An involvement of adenosine in cerebral blood flow regulation during hypercapnia.

The possibility that endogenously released adenosine, a potent vasodilator, is involved in the increase in cerebral blood flow (CBF) response to hypercapnia has been investigated in an anesthetized, paralyzed rat model. The left retroglenoid vein was cannulated and cerebral venous blood flow measured with a drop counter. Animals were ventilated with a 40% oxygen, 60% nitrogen gas mixture. At 20 min intervals, at a constant rate of flow, the inspired gas mixture was altered to 10% carbon dioxide, 40% oxygen, 50% nitrogen for periods of between 30-90 sec. This brief hypercapnic challenge induced a rapid increase in CBF in the absence of any change in MABP. An involvement of adenosine in this response was demonstrated using an adenosine antagonist, caffeine, an uptake inhibitor, dipyridamole and an adenosine deaminase inhibitor, deoxycoformycin. Caffeine (10 and 20 mg/kg i.p.) 15 min prior to hypercapnic challenges significantly decreased the peak increases in CBF. Dipyridamole (0.1 mg/kg) and deoxycoformycin (0.1 microgram/kg) enhanced the peak increases in flow. These results are consistent with an important role for adenosine in coupling PCO2 to cerebral blood flow.

The role of adenosine in cerebral vascular regulation during reductions in perfusion pressure.

The adenosine antagonist caffeine was used to test the hypothesis that endogenous adenosine contributes to the regulation of cerebral blood flow during acute reductions in mean arterial blood pressure. Caffeine, administered intraperitoneally in 20 and 40 mg kg-1 doses, failed to alter the autoregulatory flow responses to marked reductions in arterial blood pressure, showing that adenosine is not essential for cerebrovascular regulation during severe hypotension.

Indomethacin and ibuprofen enhance anoxia-induced hyperemia in rat brain.

Cerebral blood flow (CBF) in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of CBF over periods of several hours. Following intraperitoneal administration, two non-steroidal anti-inflammatory agents, indomethacin and ibuprofen (0.01 and 0.1 mg/kg) showed a tendency to increase resting CBF and the reactive hyperemia elicited by a brief (24 s) anoxic challenge was potentiated. A third agent, diclofenac sodium, was less effective, enhancing the hyperemic response only at the higher (0.1 mg/kg) dose level. The results indicate that indomethacin and ibuprofen may be of value in the treatment of diseases involving cerebrovascular insufficiency.

The effects of nifedipine and felodipine on cerebral blood flow during anoxic episodes.

Cerebral blood flow (CBF) in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of flow over periods of several hours. Brief periods of anoxia increase the rate of flow. The dihydropyridine calcium antagonists did not affect basal flow rate and depressed the increase in CBF elicited by anoxia. These findings may have significant implications for the therapeutic use of dihydropyridine calcium antagonists in brain ischaemia.

Behavioral characteristics of centrally administered adenosine analogs.

Mice were implanted with chronic indwelling cannulae in the lateral cerebral ventricle. A series of adenosine analogs and related compounds were injected into the lateral ventricle (ICVT) and their effects on spontaneous locomotor activity recorded. All analogs produced dose-related decreases in locomotor activity. 5'-N6-ethyl-carboxamidoadenosine (NECA) was the most potent compound tested, with a number of N6-substituted analogs also being effective depressants of activity. Caffeine, administered either intracerebroventricularly or intraperitoneally, antagonized the depressant effects of the adenosine analogs. 3-Isobutyl-1-methylxanthine, administered ICVT, depressed locomotor activity. However, after caffeine, IBMX elicited behavioral stimulation. Agents which inhibit the transport of adenosine (dipyridamole, dilazep, papaverine) depressed locomotor activity, as did erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, an inhibitor of adenosine deaminase. The effects of dilazep, papaverine and EHNA, but not of dipyridamole, were antagonized by caffeine. These results further substantiate the notion that endogenous adenosine is involved in the regulation of central nervous system excitability.

