Adenosine hypothesis of antipsychotic drugs revisited: pharmacogenomics variation in nonacute schizophrenia.
Turčin A1, Dolžan V2, Porcelli S3, Serretti A3, Plesničar BK1.
1 University Psychiatric Clinic Ljubljana, Ljubljana, Slovenia.
2 Pharmacogenetics Laboratory, Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia.
3 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
The existing antipsychotic therapy is based on dopamine hyperfunction and glutamate hypofunction hypotheses of schizophrenia. Adenosine receptors (ADORA) have a neuromodulatory role and can control dopaminergic and glutamatergic systems. To elucidate the effect of ADORA polymorphisms on psychopathological symptoms and adverse effects in patients with schizophrenia on long-term antipsychotic treatment, we examined 127 nonacute schizophrenia outpatients in a cross-sectional study using the Positive and Negative Symptoms Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale. All patients were genotyped for 18 polymorphisms in ADORA1, ADORA2A, and ADORA3. We found an association between ADORA1 rs3766566 and psychopathological symptoms (p=0.006), in particular, with positive psychopathological symptoms (p=0.010) and general psychopathological symptoms (p=0.023), between ADORA2A rs2298383 and general psychopathological symptoms (p=0.046), and between ADORA2A rs5751876 and akathisia (p=0.015). Haplotype analysis showed an association between ADORA1 CTCAACG haplotype and overall psychopathological symptoms (p=0.019), positive psychopathological symptoms (p=0.021), and akathisia (p=0.028). ADORA2A TCCTC haplotype was associated with parkinsonism (p=0.014). ADORA3 CACTAC was associated with akathisia (p=0.042), whereas CACTAT was associated with akathisia (p=0.045) and tardive dyskinesia (p=0.023). The results of this first comprehensive study on ADORA polymorphisms in patients with nonacute schizophrenia receiving long-term antipsychotic therapy might suggest an important neuromodulatory role of ADORA receptors in both psychopathological symptoms and adverse effects of antipsychotics.
PMID: 27195966; DOI:10.1089/omi.2016.0003
Schizophrenia is a chronic psychotic disorder, typically presented with delusions, hallucinations, blunted affect, social withdrawal, lack of reality-check, and many general symptoms (i.e. anxiety, depression, somatic concern etc.). It is a very disabling disease and is treated at least with antipsychotics – medications with a lot of benefits, but also too many almost unavoidable side effects). The patients’ everyday functioning is poorer, if either psychpathological sympoms, or the side effects (or both) are more prominent. The current knowledge of schizophrenia psychopathology predominantly combines the dopamine-hyperfunction and the glutamate-hypofunction hypotheses, but it still doesn’t explain the vast plethora of psychopathological symptoms and its consequences (1). The activity of both of these neurotransmitter pathways can be modulated with purinergic P1 adenosine receptors (ADORA) as proposed by a novel adenosinergic hypothesis of schizophrenia (2).
Adenosine, the homeostatic intracellular and extracellular modulator, bonds to four subtypes of adenosine receptors: ADORA1, ADORA2A, ADORA2B, and ADORA3 (2, 3, 4, 5, 6). ADORA1 is abundant in the brain (2, 4, 7, 8), ADORA2A is highly concentrated and expressed in the striatum (2, 9), ADORA2B is thought to be activated only with very high adenosine levels in the brain (10), and ADORA3 is mostly connected to ischaemic and neuroinflammatory processes in the brain (11, 12, 13, 14). On the neuron membranes, ADORA1 and ADORA2A are co-localized and form heterodimers with dopamine D1 and D2 receptors, respectively (15).
The adenosine hypofunction hypothesis of schizophrenia is also supported by genetic studies (16, 17, 18, 19), but the comprehensive information is limited (20). The studies published so far described either psychopathological phenomena or extrapyramidal symptoms. Therefore, we studied the associations of schizophrenia psychopathology and iatrogenic extrapyramidal side effects with seven ADORA1, five ADORA2A and six ADORA3 polymorphisms in a group of 53 male and 73 female non-acute schizophrenia patients on long-term antipsychotic treatment. We assessed the patients clinically and subsequently genotyped all the subjects in the sample.
