitiba 81.530-980, PR, Brazil.
authors.forename: Claudio
authors.identifier: 0000-0001-6920-8561
authors.initials: C
authors.lastname: Da Cunha
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D055664:Electrochemical Techniques; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D051379:Mice; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects*
chemical_list: D000697:Central Nervous System Stimulants; D018757:GABA Modulators; D005442:Flumazenil; D000661:Amphetamine; D003975:Diazepam; D004298:Dopamine
keywords: Anticonvulsant; Anxiolytic; Dopaminergic neurons; Electrochemistry; GABA; Nucleus accumbens core; Ventral tegmental area