Research suggests the neurotransmitter called adenosine builds up in our blood while we are awake and causes drowsiness and gradually breaks when we sleep.
Caffeine is an competitive antagonist to adenosine. It binds to its receptor and prevents post binding changes from taking place. It blocks the effects of adenosine and leads to increased firing of dopaminergic neurons. Sleep is a huge problem with bipolars especially when they go into the manic or hypomanic phases when they function on little or no sleep even if they feel exhausted.

1: Neuropsychopharmacology. 2003 Jul;28(7):1281-91. : Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.
Karcz-Kubicha M, Antoniou K, Terasmaa A, Quarta D, Solinas M, Justinova Z, Pezzola A, Reggio R, Muller CE, Fuxe K, Goldberg SR, Popoli P, Ferre S.
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, NIDA, NIH, IRP, Department of Health and Human Services, Baltimore, MD, USA.

The involvement of adenosine A(1) and A(2A) receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A(1) receptor agonist CPA and the A(2A) receptor agonist CGS 21680 by caffeine, the selective A(1) receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 21680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation. However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 21680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor-activating effects of acutely administered caffeine in rats involve the central blockade of both A(1) and A(2A) receptors. Chronic exposure to caffeine in the drinking water (1.0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its 'bell-shaped' dose-response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A(1) receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A(2A) receptor blockade.
Synapse. 2003 Sep 15;49(4):279-286. : Effects of an adenosine A2A receptor blockade in the nucleus accumbens on locomotion, feeding, and prepulse inhibition in rats.
Nagel J, Schladebach H, Koch M, Schwienbacher I, Muller CE, Hauber W.
Department of Animal Physiology, University of Stuttgart, D-70550 Stuttgart, Germany.

The nucleus accumbens (NAc) subserves behaviors governed by natural rewards, i.e., feeding or exploration, and has been implicated in control of prepulse inhibition (PPI), a measure of sensorimotor gating. The present study sought to determine whether a tonic stimulation of adenosine A(2A) receptors in the rat NAc is involved in control of spontaneous locomotor activity, feeding behavior, and PPI. To this end, bilateral microinfusions of a prodrug (MSX-3) (3 &mgr;g and 5 &mgr;g in 1 &mgr;l per side) of the selective A(2A) receptor antagonist MSX-2 or vehicle (1 &mgr;l per side) were administered into the NAc. Results show that blockade of intra-NAc adenosine A(2A) receptors by a high (5 &mgr;g), but not by a low (3 &mgr;g), dose of MSX-3 increased locomotor activity in an open field, reduced food intake, and delayed intake onset in food-deprived rats examined in a test cage with standard laboratory chow. Furthermore, PPI was significantly disrupted after intra-NAc infusion of 5 &mgr;g, but not 3 &mgr;g, MSX-3. These findings suggest that locomotor activity as well as intact PPI and feeding behavior rely on tonic activation of intra-NAc A(2A) receptors. The data add further support to the view that adenosine is a tonically active modulator of striatal function through actions on A(2A) receptors. Synapse 49:279-286, 2003. Copyright 2003 Wiley-Liss, Inc.
1: Pharmacol Biochem Behav 2002 Dec;74(1):111-8 : Broad spectrum anticonvulsant activity of BW534U87: possible role of an adenosine-dependent mechanism.
Southam E, Stratton SC, Sargent RS, Brackenborough KT,
Duffy C, Hagan RM, Pratt GD, Jones SA, Morgan PF.
GlaxoSmithKline, New Frontiers Science Park, Essex CM195AW, Harlow, UK.

The novel putative anticonvulsant drug 1-[2,6-difluorophenyl)-methyl]-1H-1,2,3-triazolo[4,5-c]) pyridine-4-amine monohydrochloride (BW534U87) effectively reduced seizures induced in rodents by threshold maximal and supramaximal electroshock, electrical kindling, pentylenetetrazole (PTZ) infusion and by vestibular stimulation in the genetically seizure-prone epilepsy-like (EL) mouse. The range of animal seizure models in which BW534U87 was effective is consistent with a broad spectrum anticonvulsant profile. In the EL mouse, the activity of BW534U87 was partially reversed by predosing with the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), suggesting that an adenosine-dependent mechanism contributed to the antiseizure activity of the drug. BW534U87 inhibited rat brain homogenate adenosine deaminase activity, thus, raising the possibility that, by blocking the metabolism of endogenous adenosine by this route, BW534U87 limited seizure activity by promoting the inhibitory tone mediated by endogenous adenosine in the brain. The seizure protection conferred by the selective adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) in EL mice and mice infused with PTZ confirms that inhibition of adenosine metabolism by deamination is an effective antiseizure strategy in these models.
  • : Eur J Neurosci 2002 Aug;16(3):547-50 : Mice lacking the adenosine A1 receptor are anxious and aggressive, but are normal learners with reduced muscle strength and survival rate.
    Gimenez-Llort L, Fernandez-Teruel A, Escorihuela RM, Fredholm BB, Tobena A, Pekny M, Johansson B.
    Medical Psychology Unit,
    Department of Psychiatry and Forensic Medicine, Neuroscience Institute,
    Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain.