A possible role of endogenous adenosine in the sedative action of meprobamate.

The behavioral interaction of intraperitoneal (i.p.) injections of meprobamate with intracerebroventricular (i.c.v.) injections of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA) was examined on spontaneous locomotor activity in mice. The locomotor depressant effect of meprobamate, an adenosine uptake inhibitor, was potentiated by adenosine, but not by NECA, an uptake-resistant adenosine analogue. These findings suggest that heightened endogenous adenosine levels could mediate some of the central actions of meprobamate.

Naloxone enhances cerebral reactive hyperemia in the rat.

Cerebral blood flow (CBF) in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of CBF over several hours. Morphine and the opiate antagonist, naloxone, were tested for their effects on the reactive hyperemia that follows a brief anoxic challenge. Morphine (5.0 mg/kg) significantly reduced the peak increase in flow during the hyperemia and, at both of the doses used (1.0 and 5.0 mg/kg), caused a small, nonsignificant increase in the duration of the reactive hyperemia. Naloxone (0.1 and 1.0 mg/kg) enhanced basal CBF rates and significantly prolonged the duration of the reactive hyperemia. These effects of naloxone may account for its beneficial effects in the treatment of cerebral ischemia.

Adenosine deaminase inhibitors enhance cerebral anoxic hyperemia in the rat.

Cerebral blood flow in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of flow over periods of several hours. The adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (1.0-100 micrograms/kg) and deoxycoformycin (0.1-1 micrograms/kg) potentiated the reactive hyperemia elicited by a brief (24-s) anoxic challenge. Basal flow rate was unaltered by EHNA administration and slightly enhanced by deoxycoformycin. The results are consistent with the hypothesis that adenosine plays a significant role in cerebral vascular regulation and suggest that low doses of these deaminase inhibitors may be useful in the treatment of cerebral vascular insufficiency.

The effects of lidoflazine and flunarizine on cerebral reactive hyperemia.

Cerebral blood flow in the rat was monitored by a venous outflow technique with an extracorporeal circulation, which allows for the continuous recording of flow over periods of several hours. The bi-fluorophenyl-piperazine derivatives, lidoflazine and flunarizine, enhanced the reactive hyperemia elicited by a brief (30 s) anoxic challenge. They did not alter resting cerebral blood flow rates. Verapamil, a potent calcium slow channel blocker, decreased resting flow rates but did not alter the duration of the reactive hyperemia. As lidoflazine and flunarizine are potent inhibitors of adenosine uptake, whereas verapamil is not, the results are consistent with the hypothesis that adenosine plays a significant role in cerebral vascular autoregulation.

Behavioral interaction of adenosine and trifluoperazine in mice.

Mice were implanted with chronic indwelling cannulae in the lateral cerebral ventricle. A dose-response curve was established for the effect of i.p. injections of trifluoperazine (TFP) on spontaneous locomotor activity. In addition, the behavioral interaction of i.p. injections of TFP with intracerebroventricular (i.c.v.) injections of adenosine (ADO) was examined. TFP depressed locomotor activity in a dose-dependent manner. A dose of ADO, which had no effect on locomotor activity when given alone, enhanced the depressant effects of TFP at all doses. As a control for the specificity of this behavioral interaction, mice also were given i.p. injections of TFP in combination with i.c.v. injections of 5'-N-ethylcarboxamidoadenosine (NECA), an uptake-resistant adenosine analogue. TFP and NECA did not interact to produce a significantly more pronounced locomotor depression. These results substantiate the notion that the sedative actions of TFP involve the inhibition of adenosine uptake and thus potentiation of extracellular adenosine levels.

Effects of anoxia on cerebral blood flow in the rat brain: evidence for a role of adenosine in autoregulation.

