Functional correlation between subclasses of brain adenosine receptor affinities and ethanol-induced motor incoordination in mice

doi:10.1016/0091-3057(90)90558-Y

Pharmacology Biochemistry and Behavior

Volume 37, Issue 4, December 1990, Pages 747-753

https://doi.org/10.1016/0091-3057(90)90558-Y Get rights and content

Abstract

To further investigate if the modulation of ethanol-induced motor incoordination is by brain adenosine A₁ and/or A₂ receptor, adenosine analogs with wide variability in their affinity for A₁ and A₂ subtypes were administered ICV and their effect on ethanol-induced (IP) motor incoordination was evaluated by rotorod. A dose-dependent marked accentuation of ethanol-induced motor incoordination by adenosine agonists (CHA, NECA, CPA, DCCA) tested, with nearly no effect on normal motor coordination in the absence of ethanol, was observed. There was a positive correlation between A₂ affinity, A₂/A₁ affinity ratio but a negative correlation between A₁ affinity and the potency (ED₅₀) of adenosine agonists to accentuate ethanol-induced motor incoordination. However, with the high potency of CHA and NECA, both having significant affinity for A₁ and A₂ receptors, together with the well known membrane perturbation by ethanol, it seems difficult to rule out until more information becomes available the contribution of A₁ receptor activation to adenosine modulation of ethanol-induced motor incoordination. The high density of high affinity A₂ (A_2a) in the striatum and of A₁ in the cerebellum and several brain areas and the known importance of these two brain areas in the motor control, indirectly supports or at least provides a circumstantial evidence for a functional correlation between ethanol-induced motor incoordination and brain adenosine receptors.

References (26)

R.A. Barraco et al.
Central effects of adenosine analogues on locomotor activity in mice and antagonism of caffeine
Brain Res.
(1983)
M. Clark et al.
Mediation of acute ethanol-induced motor disturbances by cerebellar adenosine in rats
Pharmacol. Biochem. Behav.
(1988)
M.S. Dar et al.
Possible role of adenosine in the CNS effects of ethanol in mice
Life Sci.
(1983)
T.V. Dunwiddie
The physiological role of adenosine in the CNS
Int. Rev. Neurobiol.
(1985)
M.J. Durcan et al.
Evidence for adenosine A₂ receptor involvement in the hypomobility effects of adenosine analogues in mice
Eur. J. Pharmacol.
(1989)
B.B. Fredholm et al.
Behavioral sensitivity to PIA in selectively bred mice is related to a number of A₁ adenosine receptors but not to cyclic AMP accumulation in brain slices
Eur. J. Pharmacol.
(1985)
B. Hamprecht et al.
Nomenclature of adenosine receptors
Trends Pharmacol. Sci.
(1985)
J. Patel et al.
Characterization of adenosine receptors in brain using N⁶-cyclohexyl [³H]adenosine
Brain Res.
(1982)
W.R. Proctor et al.
Adenosine inhibits calcium spikes in hippocampal pyramidal in vitro
Neurosci. Lett.
(1983)
R.F. Bruns et al.
Characteristics of the A₂ adenosine receptor labeled by [³H]NECA in rat striatal membranes
Mol. Pharmacol.
(1986)

R.F. Bruns et al.

Adenosine receptor subtypes: binding studies

M.G. Collis

Are there two types of adenosine receptors in peripheral tissues?

G. Cristalli et al.

Adenosine receptor agonists: synthesis and biological evaluation of 1-deaza analogues of adenosine derivatives

J. Med. Chem.

(1988)

Cited by (19)

