Subchronic Caffeine Exposure Induces Sensitization to Caffeine and Cross-Sensitization to Amphetamine Ipsilateral Turning Behavior Independent from Dopamine Release

Abstract

We have recently shown that repeated exposure to caffeine sensitizes rats to the motor activating effects of dopamine D 1 and D 2 receptor agonists. In order to study the role of dopamine in this effect, sensitization to caffeine and cross-sensitization between caffeine and amphetamine was evaluated by studying turning behavior and in vivo striatal dopamine release in unilaterally 6-hydroxydopaminelesioned rats. Administration of caffeine (15 mg/kg) for 2 weeks, on alternate days, induced a significant increase in ipsilateral turning behavior during the course of treatment, indicating that sensitization to caffeine took place in the intact striatum. Caffeine modestly increased dopamine release in the intact dorsa-lateral striatum and no significant difference between the first (+38%) and the last (+51%) injection was observed. Amphetamine (2 mg/kg) induced a significantly higher ipsilateral turning behavior in caffeine-sensitized rats than in vehicle-pretreated rats, however, a similar increase in dopamine release (+900 and +800%) was observed in the two groups. The results are the first demonstration that caffeine pre-exposure sensitizes the motor-stimulant effects of caffeine itself and of amphetamine. Sensitized ipsilateral turning after caffeine and amphetamine are not correlated to modification in striatal dopamine release, rather, postsynaptic modifications in dopamine and adenosine receptor interaction might be involved in the sensitization phenomena observed.

Role of the Central Ascending Neurotransmitter Systems in the Psychostimulant Effects of Caffeine

“…To reach a complete understanding of the mechanisms behind the psychostimulant effects of caffeine we still need to find out about the role of adenosine, adenosine receptors, and adenosine receptor heteromers in local modules from all the other areas of origin and projection of the ascending dopaminergic and arousal systems. Furthermore, we are only starting to understand the mechanisms underlying some temporal properties of the psycostimulant effects of caffeine, such as sensitization and tolerance [22,50,[117][118][119]. In addition to pharmacokinetic mechanisms [117], we need to establish which pharmacodynamic changes, such as modifications in the expression and function of adenosine and dopamine receptors and receptor heteromers [22,50,119], are involved.…”

Repeated administration of caffeine induces either sensitization or tolerance of locomotor stimulation depending on the environmental context

“…However, De Luca et al [9] showed that similar doses of caffeine increase extracellular levels of dopamine preferentially in the medial prefrontal cortex and not in the nucleus accumbens. Caffeine locomotor sensitization has been associated with a decreased A ) receptor in the nucleus accumbens [47], a sensitized response to dopaminergic indirect agonists [7,42] and increased dopamine tissue levels in the striatum [20]. Caffeine tolerance is associated with decreased binding sites on the A adenosine receptor and increased binding on the same receptor during withdrawal [8,23].…”

“…Development of tolerance has been related to neuroadaptations responsible for withdrawal symptoms when the repeated administration of psychostimulants is discontinued [29,41]. In contrast, it has been shown that an ip injection of caffeine on alternate days for two weeks induces sensitization to its psychomotor stimulation [7,42]. Psychomotor sensitization is a common outcome of chronic administration of psychostimulants, such as amphetamine and cocaine, and has been related to neuroadaptations implicated in drug addiction [32,33,37].…”

Prior Treatment (Priming) with Caffeine Sensitizes D2-Dopamine-Mediated Contralateral Rotational Behavior in 6-Hydroxydopamine-Lesioned Rats

“…For example, we have found that pretreatment (priming) with 3 injections, spaced 3-6 days apart, of D1, D2 or D1/D2 dopamine agonists permits a behaviorally ineffective dose of the D2 agonist quinpirole (0.25 mg/kg) to produce robust contralateral rotational behavior in 6-OHDA rats, suggesting that prior exposure to a dopamine agonist greatly influences the subsequent behavioral response following challenge with a D2 agonist [17,18] . While some of the acute behavioral effects of caffeine in 6-OHDA rats have been characterized [10,11,13] , less is known about the role of caffeine in sensitizing (priming) dopamine-mediated behaviors in 6-OHDA rats. One study reported that intermittent, repeated treatment with caffeine (15 mg/kg) could sensitize D1-mediated contralateral rotational behavior, however, there was no effect on D2-mediated rotational behavior [19] ; this is a surprising observation given the wealth of data regarding D2/A2a receptor interactions [3-6, 20, 21] ( fig.…”

“…In 6-OHDA rats repeatedly pretreated (primed) with dopamine agonist, administration of caffeine produces contralateral rotational behavior [10,11] , an effect similar to that observed following administration of a direct acting dopamine agonist [9,12] . In contrast, when 6-OHDA rats are unprimed or given a single priming injection with a dopamine agonist, subsequent caffeine administration produces ipsilateral rotational behavior [13] , an effect similar to amphetamine which releases dopamine on the intact (unlesioned) side [12,14] . These data suggest that prior dopamine receptor stimulation has a profound influence on the behavioral effects of caffeine in dopamine-depleted rats.…”