None of the 18 observed single nucleotide polymorphisms (SNPs) or their haplotypes were correlated with negative psychopathological symptoms, i.e. blunted affect, emotional and social withdrawal, stereotyped thinking or lack of spontaneity. However, polymorphisms ADORA1 rs3766566 and ADORA2A rs2298383 were correlated with general psychopathological symptoms, such as anxiety and tension, guilt feelings, motor retardation, depression, somatic concern, lack of judgement and insight, disturbance of volition, poor attention, and so forth. Additionally, ADORA1 rs3766566 was correlated also with positive psychopathological symptoms, i.e. delusions, hallucinations, suspiciousness, conceptual disorganization, etc., thus contributing also to the correlation of this polymorphism with overall psychopathological phenomena. These were all novel findings, previously undescribed in the available literature, except for ADORA2A rs2298383 that has already been linked to anxiety and panic disorders, especially after caffeine consumption (19, 21, 22).
Antipsychotics may cause extrapyramidal side effects, i.e. parkinsonic symptoms, akathisia or tardive dyskinesia. In our study, ADORA2A polymorphism rs5751876, ADORA1 haplotype CTCAACG, ADORA3 haplotype CACTAC and ADORA3 haplotype CACTAT were associated with akathisia, the latter being associated also with involuntary movements. These were also novel findings. Most interesting were correlations of these side effects of antipsychotics with ADORA3 haplotypes. ADORA3 is biochemically linked to ischaemic and neuroinflammatory processes in the brain, and not to schizophrenia or side effects of antipsychotics (23). However, our results may add to the knowledge about the role of neuroinflammation in the pathogenetic processes in schizophrenia.
Recent studies have already described the causal relationship between the changes in neurobiology of behavior, and cytokines, cellular immune components, and glial cells (24, 25, 26, 27). Microglia immune responses were shown to be mediated with extracellular heat shock 70-kDa proteins (HSP70s), and these have been associated with the pathophysiology of schizophrenia. HSP70s are also thought to have an effect on toll-like reptors (TLRs) in the brain, and TLRs are involved in neuroimmunological responses. TLRs within microglia affect ADORA3 that subsequently may act as a suppressor of ADORA2A-mediated inhibition (28, 29). Our ADORA2A/ADORA3 findings may be by-chance, but considering the aforementioned connections in the context of neuroinflammatory processes in the brain, we allowed ourselves to speculate: a) either the associations between ADORA3 haplotypes and side effects are indirect due to the activity of ADORA2A signaling, or b) they are a result of a long-term neuroinflammatory process that causes neurodegeneration.
The limitations of our study definitely include a relatively small sample, unavailable baseline data due to the cross-sectional study design (i.e. chronic patients, already for years in therapy), the omission of a more conservative Bonferroni correction, as well as a possible modification of the prescribed antipsychotics in the past (hence, less extrapyramidal symptoms during the study). Nevertheless, the sample was genetically homogenous, the patients were well defined, and compliance issues were not considered a limitation, since the majority of the patients were receiving regular intramuscular depot therapy.
In conclusion, our study of adenosine receptor polymorphisms in non-acute patients with schizophrenia suggest that ADORA is involved in neuromodulatory processes in both psychopathological symptoms, as well as the occurrence of side effects of the antipsychotics. An important finding was the correlation of ADORA3 haplotypes with side effects of antipsychotics, which needs further clarification.
- Boison D, Singer P, Shen HY, Feldon J, and Yee BK. (2012). Adenosine hypothesis of schizophrenia – opportunities for pharmacotherapy. Neuropharmacology 62, 1527-1543.
- Gomes CV, Kaster MP, Tome AR, Agostinho PM, and Cunha RA. (2011). Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochim Biophys Acta 1808, 1380-1399.
- Cunha RA. (2001). Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 38, 107-125.
- Fredholm BB, Chen JF, Cunha RA, Svenningsson P, and Vaugeois JM. (2005). Adenosine and brain function. Int Rev Neurobiol 63, 191-270.
- Burnstock G, Krügel U, Abbracchio MP, and Illes P. (2011). Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol 95, 229-274.
- Burnstock G, and Verkhratsky A. (2012). Purinergic signalling and the nervous system (Springer-Verlag, Berlin, Heidelberg).