Role of adenosine A<inf>1</inf> and A(2A) receptors in the alcohol withdrawal syndrome
1999, Alcohol
The role of adenosine receptor-mediated signaling was examined in the alcohol withdrawal syndrome. CD-1 mice received a liquid diet containing ethanol (6.7%, v/v) or a control liquid diet that were abruptly discontinued after 14 days of treatment. Mice consuming ethanol showed a progressive increase in signs of intoxication throughout the drinking period. Following abrupt discontinuation of ethanol diet, mice demonstrated reversible signs of handling-induced hyperexcitability that were maximal between 5–8 h. Withdrawing mice received treatment with adenosine receptor agonists at the onset of peak withdrawal (5.5 h) and withdrawal signs were blindly rated (during withdrawal hours 6 and 7). Adenosine A₁-receptor agonist R-N⁶(phenylisopropyl)adenosine (0.15 and 0.3 mg/kg) reduced withdrawal signs 0.5 and 1.5 h after drug administration in a dose-dependent fashion. Adenosine A_2A-selective agonist 2-p-(2-carboxethyl)phenylethyl-amino-5′-N-ethylcarboxamidoadenosine (0.3 mg/kg) reduced withdrawal signs at both time points. In ethanol-withdrawing mice, there were significant decreases in adenosine transporter sites in striatum without changes in cortex or cerebellum. In ethanol-withdrawing mice, there were no changes in adenosine A₁ and A_2A receptor concentrations in cortex, striatum, or cerebellum. There appears to be a role for adenosine A₁ and A_2A receptors in the treatment of the ethanol withdrawal syndrome. Published by Elsevier Science Inc.
Central adenosine A(2A) receptors: An overview
1999, Brain Research Reviews
Recent advances in molecular biology, biochemistry, cell biology and behavioral pharmacology together with the development of more selective ligands to the various adenosine receptors have increased our understanding of the functioning of central adenosine A_2A receptors. The A_2A receptor is one of four adenosine receptors found in the brain. Its expression is highest in striatum, nucleus accumbens and olfactory tubercles, although it also occurs in neurons and microglia in most other brain regions. The receptor has seven transmembrane domains and couples via Gs to adenyl cyclase stimulation. Antagonistic interactions between A_2A receptors and dopamine D₂ receptors have been described, as stimulation of the A_2A receptor leads to a reduction in the affinity of D₂ receptors for D₂ receptor agonists. The A_2A receptor is thought to play a role in a number of physiological responses and pathological conditions. Indeed, A_2A receptor antagonists may be useful for the treatment of acute and chronic neurodegenerative disorders such as cerebral ischemia or Parkinson's disease. A_2A receptor agonists may treat certain types of seizures or sleep disorders. This review discusses the characteristics, distribution, pharmacochemical properties and regulation of central A_2A receptors, as well as A_2A receptor-mediated behavioural responses and their potential role in various neuropsychiatric disorders.
The striatal adenosinergic modulation of ethanol-induced motor incoordination in rats: Possible role of chloride flux
1997, Brain Research
Previous studies from our laboratory have provided strong evidence that brain adenosine modulates acute ethanol (i.p.)-induced motor incoordination (MI) through receptor mediated mechanism(s). Recently, we have reported the involvement of the striatum in ethanol-induced MI as well as the striatal adenosinergic modulation of the ethanol-induced motor deficit. The present study was thus designed to further characterize the modulatory effect of striatal adenosine on ethanol-induced MI and to look for its functional correlation with chloride flux within the rat striatum. Intrastriatal microinfusion of adenosine A₁ receptor agonist N⁶-cyclohexyladenosine (CHA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), significantly accentuated and attenuated, respectively, the motor incoordinating effect of ethanol while having no effect on the normal motor coordination in saline-treated control animals. These data confirmed the role of striatal adenosine in ethanol-induced MI. The selectivity of interactions between adenosine A₁ agonist and antagonist and ethanol was further confirmed by the study in which neither intrastriatal CHA nor DPCPX significantly altered the MI induced by sodium pentobarbital. Previously, we have shown that intrastriatal Ro15-4513 not only significantly attenuated ethanol-induced MI but also blocked its accentuation by intrastriatal CHA. It is well known that Ro15-4513 antagonizes many, but not all, CNS effects of ethanol by blocking the ethanol potentiation of GABA-stimulated uptake of chloride. Therefore, experiments using striatal microsac preparations were carried out to investigate the possible modulation of chloride conductance by CHA and its relationship to ethanol. High concentrations of CHA (10 and 100 nM) increased the total chloride uptake by the striatal microsacs. Corresponding to the ethanol–adenosine interaction observed behaviorally, a much lower concentration (1 nM) of CHA, being ineffective itself, significantly enhanced the stimulatory action of ethanol on chloride uptake. This effect was blocked by either Ro15-4513 (100 nM) or DPCPX (10 nM). The modulatory effect of GABA and/or ethanol on chloride influx was also evaluated, and the results supported the appropriateness to use striatal microsac preparations in the present study. Overall, the data suggested a functional interaction between ethanol and striatal adenosine and further supported the hypothesis that striatal adenosine might, in part, modulate ethanol-induced MI through its effect on chloride conductance through chloride channels coupled to GABA–benzodiazepine receptor complex.
Adenosine A<inf>2</inf> receptor-mediated excitatory actions on the nervous system
1996, Progress in Neurobiology
