Adenosine receptor agonists attenuate the development of diazepam withdrawal-induced sensitization in mice

Eur J Pharmacol. 2008 Jun 24;588(1):72-7. doi: 10.1016/j.ejphar.2008.04.011. Epub 2008 Apr 8.

Abstract

In the present study, the effects of adenosine agonists on the development of sensitization to withdrawal signs precipitated after sporadic treatment with diazepam, in mice, were investigated. To obtain the sensitization, the animals were divided into groups: continuously and sporadically treated with diazepam (15.0 mg/kg, s.c.). The adenosine receptor agonists (CPA, CGS 21,680 and NECA) were administered in sporadically diazepam treated mice during two diazepam-free periods. Concomitant administration of pentetrazole (55.0 mg/kg, s.c.) with flumazenil (5.0 mg/kg, i.p.) after the last injection of diazepam or vehicle, induced the withdrawal signs, such as clonic seizures, tonic convulsion and death episodes. The major finding of our experiments is attenuation of withdrawal signs in sensitized mice, inducing by all adenosine agonists. Only higher dose of CPA produced significantly decreased the number of withdrawal incidents, while both used doses of CGS 21,680 and NECA produced more clear effects. These results support the hypothesis that adenosinergic system is involved in the mechanisms of sensitization to the benzodiazepine withdrawal signs, and adenosine A(2A) receptors play more important role in that process.

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Adenosine A1 Receptor Agonists
  • Adenosine A2 Receptor Agonists
  • Adenosine-5'-(N-ethylcarboxamide) / pharmacology
  • Animals
  • Convulsants
  • Diazepam / adverse effects*
  • Hypnotics and Sedatives / adverse effects*
  • Male
  • Mice
  • Pentylenetetrazole
  • Phenethylamines / pharmacology
  • Purinergic P1 Receptor Agonists*
  • Seizures / chemically induced
  • Seizures / etiology
  • Seizures / physiopathology
  • Substance Withdrawal Syndrome / prevention & control*
  • Substance Withdrawal Syndrome / psychology
  • Substance-Related Disorders / psychology

Substances

  • Adenosine A1 Receptor Agonists
  • Adenosine A2 Receptor Agonists
  • Convulsants
  • Hypnotics and Sedatives
  • Phenethylamines
  • Purinergic P1 Receptor Agonists
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • Adenosine-5'-(N-ethylcarboxamide)
  • N(6)-cyclopentyladenosine
  • Adenosine
  • Diazepam
  • Pentylenetetrazole