Previous studies have demonstrated opposing roles for adenosine A 1 and A 2A receptors in the modulation of extracellular levels of glutamate and dopamine in the striatum. In the present study, acute systemic administration of motoractivating doses of the A 2A receptor antagonist MSX-3 significantly decreased extracellular levels of dopamine and glutamate in the shell of the rat nucleus accumbens (NAc) and counteracted both dopamine and glutamate release induced by systemic administration of motor-activating doses of either the A 1 receptor antagonist CPT or caffeine. Furthermore, exposure to caffeine in the drinking water (1 mg/mL, 14 days) resulted in tolerance to the effects of systemic injection of CPT or caffeine, but not MSX-3, on extracellular levels of dopamine and glutamate in the NAc shell. The present results show: first, the existence of opposite tonic effects of adenosine on extracellular levels of dopamine and glutamate in the shell of the NAc mediated by A 1 and A 2A receptors; second, that complete tolerance to caffeine's dopamine-and glutamatereleasing effects which develops after chronic caffeine exposure is attributable to an A 1 receptor-mediated mechanism. Development of tolerance to the dopamine-releasing effects of caffeine in the shell of the NAc may explain its weak addictive properties and atypical psychostimulant profile.
Adenosine, by acting on adenosine A 1 and A 2A receptors, exerts opposite modulatory roles on striatal extracellular levels of glutamate and dopamine, with activation of A 1 inhibiting and activation of A 2A receptors stimulating glutamate and dopamine release. Adenosine-mediated modulation of striatal dopaminergic neurotransmission could be secondary to changes in glutamate neurotransmission, in view of evidence for a preferential colocalization of A 1 and A 2A receptors in glutamatergic nerve terminals. By using in vivo microdialysis techniques, local perfusion of NMDA (3, 10 lM), the selective A 2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5¢-N-ethylcarboxamidoadenosine (CGS 21680; 3, 10 lM), the selective A 1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 300, 1000 lM), or the non-selective A 1 -A 2A receptor antagonist in vitro caffeine (300, 1000 lM) elicited significant increases in extracellular levels of dopamine in the shell of the nucleus accumbens (NAc). Significant glutamate release was also observed with local perfusion of CGS 21680, CPT and caffeine, but not NMDA. Co-perfusion with the competitive NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV; 100 lM) counteracted dopamine release induced by NMDA, CGS 21680, CPT and caffeine. Co-perfusion with the selective A 2A receptor antagonist MSX-3 (1 lM) counteracted dopamine and glutamate release induced by CGS 21680, CPT and caffeine and did not modify dopamine release induced by NMDA. These results indicate that modulation of dopamine release in the shell of the NAc by A 1 and A 2A receptors is mostly secondary to their opposite modulatory role on glutamatergic neurotransmission and depends on stimulation of NMDA receptors. Furthermore, these results underscore the role of A 1 vs. A 2A receptor antagonism in the central effects of caffeine.
Adenosine and dopamine systems interact to regulate instrumental behavior and effort-related processes, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia.
Seizures early in life cause long‐term behavioral modifications, namely long‐term memory deficits in experimental animals. Since caffeine and adenosine A2A receptor (A2AR) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long‐term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7‐days‐old (P7) rats caused a single period of self‐extinguishable convulsions which lead to a poorer memory performance in the Y‐maze only when rats were older than 90 days, without modification of locomotion or anxiety‐like behavior in the elevated‐plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP‐25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD‐95, NMDA receptor subunits (NR1, NR2A, NR2B) or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A2AR antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A2AR antagonists.
Rationale-Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors.Objective-Previous work showed that adenosine A 2A antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice. The present work used a T-maze choice procedure to assess the effects of adenosine A 2A and A 1 antagonism.Materials and methods-With this task, the two arms of the maze have different reinforcement densities (four vs. two food pellets), and a vertical 44 cm barrier is positioned in the arm with the higher density, presenting the animal with an effort-related challenge. Untreated rats strongly prefer the arm with the high density of food reward and climb the barrier in order to obtain the food. Results-Haloperidol produced a dose-related (0.05-0.15 mg/kg i.p.) reduction in the number of trials in which the rats chose the high-barrier arm. Co-administration of the adenosine A 2A receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg i.p.), but not the A 1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.75, 1.5, and 3.0 mg/kg i.p.), reversed the effects of haloperidol on effort-related choice and latency.
NIH Public AccessConclusions-Adenosine A 2A and D2 receptors interact to regulate effort-related decision making, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing or anergia that can be observed in depression, parkinsonism, and other disorders.
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