2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Schizophrenia

The adenosine A(2A) receptor forms a mutually inhibitory heteromer with the dopamine D. Male and female Sprague-Dawley rats were neonatally treated with saline (NS) or quinpirole HCl (NQ; 1 mg/kg) from postnatal days (P) 1-21. Animals were raised to P44 and behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI) from P44 to P48. Approximately 15 min before each session, animals were given an ip administration of saline or the adenosine A(2A) agonist CGS 21680 (0.03 or 0.09 mg/kg). One day after PPI was complete on P49, animals were administered a locomotor activity test in the open field after saline or CGS 21680 treatment, respectively. On P50, the nucleus accumbens (NAc) was evaluated for CREB protein.. NQ-treated rats demonstrated a deficit in PPI that was alleviated to control levels by either dose of CGS 21680. The 0.03 mg/kg dose of CGS 21680 increased startle amplitude in males. The 0.09 mg/kg dose of CGS 21680 resulted in an overall decrease in locomotor activity. NQ treatment significantly increased NAc CREB that was attenuated to control levels by either dose of CGS 21680.. This study revealed that an adenosine A(2A) receptor agonist was effective to alleviate PPI deficits in the NQ model of SZ in both male and female rats.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Animals, Newborn; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Female; Male; Motor Activity; Nucleus Accumbens; Phenethylamines; Prepulse Inhibition; Quinpirole; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptors, Dopamine D2; Schizophrenia; Sensory Gating

Adenosine A (2A) receptors have been implicated in the pathophysiology of schizophrenia by clinical, anatomical, biochemical and genetic studies. We hypothesized that a genetically determined low number of adenosine A (2A) receptors could be a vulnerability factor for the development of the disease. The density of adenosine A (2A) receptors was investigated in human postmortem striatum of patients with schizophrenia (n = 9) and matched controls ( n= 9) using [ H)CGS 21680 as a radioligand probe. The maximum number of binding sites (B) (max) was 70% higher in patients with schizophrenia than in matched controls (609.4 +/- 259.1 354.0 +/- 156.4 fmol/mg protein, p=0.04). No significant difference could be discerned for the affinity of caffeine for adenosine A receptors between patients and controls. The increase in receptor density correlated with the dose of antipsychotic medication in chlorpromazine equivalents (r =0.61, = 0.014). We failed to provide evidence for a genetically determined reduction of adenosine A 2(A) receptors in schizophrenia. Instead, consistent with findings from animal experiments, our observation supports a role of adenosine A (2A) receptors in the molecular effects of antipsychotic drugs.

Topics: Adenosine; Aged; Aged, 80 and over; Antipsychotic Agents; Cadaver; Caffeine; Control Groups; Corpus Striatum; Female; Humans; Male; Middle Aged; Phenethylamines; Purinergic P1 Receptor Agonists; Receptor, Adenosine A2A; Receptors, Purinergic P1; Schizophrenia; Up-Regulation

We measured adenosine 2a receptors in basal ganglia of 13 schizophrenics and 10 controls, using [3H] CGS21680 as a ligand for the receptor binding assay. There was a significant increase in the specific [3H] CGS21680 binding in the putamen and caudate, but not in the globus pallidus of externa, of the schizophrenic patients, compared to those of controls. These results provide evidence suggesting that adenosine 2a receptors play a role in the pathophysiology of schizophrenia.

Topics: Adenosine; Adult; Aged; Antihypertensive Agents; Brain Chemistry; Chronic Disease; Corpus Striatum; Female; Humans; Male; Middle Aged; Phenethylamines; Radioligand Assay; Receptors, Adrenergic, alpha-2; Schizophrenia; Tritium

Recent studies have shown the existence of a specific antagonistic interaction between adenosine A2a receptors and dopamine D2 receptors in the brain. This A2a-D2 interaction seems to be essential for the behavioural effects of adenosine agonists and antagonists, like caffeine. In the present study quantitative receptor autoradiography and brain microdialysis were combined to demonstrate a powerful antagonistic A2a-D2 interaction in the ventral striopallidal system. In the presence of the A2a agonist (2-p-carboxyethyl)phenylamino-5'-N carboxamidoadenosine, dopamine exhibited a lower efficacy in displacing the radiolabelled D2 receptor antagonist [125I]iodosulpiride from the rat ventral striatum, specially in the nucleus accumbens. A tonic dopaminergic modulation of the striopallidal neurons from the ventral striopallidal system was demonstrated by a dual-probe approach, by infusing selective dopamine agonists and antagonists in the nucleus and by measuring dopamine extracellular levels in the nucleus accumbens and GABA extracellular levels in the nucleus accumbens and in the ipsilateral ventral pallidum. The infusion of (2-p-carboxyethyl)phenylamino-5'-N-carboxamidoadenosine in the nucleus accumbens induced the same postsynaptic changes as the D2 antagonist raclopride, i.e. an increase in pallidal GABA extracellular levels, without changing those levels in the nucleus accumbens. Furthermore, the coinfusion in the nucleus accumbens of low concentrations of (2-p-carboxyethyl) phenylamino-5'-N-carboxamido-adenosine and raclopride, which were ineffective when administered alone, induced a significant increase in pallidal gamma-aminobutyric acids extracellular levels. These results suggest that A2a agonists, alone or in combination with D2 antagonists, could be advantageous antischizophrenic drugs, as blockage of D2 receptors in the ventral striopallidal system appears to be associated with the antipsychotic activity of neuroleptics but not with their extrapyramidal motor-side effects.

Topics: Adenosine; Animals; Antihypertensive Agents; Antipsychotic Agents; Autoradiography; Binding, Competitive; Dopamine D2 Receptor Antagonists; gamma-Aminobutyric Acid; Globus Pallidus; Microdialysis; Neostriatum; Nucleus Accumbens; Phenethylamines; Purinergic P1 Receptor Antagonists; Raclopride; Rats; Rats, Sprague-Dawley; Salicylamides; Schizophrenia; Sulpiride