- Ferraro L, Beggiato S, Tomasini MC, Fuxe K, Antonelli T, and Tanganelli S (2012). A2A/D2 receptor heteromerization in a model of Parkinson’s disease. Focus on striatal aminoacidergic signaling. Brain Res 1476, 96-107.
- Schindler M, Harris CA, Hayes B, Papotti M, and Humphrey PP (2001). Immunohistochemical localization of adenosine A1 receptors in human brain regions. Neurosci Lett 297, 211-215.
- Moreau JL, and Huber G. (1999). Central adenosine A2A receptors: an overview. Brain Research Reviews 31, 65-82.
- Fredholm BB. (1995). Purinoceptors in the nervous system. Pharmacol Toxicol 76, 228-239.
- Atkinson MR, Townsend-Nicholson A, Nicholl JK,Sutherland GR, and Schofield PR (1997). Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene. Neurosci Res 1997; 29 (1): 73-79.
- Van Muijlwijk-Koezen JE, Timmerman H, and Ijzerman AP (2001). The Adenosine A3 Receptor and its Ligands. Prog Med Chem 38, 61-113.
- Alexander SPH. A-3 Adenosine Receptor. xPharm: The Comprehensive Pharmacology Reference; 2007. p. 1-13.
- Borea PA, Gessi S, Bar-Yehuda S, and Fishman P (2009). A3 adenosine receptor: Pharmacology and role in disease. In: Wilson CN, Mustafa SJ. Handbook of Experimental Pharmacology. Berlin, Heidelberg: Springer-Verlag, p. 297-317.
- Ferre S, Ciruela F, Canals M, Marcellino D, Burgueno J, Casado V, et al (2006). Adenosine A2A–dopamine D2 receptor-receptor heteromers. Targets for neuro-psychiatric disorders. Parkinsonism and Related Disorders 10, 265-271.
- Deckert J, Nöthen MM, Rietschel M, et al. (1996). Human adenosine A2a receptor (A2aAR) gene: systematic mutation screening in patients with schizophrenia. J Neural Transm 103, 1447-1455.
- Deckert J, Nöthen MM, Bryant SP, et al. (1997). Mapping of the human adenosine A2a receptor gene: relationship to potential schizophrenia loci on chromosome 22q and exclusion from the CATCH 22 region. Hum Genet 99, 326-328.
- Hong CJ, Liu HC, Liu TY, Liao DL, and Tsai SJ. (2005). Association studies of the adenosine A2a receptor (1976T>C) genetic polymorphism in Parkinson’s disease and schizophrenia. J Neural Transm 112, 1503-1510.
- Childs E, Hohoff C, Deckert J, Xu K, Badner J, and de Wit H. (2008). Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 33, 2791-2800.
- Zhang J, Abdallah CG, Wang J, et al. (2012). Upregulation of adenosine A2A receptors induced by atypical antipsychotics and its correlation with sensory gating in schizophrenia patients. Psychiatry Res 200, 126-132.
- Hohoff C, Mullings EL, Heatherley SV, et al (2010). Adenosine A(2A) receptor gene: evidence for association of risk variants with panic disorder and anxious personality. J Psychiatr Res 44, 930-937.
- Rogers PJ, Hohoff C, Heatherley SV, et al. (2010). Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology 35, 1973-1983.
- Borea PA, Gessi S, Bar-Yehuda S, and Fishman P. (2009). A3 adenosine receptor: Pharmacology and role in disease. Handbook of Experimental Pharmacology (Springer-Verlag Berlin Heidelberg).
- Beumer W, Drexhage RC, De Wit H, Versnel MA, Drexhage HA, and Cohen D. (2012a). Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome. Psychoneuroendocrinology 37, 1901-1911.
- Beumer W, Gibney SM, Drexhage RC, et al. (2012b). The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. J Leukoc Biol 92, 959-975.
- Singhal G, Jaehne EJ, Corrigan F, and Baune BT. (2014). Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment. Front Cell Neurosci 8, 97.
- Bergink V, Gibney SM, and Drexhage HA. (2014). Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry 75, 324-331.
- van der Putten C, Zuiderwijk-Sick EA, van Straalen L, et al. (2009). Differential expression of adenosine A3 receptors controls adenosine A2A receptor-mediated inhibition of TLR responses in microglia. J Immunol 182, 7603-7612.
- Reus GZ, Fries GR, Stertz L, et al. (2015). The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300, 141-154.