**3. Adenosine agonists and antagonists in the responses induced by ethanol**

As widely described, ethanol affects several mechanisms of transmission on the central nervous system, bringing a wide range of behavioral and neurochemical responses. To reduce the risks and to prevent the damages arising from ethanol intake, many researches are engaged in finding other substances that could inhibit or reduce the responses of ethanol in the organism. An alternative for this proposition is to study the relationship of the mechanism of action of ethanol effects and substances that may interfere in these pathways. Adenosine system, as already mentioned, interacts with many effects induced by ethanol, affecting their responses as being influenced by them. This system has gained remarkable interest in research because of its neuromodulator/neuroprotective action (Halbach & Dermietzel, 2006; Wardas, 2002), and may bring about a new target for developing drugs that can interfere with the effects caused by ethanol.

Among the wide range of adenosine receptor agonists and antagonists used in experiments involving ethanol treatment, we will focus on the most common substances, like adenosine, N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine g(DPMA), 2-chloro-N6 cyclopentyladenosine (CCPA), R(−)-N6-phenylisopropyladenosine (R-PIA) as agonists, and caffeine, theophylline, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 3,7-Dimethyl-1 propargylxanthine (DMPX) as antagonists, these last being well described and characterized in a review performed by Muller & Jacobson (2011).

A moderate alcohol intake may not be harmful and has even beneficial effects in prevention of cardiovascular diseases, for example (Di Castelnuovo et al., 2010), but heavy alcohol consumption could be associated with some risks to the body, like reduced brain mass, neuronal loss, neuropathological changes, and impairment of cognitive functions, amnesia, dementia and even a significant increase in mortality. Furthermore, the consumption of significant quantities of ethanol during pregnancy is responsible for the Fetal Alcohol Syndrome (FAS), and prenatal alcohol exposure in humans, as well as in rodents, leads to an impaired cognitive and behavioral function, resulting from damage to the central nervous system (Chen et al., 2003; Riley et al., 2004; Hamilton et al., 2003). Thus, taking into account the substantial importance of this system, studies looking for the lessening of these various damages caused by ethanol intake are strictly necessary.

High amount of experimental studies, involving ethanol administration, use a chronic treatment as methodology protocol; but subchronic and acute treatments are also well used (Soares et al., 2009; Prediger et al., 2006). While acute treatment simulates hangover, chronic treatment usually refers to the withdrawal symptoms and body's adaptive responses to prolonged consumption of ethanol.

Although many studies have consistently demonstrated increases in anxiety-like behavior during the withdrawal period after chronic exposure to ethanol in rodents (Lal et al., 1991; Knapp et al., 1993; Gatch & Lal, 2001), there are limited experimental findings regarding this

Other neurotransmitters still present a few studies involving ethanol and the adenosine system, such as glycine, where ethanol inhibits their specific receptors probably via PKC (Tao & Ye, 2002), and taurine, which normalizes the activity of ATPases in tissues pretreated with ethanol (Pushpakiran et al., 2005), showing some indirect relationship with the system

**3. Adenosine agonists and antagonists in the responses induced by ethanol**  As widely described, ethanol affects several mechanisms of transmission on the central nervous system, bringing a wide range of behavioral and neurochemical responses. To reduce the risks and to prevent the damages arising from ethanol intake, many researches are engaged in finding other substances that could inhibit or reduce the responses of ethanol in the organism. An alternative for this proposition is to study the relationship of the mechanism of action of ethanol effects and substances that may interfere in these pathways. Adenosine system, as already mentioned, interacts with many effects induced by ethanol, affecting their responses as being influenced by them. This system has gained remarkable interest in research because of its neuromodulator/neuroprotective action (Halbach & Dermietzel, 2006; Wardas, 2002), and may bring about a new target for developing drugs

Among the wide range of adenosine receptor agonists and antagonists used in experiments involving ethanol treatment, we will focus on the most common substances, like adenosine, N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine g(DPMA), 2-chloro-N6 cyclopentyladenosine (CCPA), R(−)-N6-phenylisopropyladenosine (R-PIA) as agonists, and caffeine, theophylline, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 3,7-Dimethyl-1 propargylxanthine (DMPX) as antagonists, these last being well described and characterized