The purpose of these experiments was to determine the utility of a new method for monitoring CBF using a venous outflow technique with an extracorporeal circulation and to examine the effects of agents that potentiate or antagonize the actions of adenosine on the blood flow response to brief periods of anoxia. The results demonstrate the ability of the new technique to detect the increases in CBF in response to anoxia. Caffeine, an adenosine antagonist, reduced the intensity and duration of the anoxia-induced hyperemia. Dipyridamole and papaverine, inhibitors of adenosine uptake, potentiated the increase in CBF during anoxia. The results support the hypothesis that adenosine plays an important role in regulating CBF during anoxic episodes.

Behavioral interaction of adenosine and diazepam in mice.

Mice were implanted with chronic indwelling cannulae in the lateral cerebral ventricle. The behavioral interaction of intraperitoneal (i.p.) injections of diazepam with intracerebroventricular (i.c.v.t.) injections of adenosine or 5'-N-ethylcarboxamidoadenosine (NECA) was examined on spontaneous locomotor activity. Concurrent injections of i.c.v.t. adenosine and i.p. diazepam, at doses which had no significant effect on locomotor activity when given alone, acted synergistically to produce a marked depression of locomotor activity. In contrast, i.p. injections of diazepam did not potentiate the locomotor depressant effects of i.c.v.t. injections of NECA, an uptake resistant analog of adenosine. These findings support the possibility of specific benzodiazepine-adenosine interactions in the central nervous system.

A purinergic component in the central actions of meprobamate.

The anxiolytic propanediol carbamate, meprobamate, potentiates the depressant actions of adenosine on the firing of rat cerebral cortical neurons. Meprobamate inhibits the uptake of adenosine by rat cortical synaptosomes at concentrations within the therapeutic range. Potentiation of endogenously released adenosine can account for many of the central actions of meprobamate.

Control rate of response or reinforcement and amphetamine's effect on behavior.

The roles of control response rate and reinforcement frequency in producing amphetamine's effect on operant behavior were evaluated independently in rats. Two multiple schedules were arranged in which one variable, either response rate or reinforcement frequency, was held constant and the other variable manipulated. A multiple differential-reinforcement-of-low-rate seven-second yoked variable-interval schedule was used to equate reinforcement frequencies at different control response rates between multiple-schedule components. Amphetamine increased responding under the variable-interval component. In contrast, amphetamine decreased responding equivalently between components of a multiple random-ratio schedule that produced similar control response rates at different reinforcement frequencies. The results provide experimental support to the rate-dependency principle that control rate of responding is an important determinant of amphetamine's effect on operant behavior.

Effects of differential reinforcement expectancies on successive matching-to-sample performance in pigeons.

A series of experiments employed a symbolic variant of Konorski's delayed successive matching-to-sample task in order to determine whether differential reinforcement expectancies affect discriminative responding. One of two sample stimuli (S1 or S2) was followed, after a delay (0, 5, or 10 sec), by one of two test stimuli (T1 or T2). Pigeons' key pecking during test periods could produce food only on S1-T1 and S2-T2 (positive) trials; nonreinforcement invariably occurred on S1-T2 and S2-T1 (negative) trials. Differential reinforcement was scheduled by following the two positive trial sequences with different probabilities of reinforcement (.2 and 1.0); nondifferential reinforcement was scheduled by following the two positive trial sequences with a single, intermediate probability of reinforcement. (.6). Subjects given differential reinforcement acquired the conditional discriminaton more rapidly and reached higher terminal levels of performance than nondifferential controls (Experiment 1). Moreover, the magnitude of these differences increased as the delay between sample and test stimuli was lengthened. Reversing the probabilities of reinforcement in the differential problem produced a substantial and durable disruption of conditional discrimination performance (Experiment 2). The same general pattern of results was obtained when differential sample key pecking was eliminated (Experiment 3). These results can be parsimoniously interpreted by postulating the existence of learned reinforcement expectancies, and they detract from the merits of trace theory as a complete account of animal memory.