Behavioral effects of intrastriatal caffeine mediated by adenosinergic modulation of dopamine

doi:10.1016/0091-3057(91)90403-O

Pharmacology Biochemistry and Behavior

Volume 39, Issue 1, May 1991, Pages 97-103

https://doi.org/10.1016/0091-3057(91)90403-O Get rights and content

Abstract

Although caffeine is generally classified as a psychomotor stimulant, the neurotransmitter systems mediating its effect on behavior have not yet been established. Mounting evidence suggests possible involvement of adenosinergic and/or dopaminergic (DA) systems. To evaluate these possibilities, four experiments examined circling behavior in rats following unilateral intrastriatal microinjections of: 1) caffeine alone; 2) the adenosine agonist, 2-chloroadenosine (2-CADO) alone; 3) caffeine with 2-CADO pretreatment; and 4) caffeine with pretreatment of the DA receptor antagonist, cis-flupenthixol. Each experiment consisted of seven test sessions; the first and seventh were preceded by no treatment, the second and sixth by control microinjections (saline or cis-flupenthixol) and the third, fourth and fifth by drug microinjections. Results showed that 10.0 and 20.0 but not 1.0 μg of caffeine produced a significant contraversive bias in circling behavior, while 2.0 and 5.0 but not 1.0 μg doses of 2-CADO produced significant ipsiversive circling. Rats pretreated with central 2-CADO or cis-flupenthixol (in doses that did not influence circling bias when administered alone) prior to caffeine (10.0 μg) failed to exhibit a contraversive bias. Taken together, the present studies provide compelling support for the suggestion that the motor effects of intrastriatal caffeine are mediated by the antagonism of endogenous adenosine which, in turn, functionally increases DA.

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Intrastriatal injection of caffeine also induced rotation both in normal and in 6-OHDA-lesioned rats [20]. Since both the non-selective adenosine receptor agonist NECA and the selective adenosine A2A receptor agonist CGS21680 inhibited dopamine agonist-induced rotational behavior in 6-OHDA lesioned rats [20,21], these effects seem to be mediated at least in part by adenosine A2A receptors. From the mid-1990s, a number of selective A2A receptor antagonists have been synthesized and their effects on motor behaviors assessed in a range of preclinical studies.
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MOD appears to influence general activity primarily via the DA R1 receptor, but also modifies locomotor activity through multiple systems in mice and rats (Minzenberg and Carter, 2008; Young et al., 2011). CAF directly antagonizes receptors of the rat adenosine system with its locomotion facilitating actions likely occurring via consequent DA release (Josselyn and Beninger, 1991). A proposed model (Morin, 2013b) suggests that light acts via the SCN to induce phase shifts, locomotor suppression and the Tc drop.
Exposure of mice to a brief light stimulus during their nocturnal active phase induces several simultaneous behavioral or physiological responses, including circadian rhythm phase shifts, a drop in core body temperature (Tc), suppression of locomotor activity and sleep. Each response is triggered by light, endures for a relatively fixed interval and does not require additional light for expression. The present studies address the ability of the psychostimulant drugs, methamphetamine (MA), modafinil (MOD) or caffeine (CAF), to modify the light-induced responses. Drug or vehicle (VEH) was injected at CT11 into constant dark-housed mice then exposed to 5-min 100 μW/cm² light or no light at CT13. Controls (VEH/Light) showed approximately 60-min phase delays. In contrast, response was substantially attenuated by each drug (only 12–15 min delays). Under a 12-h light:12-h dark (LD12:12) photoperiod, VEH/light-treated mice experienced a Tc drop of about 1.3 °C coincident with locomotor suppression and both effects were abolished by drug pre-treatment. Each drug elevated activity during the post-injection interval, but there was also evidence for CAF-induced hypoactivity in the dark prior to the photic test stimulus. CAF acutely elevated Tc; MA acutely lowered it, but both drugs reduced Tc during the early dark (ZT12.5–ZT13). The ability of the psychostimulant drugs to block the several effects of light exposure is not the result of drug-induced hyperactivity. The results raise questions concerning the manner in which drugs, activity, sleep and Tc influence behavioral and physiological responses to light.
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The acute motor response to caffeine was studied in rats repeatedly treated with vehicle or the dopamine D₂ agonist bromocriptine either in a novel cage or in the home cage. Rats receiving bromocriptine (5 mg/kg i.p.) in a novel cage were sensitized to the motor stimulating effects of bromocriptine itself and showed cross-sensitization to the acute administration of low (10 mg/kg s.c.) but not high (25 mg/kg s.c.) doses of caffeine, no matter if the novel cage was identical or different from the test cage. In contrast, caffeine (10 mg/kg i.p.) administered to rats which had received bromocriptine (5 mg/kg i.p.) in the home cage and which showed no sign of a sensitized response to bromocriptine, failed to show an increased locomotor and stereotyped response as compared to vehicle pretreated rats. Similarly to caffeine, the selective adenosine A_2A antagonist SCH 58261 (3 mg/kg i.p.) showed an increased motor response in bromocriptine sensitized rats. The sensitized response to caffeine or SCH 58261 did not appear to be due to an higher basal motor activity of bromocriptine sensitized rats since acute administration of vehicle induced a similar motor response in bromocriptine and vehicle pretreated rats. Dopamine D₂ and adenosine A_2A receptors are colocalized in striatal efferent neurons where they control in an opposite direction motor behavior. The results of the present study showed that changes in the sensitivity of D₂ receptors influenced the sensitivity of the adenosine antagonist caffeine through an action on A_2A receptors. D₂ and A_2A receptors, therefore, not only acutely interact in the mediation of motor behavior but long-term modification of the D₂ receptors, such as sensitization, affected the response of adenosine A_2A receptors.
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The novel selective adenosine A_2A receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with $l$ -DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of $l$ -DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with $l$ -DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate $l$ -DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to $l$ -DOPA. Selective adenosine A_2A receptor antagonists, such as KW-6002, may be one means of reducing the dosage of $l$ -DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.
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Behavioral effects of intrastriatal caffeine mediated by adenosinergic modulation of dopamine