A moderate alcohol intake may not be harmful and has even beneficial effects in prevention of cardiovascular diseases, for example (Di Castelnuovo et al., 2010), but heavy alcohol consumption could be associated with some risks to the body, like reduced brain mass, neuronal loss, neuropathological changes, and impairment of cognitive functions, amnesia, dementia and even a significant increase in mortality. Furthermore, the consumption of significant quantities of ethanol during pregnancy is responsible for the Fetal Alcohol Syndrome (FAS), and prenatal alcohol exposure in humans, as well as in rodents, leads to an impaired cognitive and behavioral function, resulting from damage to the central nervous system (Chen et al., 2003; Riley et al., 2004; Hamilton et al., 2003). Thus, taking into account the substantial importance of this system, studies looking for the lessening of these various

High amount of experimental studies, involving ethanol administration, use a chronic treatment as methodology protocol; but subchronic and acute treatments are also well used (Soares et al., 2009; Prediger et al., 2006). While acute treatment simulates hangover, chronic treatment usually refers to the withdrawal symptoms and body's adaptive responses to

Although many studies have consistently demonstrated increases in anxiety-like behavior during the withdrawal period after chronic exposure to ethanol in rodents (Lal et al., 1991; Knapp et al., 1993; Gatch & Lal, 2001), there are limited experimental findings regarding this

that can interfere with the effects caused by ethanol.

in a review performed by Muller & Jacobson (2011).

damages caused by ethanol intake are strictly necessary.

prolonged consumption of ethanol.

in focus.

symptom after a single ethanol challenge dose. Prediger et al. (2006) designed an experimental study of acute ethanol withdrawal (hangover) in mice, in which a timedependent development of anxiety-like behavior after an intraperitoneal administration of a single dose of ethanol (4 g/kg) in mice was assessed, and the potential of adenosine A1 and A2A receptor agonists in reducing this behavior was evaluated. They presented evidence that

acute administration of 'nonanxiolytic' doses of adenosine (5–10 mg/kg, i.p.) or the selective adenosine A1 receptor agonist CCPA (0.05–0.125 mg/kg, i.p.), but not the adenosine A2A receptor agonist DPMA (0.1–5.0 mg/kg, i.p.), which reduces the anxiety-like behavior during ethanol hangover in mice, as indicated by a significant increase in the exploration of the open arms of the elevated plus maze. In addition, the effect of CCPA (0.05 mg/kg, i.p.) was prevented by the pretreatment with the selective adenosine A1 receptor antagonist DPCPX (3.0 mg/kg, i.p.), demonstrating that the activation of adenosine A1 receptors, but not adenosine A2A receptors, reduces the anxiogenic-like behaviour observed during acute ethanol withdrawal in mice.

In general, sensitivity to the adverse effects of ethanol is inversely correlated with alcohol consumption. In a study with mice lacking the A2A receptor, Naassila et al. (2002) showed that these animals are less sensitive to the acute effects of ethanol as hypothermia and sedation, and consume more ethanol in a two-bottle choice paradigm compared with wildtype littermate control mice, demonstrating that the A2AR is involved in the sensitivity to the hypothermic and sedative effects of ethanol playing a role in alcohol-drinking behavior.

Furthermore, caffeine presents an ability to decrease sensitivity to the stumbling and tiredness associated with drinking large quantities of ethanol. Thus, adenosine receptors antagonists also appear to mediate some of the reinforcement effects of ethanol. This reinforcement is in part mediated via A2AR activation and probably associated with intracellular A2 activation of cAMP/PKA signalling cascades in the nucleus accumbens (Thorsell, et al., 2007; Adams et al., 2008), but the exact mechanism of action remains unclear. Studies in humans examining methylxanthine and ethanol interactions have mostly focused on the influence that caffeine exerts on ethanol intoxication, and have yielded mixed results (Liguori and Robinson 2001; Drake et al. 2003); but a point that needs further attention is the fact that these studies converge upon the point that caffeine consumed in association with ethanol, rather than improving ethanol-induced impairments, would reduce the self-perception of ethanol intoxication (Morelli & Simola, 2011), since human data also show that caffeine enhances tolerance to ethanol (Fillmore, 2003).

In addition to reinforcing effects, adenosine also appears to be related to locomotive effects of ethanol at high dose (6 g/kg) in subchronic treatment during 5 days, as shown in the experimental study of Soares et al. (2009), in which the administration of Aminophylline, a non-selective adenosine receptor antagonist, at low doses (5 and 10 mg/kg) produced some degree of locomotion stimulation, and was able to reverse the depressive effects produced by ethanol on the number of falls and time spent in the bar, in the Rota rod test, suggesting a partial blockage of the action of ethanol. The selective A1R agonist *N*6-cyclohexyladenosine (CHA) has also been found to potentiate, and the antagonist DPCPX attenuates ethanolinduced motor incoordination in mice (Meng et al., 1997).

