Ceftriaxone attenuates acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens of the rat

J. L. Barr, B. A. Rasmussen, C. S. Tallarida, J. L. Scholl, G. L. Forster, E. M. Unterwald, S. M. Rawls

Research output: Contribution to journalArticle

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Abstract

Background and Purpose Ceftriaxone is a β-lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Experimental Approach Adult male Sprague-Dawley rats were pretreated with saline or ceftriaxone (200 mg kg-1, i.p. × 10 days) and then challenged with cocaine (15 mg kg-1, i.p.). Motor activity, dopamine efflux (via in vivo microdialysis) and protein levels of tyrosine hydroxylase (TH), the dopamine transporter and organic cation transporter as well as α-synuclein, Akt and GSK3β were analysed in the nucleus accumbens. Key Results Ceftriaxone-pretreated rats challenged with cocaine displayed reduced locomotor activity and accumbal dopamine efflux compared with saline-pretreated controls challenged with cocaine. The reduction in cocaine-evoked dopamine levels was not counteracted by excitatory amino acid transporter 2 blockade in the nucleus accumbens. Pretreatment with ceftriaxone increased Akt/GSK3β signalling in the nucleus accumbens and reduced levels of dopamine transporter, TH and phosphorylated α-synuclein, indicating that ceftriaxone affects numerous proteins involved in dopaminergic transmission. Conclusions and Implications These results are the first evidence that ceftriaxone affects cocaine-evoked dopaminergic transmission, in addition to its well-described effects on glutamate, and suggest that its ability to attenuate cocaine-induced behaviours, such as psychomotor activity, is due in part to reduced dopaminergic neurotransmission in the nucleus accumbens.

Original languageEnglish (US)
Pages (from-to)5414-5424
Number of pages11
JournalBritish Journal of Pharmacology
Volume172
Issue number22
DOIs
StatePublished - Nov 1 2015

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Ceftriaxone
Nucleus Accumbens
Cocaine
Synaptic Transmission
Dopamine
Synucleins
Dopamine Plasma Membrane Transport Proteins
Tyrosine 3-Monooxygenase
Excitatory Amino Acid Transporter 2
Amino Acid Transport System X-AG
Lactams
Aptitude
Microdialysis
Locomotion
Sprague Dawley Rats
Cations
Glutamic Acid
Proteins
Motor Activity
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Pharmacology

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Ceftriaxone attenuates acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens of the rat. / Barr, J. L.; Rasmussen, B. A.; Tallarida, C. S.; Scholl, J. L.; Forster, G. L.; Unterwald, E. M.; Rawls, S. M.

In: British Journal of Pharmacology, Vol. 172, No. 22, 01.11.2015, p. 5414-5424.

Research output: Contribution to journalArticle

Barr, J. L. ; Rasmussen, B. A. ; Tallarida, C. S. ; Scholl, J. L. ; Forster, G. L. ; Unterwald, E. M. ; Rawls, S. M. / Ceftriaxone attenuates acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens of the rat. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 22. pp. 5414-5424.
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AU - Barr, J. L.

AU - Rasmussen, B. A.

AU - Tallarida, C. S.

AU - Scholl, J. L.

AU - Forster, G. L.

AU - Unterwald, E. M.

AU - Rawls, S. M.

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AB - Background and Purpose Ceftriaxone is a β-lactam antibiotic and glutamate transporter activator that reduces the reinforcing effects of psychostimulants. Ceftriaxone also reduces locomotor activation following acute psychostimulant exposure, suggesting that alterations in dopamine transmission in the nucleus accumbens contribute to its mechanism of action. In the present studies we tested the hypothesis that pretreatment with ceftriaxone disrupts acute cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Experimental Approach Adult male Sprague-Dawley rats were pretreated with saline or ceftriaxone (200 mg kg-1, i.p. × 10 days) and then challenged with cocaine (15 mg kg-1, i.p.). Motor activity, dopamine efflux (via in vivo microdialysis) and protein levels of tyrosine hydroxylase (TH), the dopamine transporter and organic cation transporter as well as α-synuclein, Akt and GSK3β were analysed in the nucleus accumbens. Key Results Ceftriaxone-pretreated rats challenged with cocaine displayed reduced locomotor activity and accumbal dopamine efflux compared with saline-pretreated controls challenged with cocaine. The reduction in cocaine-evoked dopamine levels was not counteracted by excitatory amino acid transporter 2 blockade in the nucleus accumbens. Pretreatment with ceftriaxone increased Akt/GSK3β signalling in the nucleus accumbens and reduced levels of dopamine transporter, TH and phosphorylated α-synuclein, indicating that ceftriaxone affects numerous proteins involved in dopaminergic transmission. Conclusions and Implications These results are the first evidence that ceftriaxone affects cocaine-evoked dopaminergic transmission, in addition to its well-described effects on glutamate, and suggest that its ability to attenuate cocaine-induced behaviours, such as psychomotor activity, is due in part to reduced dopaminergic neurotransmission in the nucleus accumbens.

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