Abstract

Central effects of adenosine analogs on locomotor activity in mice and antagonism of caffeine

Brain Res.

Human consumption of caffeine

Unilateral injections of a D2 but not D1 agonist into the frontal cortex of rats produce a contralateral directional bias

Pharmacol. Biochem. Behav.

Neural basis of psychomotor stimulant and opiate reward: Evidence suggesting the involvement of a common dopaminergic system

Brain Res.

Central nervous system stimulants

Effects of pentoxifylline and theophylline on neurotransmitter uptake and release by synaptosome-rich homogenates of the rat hypothalamus

Eur. J. Pharmacol.

Relationship between rotational behavior induced by apomorphine and caffeine in rats with unilateral lesions of the nigro-straital pathway

J. Pharm. Pharmacol.

Theophylline reverses haloperidol-induced catalepsy in the rat: Its possible relevance to the pharmacological treatment of psychosis

Biol. Psychiatry

Effects of caffeine on central monoamine neurons

J. Pharm. Pharmacol.

The production of asymmetry and circling behavior following unilateral, intrastriatal administration of neuroleptic agents: A comparison of abilities to antagonist striatal function

Eur. J. Pharmacol.

Adenosine receptors in the central nervous system: Relationship to the central actions of methylxanthines

Life Sci.

Interaction of caffeine with benzodiazepines: Behavioral effects in mice

Arch. Int. Pharmacodyn. Ther.

The measurement of the influence of drugs on voluntary activity in mice

Br. J. Pharmacol.

Alkylxanthines elevated hippocampal excitability: Evidence for a role of endogenous adenosine

Naunyn Schmiedebergs Arch. Pharmacol.

Sedative and anticonvulsant effects of adenosine analogs in mouse and rat

J. Pharmacol. Exp. Ther.

NECA-induced hypomotility in mice: Evidence for a predominantly central site of action

Pharmacol. Biochem. Behav.

Release of norpinephrine and dopamine from brain vesicular preparations: Effects of adenosine analogues

Cell. Mol. Neurobiol.

Influence of pimozide on the locomotor activity produced by caffeine

J. Pharm. Pharmacol.

On the mechanism by which methylxanthines enhance apomorphine-induced rotation behavior in the rat

Pharmacol. Biochem. Behav.

Dopamine receptors and phosphodiesterases

Are methylxanthine effects due to antagonism of endogenous adenosine?

Trends Pharmacol. Sci.

Rotational behavior induced by methylxanthines: Phosphodiesterase inhibition, adenosine antagonism or some unknown mechanism of action?

Acta Pharmacol. Toxicol.

Action of caffeine and theophyllamine on supersensitive dopamine receptors: Considerable enhancement of receptor response to treatment with dopa and dopamine agonists

Med. Biol.

Caffeine as a drug of abuse

Turning in circles: The neuropharmacology of rotation

Life Sci.

Behavioral effects of caffeine, (−)N-(R)-1-methyl-2-phenylethyl)-adenosine (PIA), and their combination in the mouse

Psychopharmacology (Berlin)

Stereoselective behavioral effects of N6-phenylisopropyl-adenosine and antagonism by caffeine

Psychopharmacology (Berlin)