n(6)-cyclohexyladenosine and Ataxia

The possible modulation and of co-modulation by the cerebellar GABAB and adenosine A1 receptors of ethanol-induced motor impairment were investigated in the mice using rotorod performance as the test response. Direct cerebellar microinfusion of GABAB agonist, baclofen, and antagonist, phaclofen, into the permanently cannulated mice, produced a dose-dependent accentuation and attenuation, respectively of ethanol-induced motor impairment. The baclofen and phaclofen exhibited accentuation and attenuation, respectively, via GABAB receptors linked to pertussis toxin-sensitive G protein. A comodulation by the cerebellar adenosine A1 receptors was also observed because intracerebellar microinfusion of adenosine agonists NB-cyclohexyladenosine (CHA), 5'-N-ethylcarbox-amidoadenosine (NECA), and 2-p-(2-carboxyethyl)-phenyl-ethylamino-5'-N-ethylacarbox- amidoadenosine (CGS-21680), and antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), also accentuated and attenuated, respectively, ethanol-induced motor impairment. The accentuation of ethanol-induced motor impairment by baclofen was further enhanced after the intracerebellar microinfusion of CHA, suggesting a co-modulation by the co-localized adenosine A1 receptors. A similar response was observed after the intracerebellar microinfusion of adenosine A1 = A2 agonist NECA and the several-fold higher dose of adenosine A2-selective agonist CGS-21680. Ethanol-induced motor impairment was markedly blocked by intracerebellar A1-selective antagonist, DPCPX, as well as by the intracerebellar pertussis toxin pretreatment suggesting again a co-modulation by the adenosine A1 receptors and the involvement of pertussis toxsin-sensitive G protein, respectively. The almost 25-fold higher dose of CGS-21680 to accentuate and DPCPX to attenuate, respectively, ethanol-induced motor impairment together with the reported cerebellar localization of adenosine A1 subtype only, suggested A1 receptor activation by NECA and CGS-21680. The functional similarity between GABAB and adenosine A1, receptors associated with their anatomical co-localization on the cerebellar granule cells, mainly axons and axonal terminals, may suggest a possible common adenylate cyclase catalytic unit as the basis of modulation of ethanol's motor impairment by these two receptor mechanisms.

Topics: Adenosine; Adenylate Cyclase Toxin; Animals; Ataxia; Baclofen; Behavior, Animal; Cerebellum; Dose-Response Relationship, Drug; Ethanol; GABA Agonists; GTP-Binding Proteins; Male; Mice; Mice, Inbred Strains; Microinjections; Motor Activity; Muscimol; Pertussis Toxin; Receptors, GABA-B; Receptors, Purinergic P1; Virulence Factors, Bordetella

To study the role of the striatum in modulating the effects of adenosine agonists and benzodiazepine inverse agonists on acute ethanol-induced motor impairment, we evaluated the effect of direct intrastriatal Ro15-4513 [0.625, 1.25 and 2.5 ng], a partial inverse agonist of benzodiazepine receptor, on ethanol-induced motor incoordination. A significant and nearly dose-dependent antagonism by Ro15-4513 was observed, which suggests involvement of the striatum in ethanol-induced motor incoordination. No effect of IST Ro15-4513 on motor incoordination induced by Na-pentobarbital (10 mg/kg, i.p.) was noted, indicating the selectivity of the antiethanol action of Ro15-4513. The IST adenosine agonist N6-cyclohexyladenosine (CHA) markedly accentuated ethanol-induced motor incoordination in a dose-related manner, suggesting a striatal adenosinergic modulation of ethanol-induced motor incoordination. The IST Ro15-4513 also significantly antagonized the accentuating effects of CHA on ethanol-induced motor incoordination. No change in normal motor coordination was observed after IST CHA or Ro15-4513 when followed by saline administration instead of ethanol. No accentuating effect by intrahippocampal CHA on ethanol-induced motor incoordination was seen, which suggests the selectivity of striatal adenosinergic modulation of ethanol-induced motor incoordination. There was no significant radioactivity present in the systemic circulation, in the CSF or in brain areas other than striatum after intrastriatal [3H]Ro15-4513 or [3H]CHA and ethanol injection. Data obtained so far support the involvement of striatum in ethanol's ataxia as well as striatal adenosinergic modulation of the central effect(s) of ethanol, possibly through Ro15-4513-sensitive mechanism(s).

Topics: Adenosine; Animals; Ataxia; Azides; Benzodiazepines; Corpus Striatum; Dose-Response Relationship, Drug; Ethanol; Male; Rats; Rats, Sprague-Dawley; Receptors, GABA