Neuroscience Letters 414 (2007) 61–64 Increased serum adenosine deaminase activity in schizophrenic receiving antipsychotic treatment M.G. Brunstein a,c , E.M. Silveira Jr. a , L.S. Chaves a , H. Machado b , O. Schenkel b , P. Belmonte-de-Abreu a , D.O. Souza c , D.R. Lara d,∗ a Departamento de Psiquiatria, HCPA, UFRGS, Porto Alegre, Brazil b Laborat´ orio Weinmann, Porto Alegre, Brazil c Departamento de Bioqu´ ımica, UFRGS, Porto Alegre, Brazil d Faculdade de Biociˆ encias, PUCRS, Porto Alegre, Brazil Received 6 October 2006; received in revised form 7 November 2006; accepted 8 November 2006 Abstract Adenosine is an important modulator of the nervous system that has been implicated in the pathophysiology of schizophrenia. We studied periph- eral adenosine metabolism by determining the activity of serum adenosine deaminase, which converts adenosine into inosine, and 5 ′ -nucleotidase, which converts AMP into adenosine, in 26 DSM-IV male schizophrenic patients under antipsychotic monotherapy and 26 healthy volunteers balanced for age and race. Schizophrenic patients treated either with typical antipsychotics or clozapine showed increased serum adenosine deam- inase activity compared to controls (controls = 18.96 ± 4.61 U/l; typical = 25.09 ± 10.98 U/l; clozapine = 30.32 ± 10.83 U/l; p < 0.05, ANOVA) and 5 ′ -nucleotidase activity was also increased in patients on clozapine. After adjusting for confounding factors, adenosine deaminase, but not 5 ′ - nucleotidase, alterations remained significant particularly in the clozapine group. This result suggests that either altered adenosine metabolism is present in schizophrenic patients or is influenced by treatment with antipsychotics, particularly clozapine. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Schizophrenia; Adenosine; Adenosine deaminase; 5 ′ -Nucleotidase; Purinergic system; Antipsychotics The neuromodulator adenosine has been recently proposed to contribute to the pathophysiology of schizophrenia [19,20]. This hypothesis postulates that a dysfunction in adenosinergic activity in schizophrenia would lead to putative alterations of dopaminergic and glutamatergic activities. Moreover, the ubiq- uity of adenosine could also account for some of the systemic alterations reported in schizophrenic patients [19,20,14,8]. The proposed adenosine dysfunction in schizophrenia, leading to a synaptic adenosinergic deficit, could be due to receptor alter- ations or altered metabolism, i.e. decreased production/release or increased degradation/uptake of adenosine [19]. This model is supported by indirect neurophysiological evidence such as sen- sory gating deficits in the P50 suppression paradigm induced by the adenosine receptor antagonists theophylline and caffeine in ∗ Corresponding author at: Faculdade de Biociˆ encias, PUCRS, Av. Ipiranga, 6681 pd 12A, Porto Alegre, RS, 90619-900, Brazil. Tel.: 3320 3545x4158, fax: 3320 3612. E-mail address: drlara@pucrs.br (D.R. Lara). normal volunteers, resembling findings in schizophrenic patients [10,11]. Regarding pharmacological treatment, adjunctive treat- ment with dipyridamole, an adenosine transporter blocker, was beneficial compared to placebo for schizophrenia [2] and add-on treatment with allopurinol, which reduces purines degrada- tion, was effective as adjuctive treatment in patients with poor response to antipsychotics [4,18] and in acute patients [1]. Finally, chronic treatment with clozapine, but not haloperidol, increased striatal ecto-5 ′ -nucleotidase in rats [21]. Extracellular adenosine levels, and consequently the degree of receptor activation, depend on the rate of formation, diffusion and degradation of adenine nucleotides (ATP, ADP and AMP) and the nucleoside adenosine [3]. AMP formed from the degra- dation of released ATP can be hydrolyzed to adenosine by the action of 5 ′ -nucleotidase, the rate-limiting step in the ectonu- cleotidase chain [26] (Fig. 1). Adenosine can then be either uptaken by nucleoside transporters or deaminated to inosine by adenosine deaminase [9]. Once inside the cell, adenosine can be converted to AMP by adenosine kinase or deaminated to inosine by adenosine deaminase (ADA) [3]. 0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.11.071