Chronic ethanol intake leads to several changes in the balance of neurotransmitter pathways and its receptors, being studied oftentimes focusing withdrawal symptoms. Accordingly

Ethanol Interference on Adenosine System 715

This work was sponsored by the Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES, and Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico

Adams CL, Cowen MS, Short JL, & Lawrence AJ. (2008). Combined antagonism of

Arolfo MP, Yao L, Gordon AS, Diamond I, & Janak PH. (2004). Ethanol operant self-

Aronowski J, Strong R, Shirzadi A, & Grotta JC (2003). Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. *Stroke*, 34: 1246-1251. Barwick VS, & Dar MS. (1998). Adenosinergic modulation of ethanol induced motor

Batista LC, Prediger RD, Morato GS, Takahashi RN, (2005). Blockade of adenosine and

Belayev L, Khoutorova L, Zhang Y, Belayev A, Zhao W, Busto R, & Ginsberg MD. (2004).

Brust JCM. (2010). Ethanol and Cognition: Indirect Effects, Neurotoxicity and Neuroprotection: A Review. *Int. J. Environ. Res. Public Health,* 7: 1540-1557. Carmichael FJ, Israel Y, Crawford M, Minhas K, Saldivia V, Sandrin S, Campisi P, Orrego H.

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in rats. *International Journal Neuropsychopharmacol,* 11: 229-241.

glutamate mGlu5 and adenosine A2A receptors interact to regulate alcohol-seeking

administration in rats is regulated by adenosine A2 receptors. *Alcohol Clin Exp Res*,

incoordination in the rat motor cortex. *Prog. NeuroPsychopharmacol. Biol. Psychiatry*,

dopamine receptors inhibits the development of rapid tolerance to ethanol in mice.

Caffeinol confers cortical but not subcortical neuroprotection after transient focal

(1991). Central nervous system effects of acetate: contribution to the central effects

Activation of protein kinase C induces gamma-aminobutyric acid type A receptor

& Messing R.O. (2004). The type 1 equilibrative nucleoside transporter regulates

Goldberg SR, Mallol J, Cortes A, Canela EI, Lopez-Gimenez JF, Milligan G, Lluis C, Cunha RA, Ferre S, Franco R. (2006). Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. *J Neurosci,* 26: 2080-

cyclopentyladenosine (CCPA), an adenosine A1 receptor agonist, suppressed

**5. Acknowledgment** 

FUNCAP Grants.

**6. References** 

28: 1308–1316.

22: 587– 607.

2087.

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cerebral ischemia in rats. *Brain Res*, 1008: 278-283.

of ethanol. *J Pharmacol Exp Ther,* 259: 403-408.

Concas et al. (1994), the adenosine receptor agonist CCPA produces inhibition of these symptoms, such as tremors and audiogenically induced seizures in rats treated repeatedly with ethanol (12–18 g/kg daily for 6 days), an effect prevented by DPCPX. Similar results about the specificity of the adenosine receptor in the responses of ethanol effects have been reported by Kaplan et al (1999) in mice receiving a 14-day liquid diet containing ethanol and treated with the adenosine A1 receptor agonist R-PIA during the withdrawal period, indicating the adenosine A1R modulate anxiety-like responses in mice, not only in acute, but also in chronic treatment with ethanol.

Thus, adenosine receptor activation seems to be strongly linked with sensitivity and reinforcement properties of ethanol either in A1, or in A2AR, with an opposite relation of activation, whereas the adenosine A1R agonists reduce sensitivity, A2AR antagonists demonstrate to play this role. Despite A2A knockout mice showed reduced conditioned place preference for ethanol. Houchi et al. (2008) showed that the increased propensity to drink ethanol in A2A knockout mice was associated with an increase in sensitivity to the motor stimulant and anxiolytic effects of ethanol. Contrasting with these findings, the administration of A2A antagonist DMPX reduced ethanol reward and consumption, in a study performed by Thorsell et al. (2007), in which a decreased lever-pressing for ethanol in an operant chamber was observed.

Caffeine and selective adenosine receptor antagonists may also reduce the duration of ethanol-induced loss of the righting reflex (El Yacoubi et al., 2003), reverse deficits in motor coordination induced by ethanol (Barwick & Dar, 1998; Connole et al., 2004) and reverse retrograde memory impairment caused by a high dose of ethanol (3 g/kg) (Spinetta et al., 2008). Indeed, the combination of caffeine and ethanol produces a beneficial effect after experimental traumatism brain injury (Dash et al., 2004), projecting its effect on stroke (Aronowski et al., 2003; Belayev et al., 2004) and indicating the importance of the interaction between caffeine and ethanol.

