Preliminary data on the possible hypnogenic role of adenosine 1

Partially purified extracts of bovine brain were previously found to inhibit competitively the binding of [3HJ-diazepam to-rat brain synaptosomal membranes. The purines inosine and hypoxanthine were subsequently identified as the compounds responsible for this inhibitory activity. Intracerebroventricular administration of inosine to mice of the C3H/ HEN and NIH general purpose strains caused a dose-and time-dependent increase in the latency to clonicotonic seizures produced by intraperitoneal administration of the convulsant pentylenetetrazole. Intracerebroventricular administration of equimolar doses of 2'-deoxyinosine, which is more potent than inosine in inhibiting the binding of [3H1diazepam in vitro, significantly increased pentylenetetrazole-evoked seizure latency. In contrast, both 7-methylinosine and thymidine were ineffective in inhibiting the in vitro binding of [3Hldiazepam and increasing the latency to pentylenetetrazole-induced seizures in vivo. These results suggest that endogenously occurring purines such as inosine exhibit diazepam like effects when administered intracerebroventricularly, and these effects may be related to the interaction of inosine and related compounds with benzodiazepine receptors in the central nervous system.The characterization of saturable, high affinity, and stereospecific benzodiazepine binding sites in the central nervous system has been described in vitro and in vivo (1-7). The good correlations obtained between the binding affinity of a series of benzodiazepines in vitro and their anticonvulsant (4), anxiolytic (8), and muscle relaxant properties (4) strongly suggests that these sites may be receptors mediating the pharmacologic actions of the benzodiazepines. However, neither the regional distribution of benzodiazepine binding sites within the central nervous system nor the screening of a large number of putative neurotransmitter substances (1, 8) has provided evidence that such receptor sites are associated with classical neurotransmitter pathways. These findings have prompted a search for an endogenously occurring compound(s) that binds to the benzodiazepine receptor and functions as a physiological ligand (9, 10).Low molecular weight substances that are heat stable, dialyzable, and competitively inhibit [3H]diazepam binding to synaptosomal membranes in vitro have been isolated from bovine brain (9, 11). These substances have been subsequently identified as the purines inosine and hypoxanthine, and it has been suggested that they may modulate the benzodiazepine receptor in vivo (11). Since the inhibition of pentylenetetrazole (PTZ)-induced seizures has been used as a sensitive measure for assessing benzodiazepinelike activity in vivo, the effects of inosine and related compounds have been examined by using this paradigm. We now report that the intracerebroventricular (ICV) administration of inosine elicits a dose-and time-dependent increase in the latency period between the intraperitoneal injection of PTZ After the recovery period, mice were injected IC...

Section: Resultscontrasting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Inosine, an endogenous ligand of the brain benzodiazepine receptor, antagonizes pentylenetetrazole-evoked seizures.

Skolnick¹,

Syapin²,

Paugh³

et al. 1979

“…Hypnogenic effects of adenosine were shown by its intracerebroventricular administration in fowls (4) and dogs (5). Subsequently, the effects of adenosine and its analogues on sleep-wake activities were studied in rats by Radulovacki and coworkers (6)(7)(8)(9).…”

mentioning

confidence: 99%

Promotion of sleep mediated by the A2a-adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats.

Satoh¹,

Matsumura²,

Suzuki³

et al. 1996

145

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.Hypnogenic effects of adenosine were shown by its intracerebroventricular administration in fowls (4) and dogs (5). Subsequently, the effects of adenosine and its analogues on sleep-wake activities were studied in rats by . Recently, Rainnie et al. (10) suggested the cholinergic neurons of the mesopontine tegmentum and in the diagonal band of Broca as the target site of adenosine for sleep promotion in vitro. These studies suggested that the A1-adenosine receptor may be involved in the regulation of sleep. On the other hand, the role of A2a-adenosine receptor on behavior had focused on the locomotor depression (11-13) and had not been linked to the sleep-wake phenomena.In the current study, we demonstrated that stimulation of A2-adenosine receptors located in the rostral basal forebrain caused a marked increase in sleep. We also showed that this receptor subtype plays a crucial role in the sleep-promoting mechanism triggered by PGD2.

“…Behaviorally, Ado has sedative, hypnotic, and anticonvulsant activity (13)(14)(15)(16), in contrast to caffeine and theophylline, which are central stimulants (17).…”

mentioning

confidence: 99%

Biochemical characterization of putative central purinergic receptors by using 2-chloro[3H]adenosine, a stable analog of adenosine.

Williams¹,

Risley²

1980

120

After pretreatment of rat brain synaptic membranes with adenosine deaminase to remove endogenous adenosine, 2-chloroeHladenosine, a stable analog of adenosine, binds to two sites with The concept that adenosine (Ado) and ATP can function as modulators or neurotransmitters in mammalian tissues has been developed by Burnstock (1) from pharmacological data generated in peripheral systems; it is postulated that the nucleoside produces its effects via specific P1 purinergic receptors and the nucleotide produces its effects via P2 type receptors. Biochemical, electrophysiological and, to a lesser extent, behavioral and autoradiographical data have suggested a similar neuromodulatory-neurotransmitter role for these purines in central nervous system function (2, 3).Ado is an effective regulator of cyclic AMP formation in brain slices (4, 5) and homogenates (6), acting via membranelocalized extracellular receptor mechanisms that are susceptible to blockade by alkylxanthines such as theophylline (7). It is also a potent inhibitor of neurotransmitter release, modulating the release of acetylcholine, norepinephrine, and dopamine in central and peripheral nervous tissue (8-10). It is especially active in striatal synaptosomal preparations, where the nucleoside inhibits dopamine release [50% inhibition concentration (IC5o) = 10 nM; 10].Both Ado and ATP depress cell firing in the mammalian central nervous system (3,11,12), acting via alkylxanthinesensitive receptor mechanisms. Conversely, theophylline and other adenosine antagonists increase cell firing (11). Although the effects of the purines on cell firing may be attributed to inhibition of excitatory neurotransmitter release, it is thought that a direct inhibitory effect via purinergic PI receptors may also occur; however, there is controversy about the evidence for the existence of P2 receptors in the central nervous system (3).Behaviorally, Ado has sedative, hypnotic, and anticonvulsant activity (13-16), in contrast to caffeine and theophylline, which are central stimulants (17).Evidence for depolarization-evoked, calcium-dependent release of Ado and ATP from brain slices (18,19) and synaptosomal preparations (12, 20) suggests a potential physiological role for purine-modulated alterations in cell firing, transmitter release and cyclic AMP metabolism, and their sequelae.Demonstration of high-affinity binding of a suitable radioligand to brain membranes has become an additional criterion for the identification of an endogenous substance as a putative neurotransmitter. For Ado and ATP, their involvement in nearly all facets of cell function (21) Subcellular fractions from rat brain were prepared by the method of Whittaker (27); the nuclear, crude synaptosomal, myelin, enriched synaptosomal, mitochondrial, and microsomal subfractions were homogenized by using a Polytron (Brinkmann PT 20-ST generator, setting 5.5 for 10 sec) in distilled water; centrifuged at 48,000 X g for 10 min; and stored at -80°C for at least 18 hr before use. After dissection of rat brain r...