Anticonvulsant doses of 2-chloro-N6-cyclopentyladenosine, an adenosine A1 receptor agonist, reduce GABAergic transmission in different areas of the mouse brain.
The possible relationship between A1 adenosine receptors and the gamma-aminobutyric acid (GABAA) receptor complex was evaluated in the mouse brain. We studied the effect of in vitro addition and in vivo administration of 2-chloro-N6-cyclopentyladenosine (CCPA), the most selective ligand for A1 receptors, on the biochemical parameters used currently to evaluate GABAergic function. In vitro, CCPA (0.01-100 microM) failed to modify [3H] GABA binding, [3H]flunitrazepam binding, t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and muscimol-stimulated 36Cl- uptake. On the contrary, in vivo, CCPA (1.4-27.6 mumol/kg i.p.) increased [35S]TBPS binding in membranes from the cerebral cortex, hippocampus, striatum and substantia nigra, but not from the cerebellum, thalamus, hypothalamus and olfactory tubercle. The specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxantine (9.8 mumol/kg i.p.) abolished the effect of CCPA on [35S]TBPS binding, indicating that the action of this compound is mediated by its interaction with A1 receptors. Diazepam (1.7 mumol/kg i.p.), a positive modulator of GABAergic transmission, antagonized the increase of [35S]TBPS binding induced by CCPA. CCPA (2.8-8.3 mumol/kg i.p.) antagonized convulsions induced by isoniazid, an inhibitor of GABA synthesis, but neither antagonized nor potentiated isoniazid-induced increase of [35S]TBPS binding. CCPA (2.8-8.3 mumol/kg i.p.) antagonized the convulsions induced by pentylenetetrazol (398 mumol/kg i.p.), methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (50 mumol/kg i.p.) and bicuculline methiodide (9.8 mumol/kg i.p.). The results show that, in spite of its anticonvulsant activity, CCPA reduces the function of the GABA-coupled chloride channel function. This finding suggests that the anticonvulsant target sites are different from those involved in the action of CCPA on GABAA receptors.
Concas
A
A
Department of Experimental Biology, University of Cagliari, Italy.
Santoro
G
G
Mascia
M P
MP
Maciocco
E
E
Dazzi
L
L
Ongini
E
E
Biggio
G
G
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000493:pharmacokinetics; D003292:Convulsants; D003864:Depression, Chemical; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005445:Flunitrazepam / Q000378:metabolism; D007538:Isoniazid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058915:Purinergic P1 Receptor Antagonists; D018079:Receptors, GABA / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013462:Sulfur Radioisotopes; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014316:Tritium; D014970:Xanthines / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D000927:Anticonvulsants; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D003292:Convulsants; D058915:Purinergic P1 Receptor Antagonists; D018079:Receptors, GABA; D018047:Receptors, Purinergic P1; D013462:Sulfur Radioisotopes; D014970:Xanthines; D014316:Tritium; C058394:2-chloro-N(6)cyclopentyladenosine; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D003975:Diazepam; D007538:Isoniazid