adenosine-5--(n-ethylcarboxamide) and Substance-Withdrawal-Syndrome

In the present study, the effects of adenosine agonists on the development of sensitization to withdrawal signs precipitated after sporadic treatment with diazepam, in mice, were investigated. To obtain the sensitization, the animals were divided into groups: continuously and sporadically treated with diazepam (15.0 mg/kg, s.c.). The adenosine receptor agonists (CPA, CGS 21,680 and NECA) were administered in sporadically diazepam treated mice during two diazepam-free periods. Concomitant administration of pentetrazole (55.0 mg/kg, s.c.) with flumazenil (5.0 mg/kg, i.p.) after the last injection of diazepam or vehicle, induced the withdrawal signs, such as clonic seizures, tonic convulsion and death episodes. The major finding of our experiments is attenuation of withdrawal signs in sensitized mice, inducing by all adenosine agonists. Only higher dose of CPA produced significantly decreased the number of withdrawal incidents, while both used doses of CGS 21,680 and NECA produced more clear effects. These results support the hypothesis that adenosinergic system is involved in the mechanisms of sensitization to the benzodiazepine withdrawal signs, and adenosine A(2A) receptors play more important role in that process.

Topics: Adenosine; Adenosine A1 Receptor Agonists; Adenosine A2 Receptor Agonists; Adenosine-5'-(N-ethylcarboxamide); Animals; Convulsants; Diazepam; Hypnotics and Sedatives; Male; Mice; Pentylenetetrazole; Phenethylamines; Purinergic P1 Receptor Agonists; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

The involvement of adenosine receptor agonists in benzodiazepine withdrawal signs was evaluated as the seizure susceptibility of mice. The concomitant administration of subthreshold dose of pentetrazole (55.0 or 60.0 mg/kg, s.c.) with flumazenil (10.0 mg/kg, i.p.) in mice chronically treated with temazepam or diazepam induced the appearance of withdrawal signs: clonic seizures, tonic convulsions and death episodes. The administration of the selective A1 (CPA-N6-cyclopentyladenosine), A2A (CGS 21680-2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride) and the non-selective A1/A2A (NECA-5'-N-ethylcarboxamidoadenosine) adenosine receptor agonists (i.p.) evoked the significant attenuation of benzodiazepine withdrawal signs, and these effects were more expressed in temazepam- than in diazepam-dependent mice. CPA has shown the most apparent and dose-dependent attenuating effect. The results confirm that adenosine A1 and A2A receptors are involved in benzodiazepine withdrawal signs, and adenosine A1 receptor plays a predominant role in this phenomenon.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Diazepam; Dose-Response Relationship, Drug; Flumazenil; Male; Mice; Pentylenetetrazole; Phenethylamines; Purinergic Agonists; Purinergic P1 Receptor Agonists; Purinergic P2 Receptor Agonists; Seizures; Substance Withdrawal Syndrome; Temazepam

The aim of this study was to investigate whether the A1/A2 receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), and the selective A1 agonist, N6-cyclopentyladenosine (CPA), induced physical dependence by quantifying specific antagonist-precipitated withdrawal syndromes in conscious rats. In addition, the presence of bidirectional cross-withdrawal was also investigated. The agonists were administered s.c. to groups of rats at 12 h intervals. Antagonists were administered s.c., 12 hours after the last dose, followed by observation and measurement of faecal output for 20 min. NECA (4 x 0.03 mg kg(-1), s.c) and CPA (4 x 0.03, 0.1 and 0.3 mg kg(-1), s.c.) induced physical dependence, as shown by the expression of a significant withdrawal syndrome when challenged with the adenosine A1/A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX, 0.1 mg kg(-1), s.c.) and the A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPDPX, 0.1 mg kg(-1), s.c.) respectively. The syndromes consisted of teeth chattering and shaking behaviours shown to occur in morphine-dependent animals withdrawn with naloxone viz, paw, body and 'wet-dog' shakes, but with the additional behaviours of head shaking and yawning. In further contrast to the opiate withdrawal syndrome, no diarrhoea occurred in the groups of animals treated with adenosine agonists and withdrawn with their respective antagonists. Bidirectional cross-withdrawal syndromes were also revealed when naloxone (3 mg kg(-1), s.c.) was administered to adenosine agonist pre-treated rats and adenosine antagonists were given to morphine pre-treated rats. This study provides further information illustrating that close links exist between the adenosine and opiate systems.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Behavior, Animal; Female; Injections, Subcutaneous; Male; Morphine; Morphine Dependence; Muscle Contraction; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Theobromine; Xanthines