    Behavioural assessment of mice lacking adenosine A1 receptors (A1Rs) showed reduced activity in some phases of the light-dark cycle, reduced exploratory behaviour in the open-field and in the hole-board, increased anxiety in the plus maze and dark-light box and increased aggressiveness in the resident-intruder test. No differences were found in spatial reference and working memory in several Morris water maze tasks. Both mutant mice had reduced muscle strength and survival rate. These results confirm the involvement of adenosine in motor activity, exploratory behaviour, anxiety and aggressiveness. A1Rs also appear to play a critical role in ageing-related deterioration.
    Proc Natl Acad Sci U S A 2001 Jul 31;98(16):9407-12 : Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor.
    Johansson B, Halldner L, Dunwiddie TV, Masino SA, Poelchen W, Gimenez-Llort L, Escorihuela RM, Fernandez-Teruel A, Wiesenfeld-Hallin Z, Xu XJ, Hardemark A, Betsholtz C, Herlenius E, Fredholm BB.
    Department of Physiology and Pharmacology,
    Karolinska Institutet, S-171 77 Stockholm, Sweden.

    Caffeine is believed to act by blocking adenosine A(1) and A(2A) receptors (A(1)R, A(2A)R), indicating that some A(1) receptors are tonically activated. We generated mice with a targeted disruption of the second coding exon of the A(1)R (A(1)R(-/-)). These animals bred and gained weight normally and had a normal heart rate, blood pressure, and body temperature. In most behavioral tests they were similar to A(1)R(+/+) mice, but A(1)R(-/-) mice showed signs of increased anxiety. Electrophysiological recordings from hippocampal slices revealed that both adenosine-mediated inhibition and theophylline-mediated augmentation of excitatory glutamatergic neurotransmission were abolished in A(1)R(-/-) mice. In A(1)R(+/-) mice the potency of adenosine was halved, as was the number of A(1)R. In A(1)R(-/-) mice, the analgesic effect of intrathecal adenosine was lost, and thermal hyperalgesia was observed, but the analgesic effect of morphine was intact. The decrease in neuronal activity upon hypoxia was reduced both in hippocampal slices and in brainstem, and functional recovery after hypoxia was attenuated. Thus A(1)Rs do not play an essential role during development, and although they significantly influence synaptic activity, they play a nonessential role in normal physiology. However, under pathophysiological conditions, including noxious stimulation and oxygen deficiency, they are important.
    : Int J Neuropsychopharmcol 1998 Dec;1(2):187-190 : The adenosine A(2A) receptor knockout mouse: a model for anxiety?
    Deckert J.
    Department of Psychiatry, University of Wurzburg, Germany.

    The main behavioural features of the adenosine A(2A) receptor knockout mouse include anxiety, aggressiveness in males and a paradoxical response to caffeine. These behavioural characteristics caused by the lack of adenosine A(2A) receptor function in mice correspond to the effects of functional antagonism of adenosine A(2A) receptors in humans and rodents. Increased anxiety in patients with panic disorder and increased psychotic symptomatology in patients with schizophrenia have been observed after caffeine administration. Several hypotheses have been developed suggesting a reduced adenosine A(2A) receptor-mediated transmission as a contributing factor in the pathogenesis of these disorders. Recent genetic studies, in particular of panic disorder, suggest an involvement of adenosine A(2A) receptor gene variation. If future studies prove a pathogenetic role for a genetically determined loss of A(2A) receptor function in psychiatric disorders, the A(2A) receptor knockout mouse will be a valuable model to develop novel pharmacological therapies for these disorders.
    Am J Hum Genet 2002 Sep;71(3):651-5 : The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study.
    Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL.
    Neurogenetics Section, Centre for Addiction and Mental Health,
    Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada.