Beyond neurotransmission/neuromodulation, it is important to give attention to other factors that contribute to the relationship between adenosine system and ethanol effects, as indicated in a review performed by Ruby et al. (2011) about adenosine signalling in anxiety, which underlies the importance of the adenosine transporter ENT1. Many aspects of ethanol-related behaviors and anxiety appear to be involved in genetic factors as polymorphism and in the gene encoding ENT1 could be associated with alcoholism and depression in women (Gass et al., 2010). Further, acute ethanol inhibits ENT1, while chronic ethanol treatment leads to decreased ENT1 expression (Short et al., 2006; Sharma et al., 2010). Also, mice lacking this adenosine transporter displayed a decreased A1 adenosine tone in the nucleus accumbens and elevated levels of ethanol consumption compared with wild-type mice (Choi et al., 2004). In contrast, it has been shown that ethanol operant selfadministration is not altered by an A1R antagonist while it is bimodally affected by an A2AR antagonist (Arolfo et al., 2004).

#### **4. Conclusion and future prospects**

As noted above, there are many different points of adenosine system interference on the effects of ethanol administration. This interaction is of fundamental importance because it could be a new target for developing drugs that may interfere, reducing the damage caused by ethanol.

#### **5. Acknowledgment**

714 Pharmacology

Concas et al. (1994), the adenosine receptor agonist CCPA produces inhibition of these symptoms, such as tremors and audiogenically induced seizures in rats treated repeatedly with ethanol (12–18 g/kg daily for 6 days), an effect prevented by DPCPX. Similar results about the specificity of the adenosine receptor in the responses of ethanol effects have been reported by Kaplan et al (1999) in mice receiving a 14-day liquid diet containing ethanol and treated with the adenosine A1 receptor agonist R-PIA during the withdrawal period, indicating the adenosine A1R modulate anxiety-like responses in mice, not only in acute, but

Thus, adenosine receptor activation seems to be strongly linked with sensitivity and reinforcement properties of ethanol either in A1, or in A2AR, with an opposite relation of activation, whereas the adenosine A1R agonists reduce sensitivity, A2AR antagonists demonstrate to play this role. Despite A2A knockout mice showed reduced conditioned place preference for ethanol. Houchi et al. (2008) showed that the increased propensity to drink ethanol in A2A knockout mice was associated with an increase in sensitivity to the motor stimulant and anxiolytic effects of ethanol. Contrasting with these findings, the administration of A2A antagonist DMPX reduced ethanol reward and consumption, in a study performed by Thorsell et al. (2007), in which a decreased lever-pressing for ethanol in

Caffeine and selective adenosine receptor antagonists may also reduce the duration of ethanol-induced loss of the righting reflex (El Yacoubi et al., 2003), reverse deficits in motor coordination induced by ethanol (Barwick & Dar, 1998; Connole et al., 2004) and reverse retrograde memory impairment caused by a high dose of ethanol (3 g/kg) (Spinetta et al., 2008). Indeed, the combination of caffeine and ethanol produces a beneficial effect after experimental traumatism brain injury (Dash et al., 2004), projecting its effect on stroke (Aronowski et al., 2003; Belayev et al., 2004) and indicating the importance of the interaction

Beyond neurotransmission/neuromodulation, it is important to give attention to other factors that contribute to the relationship between adenosine system and ethanol effects, as indicated in a review performed by Ruby et al. (2011) about adenosine signalling in anxiety, which underlies the importance of the adenosine transporter ENT1. Many aspects of ethanol-related behaviors and anxiety appear to be involved in genetic factors as polymorphism and in the gene encoding ENT1 could be associated with alcoholism and depression in women (Gass et al., 2010). Further, acute ethanol inhibits ENT1, while chronic ethanol treatment leads to decreased ENT1 expression (Short et al., 2006; Sharma et al., 2010). Also, mice lacking this adenosine transporter displayed a decreased A1 adenosine tone in the nucleus accumbens and elevated levels of ethanol consumption compared with wild-type mice (Choi et al., 2004). In contrast, it has been shown that ethanol operant selfadministration is not altered by an A1R antagonist while it is bimodally affected by an A2AR

As noted above, there are many different points of adenosine system interference on the effects of ethanol administration. This interaction is of fundamental importance because it could be a new target for developing drugs that may interfere, reducing the damage caused

also in chronic treatment with ethanol.

an operant chamber was observed.

between caffeine and ethanol.

antagonist (Arolfo et al., 2004).

by ethanol.

**4. Conclusion and future prospects** 

This work was sponsored by the Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES, and Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico FUNCAP Grants.

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