Chronic exposure to caffeine increases the number of adenosine receptors (up-regulation) but these observations have been mostly limited to animal models that study A1 adenosine receptors. The regulation of adenosine receptors by caffeine in humans and, in particular A2 receptors, remains largely unexplored. The purpose of this study was to test the hypothesis that withdrawal from chronic caffeine administration results in up-regulation of A2 adenosine receptors in humans. The authors also wanted to determine whether caffeine induces homologous or heterologous up-regulation. Caffeine 250 mg three times daily was given orally to a total of 19 normal volunteers for 7 days. Platelets were obtained at base line and 12 and 60 hr after the last dose of caffeine and the antiaggregation responses to adenosine and prostacyclin receptors were evaluated ex vivo. Plasma caffeine levels remained elevated at 22 microM 12 hr after the last dose but decreased to 0.6 microM at 60 hr. Adenosine receptor activation with the agonist 5'-N-ethylcarboxamidoadenosine and prostacyclin receptor activation with iloprost or prostaglandin E1 produced a greater antiaggregation effect at 60 hr postcaffeine. Increased responsiveness to both receptors could also be demonstrated at 12 hr after removal of caffeine by washing the platelets. Sensitization to the actions of prostacyclin, however, was reversed if caffeine was added ex vivo. These results support the hypothesis that chronic caffeine exposure induces heterologous up-regulation of adenosine and prostacyclin receptors in humans and implies that endogenous adenosine normally modulates platelet adenosine receptors in vivo. These findings may be relevant to the caffeine withdrawal syndrome observed in humans.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Adolescent; Adult; Alprostadil; Blood Platelets; Caffeine; Epoprostenol; Humans; Male; Models, Biological; Purinergic P1 Receptor Antagonists; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Purinergic P1; Sensitivity and Specificity; Substance Withdrawal Syndrome; Up-Regulation

Substantial in vitro and animal data suggest that methylxanthines, such as caffeine and theophylline, act as adenosine receptor antagonists. To test this hypothesis in humans, we first determined if theophylline would antagonize the effects of adenosine. Intravenous administration of adenosine, 80 micrograms/kg/min, increased heart rate 28 +/- 6 bpm, systolic blood pressure 19 +/- 5 mm Hg and minute ventilation 6.1 +/- 2.2 liters/min. All these changes were significantly attenuated during theophylline administration (17 +/- 3 bpm and 1 +/- 2 mm Hg and 1.6 +/- 0.6 liters/min, respectively, P less than .05), at a dose (10 mg/kg over 1 hr, followed by 1.8 micrograms/kg/min i.v.) that produced plasma theophylline levels of 17 +/- 2 micrograms/ml (94 microM). We then determined if chronic caffeine consumption resulted in upregulation of platelet adenosine receptors in eight normal volunteers. After 7 days of caffeine abstinence, the adenosine analog 5'-N-ethylcarboxamidoadenosine produced a dose-dependent inhibition of thrombin-induced aggregation (EC50 = 69 nM). Subjects then were given caffeine, 250 mg p.o. 3 times a day for 7 days. Actual caffeine withdrawal, that is, virtual disappearance of caffeine in plasma, was apparent 60 hr after the last dose of caffeine. Caffeine withdrawal produced a significant shift to the left of 5'-N-ethylcarboxamidoadenosine inhibition of aggregation (EC50 = 49 nM, P less than .01), implying sensitization and/or upregulation of adenosine receptors as seen after chronic exposure to an antagonist. These results suggest that methylxanthines act as adenosine receptor antagonists in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Adult; Caffeine; Heart Rate; Humans; Male; Platelet Aggregation; Purinergic Antagonists; Receptors, Purinergic; Substance Withdrawal Syndrome; Theophylline