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
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,
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
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
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
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
Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL.
Neurogenetics Section, Centre for Addiction and Mental Health,
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
Faculte des Sciences, Universite de
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,
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
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,
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
convulsions, we examined
brains of mice that had
sustained two complete
after administration of
pentylenetetrazol (PTZ 50
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
itself that can be detected
in vitro. However, use of
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
was also lower in
hippocampus (by 19%)
and cortex (by 14%) of
PTZ-treated mice. A
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
mechanism that offers
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
significant changes of A1
(detected using the
[3H]CHA) in 4 different
brain areas of the mouse,
and striatum. In
cerebellum, a rapid
increase in [3H]CHA
binding, by 26% and 30%
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
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
convulsions at the time
when the changes in A1
adenosine receptors were
together, these results
provide further evidence
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.
Pagonopoulou O, Maraziotis T, Olivier A, Villemeure JG, Avoli M,
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.