The distribution, molecular structure and role of adenosine A₂ receptors in the nervous system, is reviewed. The adenosine A_2a receptor subtype, identified in the nervous system with ligand binding, functional studies or genetic molecular techniques, has been demonstrated in the striatum and other basal ganglia structures, in the hippocampus, in the cerebral cortex, in the nucleus tractus solitarius, in motor nerve terminals, in noradrenergic terminals in the vas deferens, in myenteric neurones of the ileum, in the retina and in the carotid body. The A_2b receptors have been identified in glial and neuronal cells, and may have a widespread distribution in the brain. Activation of adenosine A_2a receptors can enhance the release of several neurotransmitters, such as acetylcholine, glutamate, and noradrenaline. The release of GABA might be either enhanced or inhibited by A_2a receptor activation. The A₂ receptor activation also modulates neuronal excitability, synaptic plasticity, as well as locomotor activity and behaviour. The ability of A₂ receptors to interact with other receptors for neurotransmitters/neuromodulators, such as dopamine D₂ and D₁ receptors, adenosine A₁ receptors, CGRP receptors, metabotropic glutamate receptors and nicotinic autofacilitatory receptors, expands the range of possibilities used by adenosine to interfere with neuronal function and communication. These A₂ receptor-mediated adenosine actions might have potential therapeutic interest, in particular in movement disorders such as Parkinson's disease and Huntington's chorea, as well as in schizophrenia, Alzheimer's disease, myasthenia gravis and myasthenic syndromes.
In vivo effects of (-)-nicotine on ethanol-induced increase in glucose utilization in the mouse cerebellum
1995, Brain Research Bulletin
The purpose of this study was to investigate the possible in vivo effects of (-)-nicotine, ethanol, and an adenosine agonist N⁶-cyclohexyladenosine (CHA) when injected individually as well as in various combinations on glucose utilization in the fresh cerebellar slices of mice. Mice received ICV (-)-nicotine or CHA followed 5 min later by a test dose of ethanol (2 g/kg; IP). Animals were killed 20 min postethanol treatment and fresh slices (300 μm) of cerebellum were incubated in a glucose medium in Warburg flasks using ¹⁴C-glucose as a tracer. Trapped ¹⁴CO₂ was counted to estimate glucose utilization. Ethanol treatment markedly accentuated glucose utilization, whereas the pretreatment with (-)-nicotine (125 and 250 ng, ICV) resulted in a significant attenuation in the ethanol-induced increase in glucose utilization. However, ICV (-)-nicotine (125 ng) alone did not produce any change in the cerebellar glucose utilization. The attenuation of ethanol-induced increase in glucose utilization by (-)-nicotine was nearly totally blocked by ICV hexamethonium, a purported nicotinic antagonist, suggesting participation of cholinergic-nicotinic receptors. The (-)-nicotine pretreatment also significantly attenuated both the ICV CHA (25 ng)-induced increase in glucose utilization and the accentuation of ethanol-induced increase in glucose utilization by CHA. The antagonistic effect of (-)-nicotine on CHA- and ethanol-induced increase in glucose utilization indicating an interaction between (−)-nicotine and ethanol and between (-)-nicotine and adenosine may suggest involvement of postreceptor (nicotinic and adenosine) mechanisms including ionic channels.
Intracerebellar nicotinic-cholinergic participation in the cerebellar adenosinergic modulation of ethanol-induced motor incoordination in mice
1994, Brain Research
Many epidemiological studies have suggested a high correlation between the use of tobacco and ethanol, the two most frequently abused psychoactive drugs. Recently, we reported behavioral interactions between (−)-nicotine, (−)-cotinine and ethanol within the CNS. The present report is a confirmation and an extension of that study. Using a 2 g/kg ethanol-induced motor incoordination (EIMI) as the test response, possible behavioral interactions between (−)-nicotine, (−)-cotinine and ethanol and between (−)-nicotine, (−)-cotinine and adenosine agonist + ethanol in the cerebellum were investigated. (−)-Nicotine, 0.625, 1.25 and 5 ng intracerebellarly (ICB) significantly attenuated EIMI in a dose-related manner. Likewise, ICB injection of 1.25, 2.5, and 5 ng (−)-cotinine, a major metabolite of nicotine, significantly attenuated EIMI after the same i.p. dose of ethanol as in case of (−)-nicotine but less markedly compared to (−)-nicotine. No change in normal motor coordination was observed when the highest dose of (−)-nicotine or (−)-cotinine was injected ICB followed by saline control, suggesting selectivity of their behavioral interactions with ethanol. The attenuation of EIMI by (−)-nicotine and (−)-cotinine was blocked by ICB hexamethonium (1 μg) and trimethaphan (100 ng), the purported nicotinic-cholinergic antagonists. Finally, the ICB injection of adenosine agonists,N⁶-cyclohexyladenosine (CHA) or5′-N-ethylcarboxamidoadenosine (NECA), produced marked accentuation of EIMI which was significantly antagonized by ICB (−)-nicotine and (−)-cotinine. The data obtained in the present study suggested, for the first time, a cerebellar adenosinergic-nicotinic cholinergic interaction and modulation of EIMI. The data also suggested participation of cerebellar nicotinic-cholinergic receptors in EIMI.

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^☆: This work was supported by U.S. Public Health Service Grant No. AA07101 from the National Institute on Alcohol Abuse and Alcoholism.

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Functional correlation between subclasses of brain adenosine receptor affinities and ethanol-induced motor incoordination in mice☆

Abstract

Brain Res.

Pharmacol. Biochem. Behav.

Life Sci.

Int. Rev. Neurobiol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Brain Res.

Neurosci. Lett.

Characteristics of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes

Mol. Pharmacol.

Adenosine receptor subtypes: binding studies

Are there two types of adenosine receptors in peripheral tissues?

Adenosine receptor agonists: synthesis and biological evaluation of 1-deaza analogues of adenosine derivatives

J. Med. Chem.

Characteristics of the A₂ adenosine receptor labeled by [³H]NECA in rat striatal membranes