Effects of Adenosine Receptor Subtypes on Hippocampal Extracellular Serotonin Level and Serotonin Reuptake Activity

Abstract

To clarify the effects of adenosine receptor subtypes (A1, A2, and A3) on hippocampal serotoninergic function, hippocampal extracellular serotonin (5‐HT) levels were determined by in vivo microdialysis in freely moving rats under various conditions. Both adenosine and an adenosine A1 receptor agonist, 2‐chloro‐N6‐cyclopentyladenosine, decreased extracellular 5‐HT levels, whereas an adenosine A1 receptor antagonist, 8‐cyclopentyl‐1,3‐dimethylxanthine (CPT), and caffeine increased these levels. A selective A2A receptor agonist (CGS‐21680), an adenosine A2 receptor agonist (PD‐125944), an adenosine A2 receptor antagonist, 3,7‐dimethyl‐1‐propargylxanthine (DMPX), and an adenosine A3 receptor agonist, N6‐2‐(4‐aminophenyl)ethyladenosine (APNEA), did not affect extracellular 5‐HT levels. When the adenosine A1 receptor was blocked by CPT, the hippocampal extracellular 5‐HT level was increased by adenosine, CGS‐21680, and PD‐125944, and decreased by caffeine, DMPX, and APNEA. When both adenosine A1 and A2 receptors were blocked by CPT and DMPX, the extracellular 5‐HT level was decreased by adenosine, caffeine, and APNEA. The hippocampal extracellular 5‐HT level was not affected by administration of APNEA alone, but was decreased by this agent when the adenosine A1 receptor was blocked, irrespective of whether the adenosine A2 receptor was functional. These inhibitory effects of adenosine, caffeine, and APNEA on extracellular 5‐HT levels, during both adenosine A1 and A2 receptor blockade, were inhibited by selective 5‐HT reuptake inhibitors. These results indicate that the stimulatory effects of the adenosine A2 receptor and the inhibitory effects of the A3 receptor on hippocampal extracellular 5‐HT levels are masked by the inhibitory effects of the adenosine A1 receptor.

Assessing a vigilance decrement in aged rats: effects of pre-feeding, task manipulation, and psychostimulants

“…An action common to nicotine, amphetamine, and caffeine appears to be the ability to enhance brain levels of acetylcholine (Meyer et al 1987;Nordberg et al 1989;Summers et al 1994;Carter et al 1995;Arnold et al 2000Arnold et al , 2001, an effect which may compensate for reduced endogenous transmitter function in aged rats, and thus reverse a within-session decline in performance. However, amongst other effects, the psychostimulants studied share the ability also to increase synaptic levels of both dopamine (Di Chiara and Imperato 1988;Pontieri et al 1996;Okada et al 1997a), and serotonin (Ribeiro et al 1993;Summers and Giacobini 1995;Okada et al 1997b), both of which will alter performance of the standard five-choice task (e.g. Cole and Robbins 1989;Carli and Samanin 1992;Ruotsalainen et al 1997).…”

Adenosine Receptor Subtypes Modulate Two Major Functional Pathways for Hippocampal Serotonin Release

“…Recently, four major classes of adenosine receptor (AD-R) subtypes have been pharmacologically identified and cloned (Linden, 1994;Olah and Stiles, 1995). Many lines of evidence suggest that an activation of adenosine A 1 receptor (A1-R) suppresses neurotransmitter release (Barraco and Stefano, 1990;Zetterstrom and Fillenz, 1990;Ambrosio et al, 1997;Okada et al, 1997Okada et al, , 1999aSatoh et al, 1997;Ribeiro, 1999;Von Lubitz, 1999) primarily by presynaptic mechanisms, including the voltage-sensitive Ca 2ϩ channel (VSCC) and the K ϩ channel (Yawo and Chuhma, 1993;Ambrosio et al, 1997;Wu and Saggau, 1997;Wu et al, 1999). Activation of the adenosine A 2 receptor (A2-R) enhances the evoked release of various neurotransmitters (Popoli et al, 1995;Ambrosio et al, 1997;Satoh et al, 1997) that may involve P-type VSCC (P-VSCC) (Umemiya and Berger, 1994;Satoh et al, 1997).…”

“…It has been recognized that the response to adenosine is a balance between A1-R and A2-R activations because monoamine release is reduced and enhanced by agonists of A1-R and A2-R, respectively. The stimulatory effects of A2-R can be masked by activation of A1-R (Correia- de-Sa et al, 1996;Okada et al, 1997Okada et al, , 1999a. However, the mechanisms of this interaction between A1-R and A2-R have not been clarified yet.…”

Adenosine A3 receptors in the rat hippocampus: Lack of interaction with A1 receptors

“…It is possible that presynaptic A 3 receptors might be especially important in a particular subtype of hippocampal nerve terminals. In this respect, it has been reported that A 3 receptor activation has a minor role in the control of serotonin release in the hippocampus [Okada et al, 1997], but to the best of our knowledge no information is available on the ability of A 3 receptors to control noradrenaline, dopamine, or acetylcholine release in the hippocampus. Another possible role for these presynaptic A 3 receptors might be their ability to act as fine-tuning neuromodulators [Sebastião and Ribeiro, 2000].…”