    Bipolar disorder (BP) is a severe psychiatric disease, with a strong genetic component, that affects 1% of the population worldwide and is characterized by recurrent episodes of mania and depression. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders, and the aim of the present study was to test for the presence of linkage disequilibrium between two polymorphisms in the BDNF gene and BP in 283 nuclear families. Family-based association test (FBAT) results for the dinucleotide repeat (GT)(N) polymorphism at position -1040 bp showed that allele A3 was preferentially transmitted to the affected individuals (Z=2.035 and P=.042). FBAT results for the val66met SNP showed a significant association for allele G (Z=3.415 and P=.00064). Transmission/disequilibrium test (TDT) haplotype analysis showed a significant result for the 3-G allele combination (P=.000394), suggesting that a DNA variant in the vicinity of the BDNF locus confers susceptibility to BP. Given that there is no direct evidence that either of the polymorphisms we examined alters function, it is unlikely that the actual risk-conferring allele is from these two sites. Rather, the causative site is likely nearby and in linkage disequilibrium with the 3-G haplotype that we have identified.
    Curr Mol Med 2002 Nov;2(7):629-38 : Stress, metaplasticity, and antidepressants
    . Garcia R.
    Neurobiologie Comportementale,
    Faculte des Sciences, Universite de Nice-Sophia Antipolis,
    Nice, France.

    A large body of evidence has established a link between stressful life events and development or exacerbation of depression. At the cellular level, evidence has emerged indicating neuronal atrophy and cell loss in response to stress and in depression. At the molecular level, it has been suggested that these cellular deficiencies, mostly detected in the hippocampus, result from a decrease in the expression of brain-derived neurotrophic factor (BDNF) associated with elevation of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both neuronal survival and neurogenesis, is thought to represent a converging mechanism of action of various types of antidepressant treatments (e.g., antidepressant drugs and transcranial magnetic stimulation). However, as also revealed by converging lines of evidence, high levels of glucocorticoids down-regulate hippocampal synaptic connectivity ('negative' metaplasticity), whereas an increase in expression of BDNF up-regulates connectivity in the hippocampus ('positive' metaplasticity). Therefore, antidepressant treatments might not only restore cell density but also regulate higher-order synaptic plasticity in the hippocampus by abolishing 'negative' metaplasticity, and thus restore hippocampal cognitive processes that are altered by stress and in depressed patients. This antidepressant regulatory effect on hippocampal synaptic plasticity function, which may, in turn, suppress 'negative' metaplasticity in other limbic structures, is discussed.
    Bipolar Disord 2002 Jun;4(3):183-94 : Antidepressants and neuroplasticity.
    D'Sa C, Duman RS.
    Division of Molecular Psychiatry,
    Abraham Ribicoff Research Facilities,
    Department of Psychiatry, Yale University School of Medicine,
    Connecticut Mental Health Center, New Haven, CT, USA.

    OBJECTIVE: We review the literature on the cellular changes that underlie the structural impairments observed in brains of animals exposed to stress and in subjects with depressive disorders. We discuss the molecular, cellular and structural adaptations that underlie the therapeutic responses of different classes of antidepressants and contribute to the adaptive plasticity induced in the brain by these drugs. METHODS: We review results from various clinical and basic research studies. RESULTS: Studies demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Studies also show that antidepressants up-regulate the cyclic adenosine monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response element-binding protein (CREB) and the neurotrophin, brain derived-neurotrophic factor (BDNF) are key mediators of the therapeutic response to antidepressants. CONCLUSIONS: These results suggest that depression maybe associated with a disruption of mechanisms that govern cell survival and neural plasticity in the brain. Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival.
    Emerg Med (Fremantle) 2001 Mar;13(1):51-6 : Randomized controlled trial of midazolam premedication to reduce the subjective adverse effects of adenosine.
    Hourigan C, Safih S, Rogers I, Jacobs I, Lockney A.
    Department of Emergency Medicine,
    Sir Charles Gairdner Hospital,
    Perth, WA, Australia.

    OBJECTIVE: To determine the safety and efficacy of midazolam premedication to minimize the subjective adverse effects of adenosine. METHODS: Double-blind prospective randomized controlled trial of patients presenting to an urban emergency department. Included were a convenience sample of patients who would have received adenosine by the existing department protocol. Exclusion criteria were pregnancy, benzodiazepine allergy, regular benzodiazepine medication, alcoholism, altered mental state (precluding informed consent), and age less than 18 or greater than 65 years. Subjects received either 1.5 mg of intravenous midazolam or normal saline placebo 5 min prior to the administration of adenosine. Side-effect recall was judged by a questionnaire at 1 h and 24 h postadenosine administration. RESULTS: A total of 34 patients were recruited into the trial, 16 in the placebo group and 18 in the midazolam group. The groups were well matched for demographics, treatment and outcome. There was a significant reduction in the midazolam group for complaint scores of palpitations (P = 0.04) and chest pain (P = 0.02) and a trend to reduction in complaint scores for most other parameters. There were no adverse outcomes in any of the patients studied. CONCLUSIONS: Co-administration of midazolam can safely reduce the recall of the unpleasant adverse effects of adenosine. Its use may be most appropriate in patients who are particularly anxious or have had previous adverse experiences with adenosine.
    Neurosci Lett 2002 Sep 6;329(3):289-92 : Seizure suppression by adenosine A(2A) receptor activation in a rat model of audiogenic brainstem epilepsy.
    Huber A, Guttinger M, Mohler H, Boison D.
    Institute of Pharmacology and Toxicology,
    University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

    Adenosine is known to suppress seizure activity mainly by activation of adenosine A(1) receptors. However, little is known about the potential involvement of other types of adenosine receptors in seizure suppression. It was now tested whether activation of adenosine A(2A) receptors would be effective in the suppression of generalized brainstem seizures. Genetically epilepsy-prone rats were intraperitoneally injected with increasing doses of the A(2A) receptor agonist, 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA), and, for comparison, with the A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA). Both CPCA and CCPA were effective in suppressing generalized brainstem seizures with minimal effective concentrations of 2.5 and 1.5 mg/kg, respectively. Seizure suppression was maintained when CPCA was co-injected with the peripherally acting adenosine receptor antagonist 8-(p-sulphophenyl)theophylline, suggesting that central activation of A(2A) receptors effectively contributes to seizure suppression.
    Epilepsia 2002 Aug;43(8):788-96 : Seizure suppression by adenosine-releasing cells is independent of seizure frequency.
    Boison D, Huber A, Padrun V, Deglon N, Aebischer P, Mohler H.
    Institute of Pharmacology and Toxicology, University of Zurich, Switzerland.

    PURPOSE: Intraventricular cellular delivery of adenosine was recently shown to be transiently efficient in the suppression of seizure activity in the rat kindling model of epilepsy. We tested whether the suppression of seizures by adenosine-releasing grafts was independent of seizure frequency. METHODS: Adenosine-releasing cells were encapsulated and grafted into the lateral brain ventricle of rats kindled in the hippocampus. During 4 weeks after grafting, electric test stimulations were delivered at a frequency of either once a week or 3 times per week. Seizure activity was evaluated by visual scoring of seizure severity and by the recording of EEGs. RESULTS: Adenosine released from encapsulated cells exerted potent antiepileptic activity for >/=2 weeks. One week after grafting, treated rats displayed a complete protection from clonic seizures, and a protection from focal seizures was observed in the majority of animals. Seizure suppression was accompanied by a reduction of afterdischarges in EEG recordings. The protective efficacy of the grafted cells was the same irrespective of whether electrical test stimulations were delivered 1 or 3 times per week. Rats receiving control grafts continued to display full clonic convulsions. CONCLUSIONS: This study demonstrated that the frequency of test stimulations did not influence the seizure-suppressive potential of adenosine-releasing grafts. Thus the local delivery of adenosine is likely to be effective in seizure control over a threefold range of seizure-discharge frequency.
    Eur Neuropsychopharmacol 2002 Apr;12(2):173-9 : 2-Chloroadenosine, a preferential agonist of adenosine A1 receptors, enhances the anticonvulsant activity of carbamazepine and clonazepam in mice.
    Borowicz KK, Luszczki J, Czuczwar SJ.
    Department of Pathophysiology,
    Lublin Medical University, Jaczewskiego 8, 20-090 Lublin, Poland.

    2-Chloroadenosine (0.25-1 mg/kg) significantly raised the threshold for electroconvulsions in mice. This preferential adenosine A(1) receptor agonist (at 0.125 mg/kg) significantly potentiated the protective activity of carbamazepine against maximal electroshock-induced seizures in mice. 2-Chloroadenosine (1 mg/kg) showed also anticonvulsive efficacy against pentylenetetrazol-evoked seizures, raising the CD(50) value for pentylenetetrazol from 77.2 to 93.7 mg/kg. The drug (at 0.5 mg/kg) significantly enhanced the protective action of clonazepam in this test, decreasing its ED(50) value from 0.033 to 0.011 mg/kg. Moreover, aminophylline, a non-selective adenosine receptor antagonist (5 mg/kg), and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX), a selective A(1) adenosine receptor antagonist (5 mg/kg) reversed the 2-chloroadenosine (0.125 mg/kg)-induced enhancement of the protective activity of carbamazepine and clonazepam. 2-Chloroadenosine administered alone or combined with antiepileptic drugs, caused neither motor nor long-term memory impairment. Finally, the adenosine A(1) agonist did not change the free plasma concentration of antiepileptics, so a pharmacokinetic factor is not probable. Summing up, 2-chloroadenosine potentiated the protective activity of both carbamazepine and clonazepam, which seems to be associated with the enhancement of purinergic transmission mediated through adenosine A(1) receptors.
  • Adenosine and sleep
  • adenosine and the heart
  • what is adenosine
    Adenosine is a naturally occurring nucleoside formed in the body by the enzymatic breakdown of adenosine triphosphate (ATP). Adenosine is not a typical hormone or neurotransmitter, but is an important neuromodulator in the central and peripheral nervous systems.1 Adenosine is released from inflamed (infected) tissues or ischemic tissues where there is a decreased blood supply to a particular body organ or part. Caffeine does not directly influence the catecholamine systems in the same way as amphetamine and cocaine. Snyder et al (1981) suggest that the stimulant effects of caffeine are due to the blockade of adenosine receptors. Adenosine inhibits the firing of neurons throughout the brain by activating potassium channels, and by inhibiting the release of a number of neurotransmitters (Acetylcholine, NorAdrenalin, Dopamine, Serotonin, GABA and Glutamate). Studies have shown that various methylxanthines including caffeine bind to adenosine receptors with a potency that correlates to their stimulant effects. Furthermore, the adenosine antagonist R-PIA is a potent behavioural depressant, and this effect can be reversed by caffeine adminstration. Based on these findings it has been proposed that the stimulant effects of caffeine are a result of adenosine receptor blockade. Adenosine usually binds to A1 and A2 receptors which cause an upgrade and inhibition of cAMP respectively. cAMP inhibits the release of ACh, NE, DA, 5-HT, GABA and glutamate by hyperpolarising such neurons. Since caffeine acts as a competitive antagonist for A2 receptors, its net effect is to increase levels of these neurotransmitters. However, the situation is complex as adenosine has a number of different receptor types that appear to be involved in different behavioural effects in different areas of the brain. Neurons in the diagonal band of Broca (DBB) are involved in attentional and possibly other cognitive processes, and these cells have been shown to be inhibited to some extent by adenosine. This provides an important means by which adenosine antagonists such as caffeine could stimulate arousal at both the electrophysiological and behavioural levels. A further possible mode of influence involves the relationship between adenosine, dopamine and caffeine. Adenosine is a dopaminergic antagonist in the striatum and nucleus accumbens, and has been shown to reduce dopamine release. Conversley, the inhibiting effect of caffeine on adenosine produces a net increase in dopamine activity. However, this area of research is still unfolding and at this time it is not possible to conclude that all the effects of caffeine can be explained through it's various interactions with adenosine.
    Adenosine receptors in epilepsy
    Abstract: To elucidate the consequences of convulsions, we examined biochemically and electrophysiologically the brains of mice that had sustained two complete tonic-clonic convulsions after administration of pentylenetetrazol (PTZ 50 mg/kg intraperitoneally, i.p.), 48 and 24 h before decapitation. Control mice were injected with saline. Input/output curves of the extracellular synaptic responses in the CA1 area of hippocampal slices showed that PTZ-induced seizures do not establish the persistent change in hippocampal excitability itself that can be detected in vitro. However, use of the paired-pulse stimulation paradigm showed that gamma-aminobutyric acid A (GABAA)-mediated recurrent inhibition was significantly weaker (by 19-25%) in the CA1 area of slices from PTZ-treated mice (PTZ slices) as compared with slices from control mice (control slices). The density of GABAA receptors (high-affinity component) was also lower in hippocampus (by 19%) and cortex (by 14%) of PTZ-treated mice. A GABA-related disinhibitory mechanism underlying PTZ seizures may thus persist for 1 day after the seizure, predisposing the brain to subsequent seizures. On the other hand, the depressant effect of a single dose of adenosine 10 microM on the CA1 synaptic response was stronger (by 35% on population spikes) and longer lasting in PTZ slices as compared with controls. This could be attributed to significantly higher adenosine A1 receptor density in hippocampus (Bmax of [3H]CHA was higher by 34%) as well as cortex and cerebellum of these animals. The phenomenon may reflect an adenosine A1-mediated adaptive mechanism that offers protection from subsequent seizures.
    Alterations of A1 adenosine receptors in different mouse brain areas after pentylentetrazol-induced seizures, but not in the epileptic mutant mouse 'tottering'.
    Angelatou F, Pagonopoulou O, Kostopoulos G
    Brain Res 1990 Nov 26 534:1-2 251-6
    Abstract: Single and repeated Pentylentetrazol (PTZ)-induced convulsions are associated with significant changes of A1 adenosine receptors (detected using the radioligand [3H]cyclohexyladenosine, [3H]CHA) in 4 different brain areas of the mouse, namely cortex, hippocampus, cerebellum and striatum. In hippocampus and cerebellum, a rapid increase in [3H]CHA binding, by 26% and 30% respectively, was observed 1 h after a single PTZ convulsion. In striatum, on the contrary, a significant decrease by 30% in [3H]CHA binding was seen, whereas in cortex no significant change could be detected. After daily repeated PTZ convulsions, a significant increase of A1 receptors by 26% appeared also in cortex, while the changes of A1 receptors observed in the other brain areas after a single PTZ convulsion were maintained in almost the same range. All the alterations observed were due to changes of the total number of A1 receptors (Bmax) without changes in receptor affinity (Kd). A significant increase in the latency of PTZ seizure (time between the PTZ-injection and the beginning of the seizure) was also observed after repeated PTZ-induced convulsions at the time when the changes in A1 adenosine receptors were noted. Considered together, these results provide further evidence for an A1receptor-mediated modulation of seizure susceptibility and indicate that specific brain areas may play different roles in this modulation. The binding of [3H]CHA to membranes from different cortical and subcortical areas of the epileptic mutant mouse 'tottering' was not different from that in control animals.
    Upregulation of A1 adenosine receptors in human temporal lobe epilepsy: a quantitative autoradiographic study.
    Angelatou F, Pagonopoulou O, Maraziotis T, Olivier A, Villemeure JG, Avoli M, Kostopoulos G
    Neurosci Lett 1993 Nov 26 163:1 11-4
    Abstract: A significant increase of A1 adenosine receptor binding (48% increase of mean) was detected in human neocortex obtained from patients suffering from temporal lobe epilepsy as compared to control neocortex from non-epileptic patients. Such increase was equally distributed in the six cortical layers and reached similar levels in each of the five specimens tested independently of age, sex and pharmacological treatment of the patient. Since adenosine exerts a depressant effect on neocortical neurons in slices obtained from epileptic patients, this upregulation of A1 receptor binding may constitute a protective mechanism against subsequent seizures, which is exerted by elevating the depressant response of the brain to endogenous adenosine.

    Neurosci Lett 2000 Apr 21;284(1-2):49-52
    Reduction of A1 adenosine receptors in rat hippocampus after kainic acid-induced limbic seizures.
    Ekonomou A, Sperk G, Kostopoulos G, Angelatou F
    Abstract: In a temporal lobe epilepsy (TLE) model induced by kainic acid (KA), we examined the effect of limbic seizures on A1 adenosine receptor distribution in hippocampus and cortex. By using quantitative autoradiography, we determined a progressive decrease in A1 receptor density in CA1 and CA3 regions of hippocampus, which coincided in time with the degenerating process of hippocampal pyramidal cells. This result indicates that a great amount of A1 receptors are located postsynaptically on pyramidal cell dendrites. No difference in A1 receptor density was observed in the inner compared to the outer molecular layer of dentate gyrus, or in the infrapyramidal band compared to the outer layer of stratum oriens of CA3. This could indicate that the newly sprouted mossy fiber glutamatergic terminals do not contain A1 receptors, thus lacking a restrain in the release of glutamate.