Clavulanic acid induces penile erection and yawning in male rats: Comparison with apomorphine

Sanna, Fabrizio; Melis, Maria Rosaria; Angioni, Lucas; Argiolas, Antonio

doi:10.1016/j.pbb.2012.12.001

Cited by 12 publications

(12 citation statements)

References 36 publications

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“…Studies have shown that D2 receptor activation and blockade of D1 receptors in the insular cortex, diminish neuropathic nociception in a nerve transection model [Coffeen et al, 2010]; while D2 receptor activation in the dorsolateral striatum reduces formalin-induced nociception [Magnusson and Fisher, 2000]. Both CLAV and CFX alter the dopaminergic pathway in other models: CLAV enhances DA release in vitro [Kost et al, 2011] while the D2 antagonist, HAL, partially reduced the in vivo effects induced by this drug, including penile erection and yawning [Sanna et al, 2013]. CFX affects cocaine-evoked dopaminergic transmission [Barr et al, 2015] and in a rat model of Parkinson's disease shows neuroprotective effects [Leung et al, 2012].…”

Section: Discussionmentioning

confidence: 99%

Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF‐α Modulation and Activation of Dopaminergic and Opioidergic Systems

Ochoa-Aguilar

Sotomayor-Sobrino

Jaimez

et al. 2017

Drug Development Research

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Preclinical Research The aim of this study was to determine the antiallodynic effect of acute administration of the β-lactam antimicrobials, ceftriaxone (CFX) and clavulanic acid (CLAV), for the control of established pain on a model of neuropathic pain (NP). We also investigated the involvement of dopaminergic and opioidergic pathways as well as alterations in serum concentrations of TNF-α in the antiallodynic actions of these drugs. CFX, CLAV, or gabapentin (GAP), a reference drug, were administered i.p. twelve days after constriction of the sciatic nerve in rats. Mechanic and cold allodynia were evaluated for 3 h and alterations in serum concentration of TNF-α determined. Both CFX and CLAV had antiallodynic effects in response to mechanical and cold stimulation, similar to GAP. The antiallodynic effects of CFX and CLAV were blocked by haloperidol (HAL), a D2 receptor antagonist, and by naloxone (NLX), an opioid receptor antagonist. Additionally, serum TNF-α levels were attenuated following CFX and CLAV administration. These results suggest that acute administration of CFX and CLAV may represent a promising approach for treating the acute allodynia of NP, and that the mechanisms involved in these effects involve activation of dopaminergic and opioidergic pathways as well as modulation of TNF-α production. Drug Dev Res 78 : 105-115, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF‐α Modulation and Activation of Dopaminergic and Opioidergic Systems

Ochoa-Aguilar

Sotomayor-Sobrino

Jaimez

et al. 2017

Drug Development Research

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“…These inconsistencies between CA and CTX in cocaine SA acquisition experiments suggest that the two β-lactam-containing compounds act through mechanisms that may not be entirely identical. One example is the increase in dopamine transmission produced by CA (Kost et al 2011; Sanna et al 2013). Some direct dopamine agonists display a profile similar to CA in that they decrease the breaking points under PR conditions but increase, or have no effect, on cocaine SA under FR reinforcement schedules (Depoortere et al 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Doses of CTX (200 mg/kg) and CA (1, 10 mg/kg) were based on prior work (Rothstein et al 2005; Trantham-Davidson et al 2012; Sanna et al 2013; Schroeder et al 2014). Dosing schedules for CTX and CA utilized repeated injections because consistent evidence across multiple laboratories shows that CTX has to be given repeatedly, for at least 5 days, and at a dose of 200 mg/kg, to detect significant efficacy in animal models of CNS diseases (Rothstein et al 2005).…”

Section: Methodsmentioning

confidence: 99%

“…Dosing schedules for CTX and CA utilized repeated injections because consistent evidence across multiple laboratories shows that CTX has to be given repeatedly, for at least 5 days, and at a dose of 200 mg/kg, to detect significant efficacy in animal models of CNS diseases (Rothstein et al 2005). For comparative purposes, CA was administered under the same schedule, and its dose of 10 mg/kg was estimated from prior in vivo work (Sanna et al 2013; Schroeder et al 2014). Cocaine hydrochloride was generously provided by the National Institute on Drug Abuse (NIDA).…”

Section: Methodsmentioning

confidence: 99%

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Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

et al. 2015

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The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine’s reinforcing efficacy at 100-fold lower doses than CTX.

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“…That this mechanism could play a role was further supported by the observations that a dopamine D 2 receptor antagonist antagonizes the pro‐erectile effect of clavulanic acid in rats . In the latter study, the effect of clavulanic acid administered by intraperitoneal injection was compared to apomorphine, and while apomorphine induced concentration‐dependent increases in the number of spontaneous erections, the concentration–response curve for clavulanic acid was bell‐shaped with maximum effect at 1 mg/kg and then decreasing with higher doses . The authors suggested that in addition to incrementing dopamine release, clavulanic acid may also increase release of serotonin acting at 5‐HT 2C receptors, as mianserin also antagonized the pro‐erectile effect of clavulanic acid.…”

Section: Pharmacological Modulation Of the Dopaminergic Pathways To Imentioning

confidence: 84%

Modulation of Dopaminergic Pathways to Treat Erectile Dysfunction

Simonsen

Comerma-Steffensen

Andersson

2016

Basic Clin Pharma Tox

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Abstract:The currently recommended first-line treatments of erectile dysfunction (ED), phosphodiesterase type 5 inhibitors (PDE5i), for example sildenafil, are efficacious in many patients with ED of vascular origin, but this therapy is insufficient in approximately 30-40% of men with ED where there is also a neuronal affection. There is a demand of novel approaches to treat the condition. We review the possibility of modulating the dopaminergic pathways to improve erectile function. Dopamine D 1 (D 1 , D 5 )-and D 2 (D 2 -D 4 )-like receptors in the paraventricular area, the medial pre-optic area, the spinal cord, and in the erectile tissue are involved in erection, and several agonists developed for the treatment of Parkinson's disease are associated with increased libido. A therapeutic window for the treatment of ED was found by sublingual administration of the general dopamine receptor agonist apomorphine, but it failed mainly due to less efficacy on erectile function compared with PDE5i. To avoid the dose-limiting side effects mediated by D 2 receptors, nausea and emesis, dopamine D 4 receptor agonists were developed, and they induce erection in rodents, but these drugs were never introduced clinically. The b-lactamase inhibitor clavulanic acid increases dopamine and serotonin and was found to increase sexual arousal and erections, but the dose-response curve is bell-shaped. Bupropion has selectivity for inhibition of the dopamine reuptake transporter and can be used to alleviate sexual symptoms caused by other antidepressant medication, hence providing an interesting approach to treat ED. In summary, modulation of the dopaminergic pathways provides a possibility to improve the treatment of ED.

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Clavulanic acid induces penile erection and yawning in male rats: Comparison with apomorphine

Cited by 12 publications

References 36 publications

Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF‐α Modulation and Activation of Dopaminergic and Opioidergic Systems

Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF‐α Modulation and Activation of Dopaminergic and Opioidergic Systems

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

Modulation of Dopaminergic Pathways to Treat Erectile Dysfunction

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