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

BACKGROUND AND PURPOSE: Ceftriaxone is a ß-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 GSK3ß 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/GSK3ß 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.

Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit.

BACKGROUND: A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines µ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit). METHODS: Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms. RESULTS: The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception. CONCLUSIONS: We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy.