Possible Role of Striatal Adenosine in the Modulation of Acute Ethanol‐Induced Motor Incoordination in Rats

Abstract

Several reports from our laboratory have suggested the involvement of the brain adenosinergic system in ethanol-induced motor incoordination (EIMI). This study is an extension of the previous work and pertains to the evaluation of the role of the striatal adenosine in EIMI in male Sprague-Dawley rats. Using the motor incoordination induced by 1.5 g/kg of ethanol (ip) as a test response, the possible behavioral interactions between ethanol and adenosine agonists and antagonists in the striatum were investigated. Intrastriatal (IST) administration of adenosine A1-, A1 = A2-, and As-selective agonists, R(-)N6-(2-phenylisopropyl)adenosine (R-PIA), 5'-N-ethylcarboxamido-adenosine (NECA), and 5'-(N-cyclopropyl)-carboxamidoadenosine, respectively, significantly and dose-dependently accentuated EIMI when evaluated by rotorod test, suggesting the striatal adenosinergic modulation of EIMI. No significant change in normal motor coordination was noted, even when the highest IST doses of adenosine agonists were followed by saline instead of ethanol, suggesting that the observed behavioral interactions of these drugs were selective to ethanol. Hippocampus, which is known not to be involved in the normal motor functions, was selected as a control brain area because of the presence of high density of adenosine receptors, as well as the high levels of adenosine. Intrahippocampal NECA failed to alter EIMI, indicating the specific role of striatal and not hippocampal adenosinergic system in the modulation of EIMI. The potentiating effects of adenosine agonists N6-cyclohexyladenosine (CHA) and CGS-21680 on EIMI were blocked by adenosine A1- and A2-selective antagonists, 8-cyclopentyl-1,3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine, respectively, suggesting the participation of specific adenosine receptors in this functional interaction. A role for the adenosine A1 receptor in the striatal adenosinergic modulation of EIMI was favored based on the rank-order potency of adenosine agonists. IST pretreatment with pertussis toxin (PT), but not with PT beta-oligomer, nearly completely eliminated the accentuation of EIMI by CHA, further supporting the favored role of adenosine A1 receptors in EIMI. Histological and IST [3H]R-PIA distribution data confirmed that the observed behavioral effects were caused by exclusive striatal distribution of intrastriatally microinjected drugs. Data obtained suggested modulation of acute EIMI by striatal adenosine receptor-mediated mechanism(s) and the coupling of these adenosine receptor to the PT-sensitive Gi protein.

Activation of Adenosine A1 Receptors Reduces Anxiety-Like Behavior During Acute Ethanol Withdrawal (Hangover) in Mice

“…In humans, the nonselective adenosine receptor antagonist caffeine reduces sleepiness and psychomotor performance impairment produced by moderate-to-high ethanol doses (Franks et al, 1975;Fillmore and Vogel-Sprott, 1995;Liguori and Robinson, 2001;Drake et al, 2003). In rodents, adenosine receptors seem to modulate some of the pharmacological properties of ethanol, such as sedative/ hypnotic effects (El Yacoubi et al, 2003), motor incoordination (Meng and Dar, 1995;Barwick and Dar, 1998;Dar, 2001), and development of rapid tolerance to ethanolinduced motor impairments (Batista et al, 2005).…”

“…Furthermore, the combined administration of caffeine and alcohol can increase the development of alcohol tolerance (Fillmore, 2003). In rodents, many studies using selective adenosine receptor agonists and antagonists have consistently demonstrated that adenosine receptors, localized in brain areas essential for motor control such as striatum, the cerebellum, and the motor cortex, are the primary site where adenosine modulates the incoordination induced by ethanol (Meng and Dar, 1995;Barwick and Dar, 1998;Dar, 2001). Additionally, we have recently demonstrated that the blockade of adenosine receptors inhibits the development of rapid tolerance to ethanol-induced motor impairment in mice (Batista et al, 2005).…”

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

“…Striatal A2AR signaling Striatal adenosine levels play an important role in ethanol sensitivity, withdrawal, and drinking (Arolfo et al, 2004;Gordon and Diamond, 1993;Meng and Dar, 1995;Nagy and DeSilva, 1994). The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, while A1Rs are widely distributed throughout the CNS.…”

Ethanol Interference on Adenosine System

“…It was found that the use of adenosine agonists accentuate the reduction in the motor coordination induced by ethanol, whereas Ro15-4513, a weak partial inverse agonist of the benzodiazepine class of drugs, attenuated by blocking the effect of the first when used in combination Dar, 1994Dar, , 1995, suggesting a participation via GABA A by an alteration in the conductance of chloride ions (Meng et al, 1997, Mohler et al, 1984. A mechanism suggested by Londos et al (1980) and Van Calk et al (1970) relates ethanol to alterations in the production of cAMP via AC through the A1 receptor, ie, increased availability of adenosine induced by ethanol leads to greater signs of adenosine on your receptor that has a higher affinity, which is related with inhibitory G protein, reducing cAMP production and concomitant modulation of the GABAergic system that increases chloride conductance.…”

“…The GABAergic system in the striatum may be modulated by adenosine with regard to the effects of ethanol on motor coordination and sleep, involving cAMP Dar, 1995;Meng et al, 1997). It was found that the use of adenosine agonists accentuate the reduction in the motor coordination induced by ethanol, whereas Ro15-4513, a weak partial inverse agonist of the benzodiazepine class of drugs, attenuated by blocking the effect of the first when used in combination Dar, 1994Dar, , 1995, suggesting a participation via GABA A by an alteration in the conductance of chloride ions (Meng et al, 1997, Mohler et al, 1984.…”