The Adenosine Antagonist Theophylline Impairs P50 Auditory Sensory Gating in Normal Subjects

Abstract

In the P50 suppression paradigm, when two auditory stimuli are presented 500 ms apart, the amplitude of the second response (S2), compared with the first (S1), is markedly attenuated in healthy subjects. This is an index of sensory gating. Most schizophrenic patients fail to inhibit the P50 response to the second stimulus, which is assumed to reflect an inhibitory deficit. Adenosine is a neuromodulator with mostly inhibitory activity which is released by physiological stimuli. Since this inhibitory pattern resembles the phenomenon of sensory gating, the contribution of adenosine to P50 suppression was investigated in normal volunteers after treatment with the adenosine antagonist theophylline or placebo. P50 recordings were conducted in thirteen healthy subjects at baseline and 5, 30, 60, and 90 min after oral administration of theophylline (0.66 mg/kg, maximum dose of 500 mg) or placebo in a cross-over design. Baseline results from 17 drug-treated schizophrenic patients were included for comparison. Compared with placebo, theophylline treatment significantly increased P50 ratio (S2/S1) from 0.28 Ϯ 0.03 to 0.82 Ϯ 0.11 at 30 min and 0.61 Ϯ 0.07 at 60 min (mean Ϯ SEM), which were not significantly different from the schizophrenia group (0.74 Ϯ 0.05). The increased P50 ratio by theophylline was due to a combined decrease in S1 and increase in S2 amplitude. The impairment of P50 suppression by theophylline in normal subjects suggests a modulatory role of adenosine in sensory gating, which may be related to P50 suppression deficit in schizophrenia and is in agreement with a hypoadenosinergic model of schizophrenia.

Lower frequency of the low activity adenosine deaminase allelic variant (ADA1*2) in schizophrenic patients

“…1 The adenosine A1 and A2A receptor antagonists theophylline and caffeine decrease P50 sensory gating in normal volunteers, mimicking the findings in schizophrenic patients, 15 and caffeine exacerbates symptoms of schizophrenia. 3 Moreover, the psychostimulant effects of caffeine are blocked by D2 receptor antagonists.…”

Potential Therapeutic Interest of Adenosine A2A Receptors in Psychiatric Disorders

“…Thus, caffeine might exacerbate positive symptoms ( [188][189][190]; but see [191]) and conversely dipyridamole and allopurinol may be beneficial for schizophrenia [192][193][194][195]; this provides compelling direct evidence since caffeine blocks adenosine A 1 and A 2A receptors and both dipyridamole and allopurinol prevent purine degradation by inhibiting adenosine transporters and xanthine oxidase. Furthermore, the expected deficiency of sensorimotor gating, evaluated as a disturbed prepulse inhibition or P50 evoked potential, which is characteristic of schizophrenic individuals [196], is mimicked by theophylline in healthy volunteers [197]. Furthermore, there are co-morbidity relations, namely with insomnia (particularly with delta activity, see [198]), which is mimicked by caffeine consumption [199] and prevented by activation of adenosine receptors [117], and after seizures [200], which is also mimicked by xanthenes and prevented by adenosine A 1 receptor activation [201].…”

The biochemical womb of schizophrenia: A review

“…The neuromodulator adenosine has been proposed as a candidate for this purpose. A state of adenosinergic hypoactivity in schizophrenia is suggested to be compatible not only with the inhibitory deficit but also with symptoms, clinical response to antipsychotics, impaired sensory gating, deteriorating course, increased smoking and sleep alterations reported in schizophrenia (214)(215).…”