Research report Up-regulation of adenosine A 1 receptor binding in pentylenetetrazol kindling in mice: effects of angiotensin IV Jana Tchekalarova a, * , Evangelos Sotiriou b , Vasil Georgiev a , George Kostopoulos b , Fevronia Angelatou b a Laboratory of Experimental Psychopharmacology, Institute of Physiology, Acad. G. Bonchev Str., Bl. 23, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria b Department of Physiology, University of Patras, Medical School, Patras 26110, Greece Accepted 2 November 2004 Available online 8 January 2005 Abstract The effects of the hexapeptide angiotensin II (3–8) ANG IV, the selective A 1 receptor agonist cyclohexyladenosine (CHA) and the combination of ANG IV + CHA on pentylenetetrazol (PTZ)-generalized seizures; kindling development and maintenance were studied. By using in vitro quantitative receptor autoradiography, the regulation of adenosine A 1 receptor density at different time points during the kindling procedure and postkindling period was determined. ANG IV and CHA effectively reduced clonic seizures in PTZ-generalized seizure model, in PTZ-kindled mice as well as during kindling development and a week later by rechallenge with PTZ. Furthermore, coadministration of ANG IV and CHA had a strong anticonvulsant effect, both compounds acting synergistically. A significant increase of adenosine A 1 receptor density was detected in somatosensory cortex, hippocampus, amygdala and geniculate nuclei early in the kindling procedure (after the 3rd injection), which persisted at least 1 month after the end of kindling procedure. In addition, a delayed up-regulation of adenosine A 1 receptor binding was observed a week after kindling in the mamillary bodies and a month later in the motor cortex. The pretreatment with ANG IV caused a down-regulation of adenosine A 1 receptor density to the control level in most time points and brain areas. In conclusion, PTZ kindling-induced increase of adenosine A 1 receptor binding at different time points and in specific brain structures might represent an adaptive mechanism for coping with the hyperexcitability typical for this phenomenon. The antiepileptogenic effect of ANG IV could be realized partly through an adenosine-dependent mechanism. D 2004 Elsevier B.V. All rights reserved. Theme: Receptor modulation, up- and down-regulation; Neurotransmitters. Modulators, transporters, and receptors Topic: Receptor modulation, up- and down-regulation Keywords: PTZ kindling; Mice; Up-regulation; ANG IV; CHA; adenosine A 1 receptor 1. Introduction Pentylenetetrazol (PTZ) kindling is generally accepted as an animal model of generalized epilepsy in which repeated administration of an initial subconvulsive dose of the convulsant results in a progressive increase of excitability, culminating in generalized clonic or tonic–clonic seizures [24,29]. Once established, this hyperexcitability persists for a long time. The kindling phenomenon is characterized with a variety of behavioral, neurochemical and neurophysio- logical changes during its development and period after maintenance. Therefore, it is of great interest to study the possible regulatory role of neuromodulators in the patho- physiological mechanisms of seizure disorders. Adenosine is commonly accepted as a neuromodulator in the CNS, with an inhibitory action on synaptic activity and neurotransmitter release [21,22,34] exerting a depressant effect on neurons [23]. This purine and its analogues have 0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2004.11.004 * Corresponding author. Fax: + 359 2 719 109. E-mail address: jane _ tch@yahoo.com (J. Tchekalarova). Brain Research 1032 (2005) 94 – 103 www.elsevier.com/locate/brainres BRES-33870; No of Pages 10