Stress and adenosine: II. Adenosine analogs mimic the effect of inescapable shock on shuttle-escape performance in rats.

Abstract

In 3 experiments, the authors examined the role of adenosine regulation in escape deficits produced by earlier exposure to inescapable shock in rats (learned helplessness). Adenosine analogs injected before escape testing mimicked the effect of earlier inescapable shock, with the magnitude of the deficit varying with dose and drug specificity for A2 adenosine receptors. Agonist-induced and stress-induced escape deficits were eliminated by pretest treatment with the centrally acting adenosine receptor antagonist theophylline but not the peripheral antagonist 8-[p-sulfophenyl]-theophylline. Finally, preexposure to an ineffective number of inescapable shocks interacted in synergy with an ineffective pretest injection of adenosine agonist to maximize deficits in escape performance. These data implicate energy regulation and a central compensatory action by adenosine in the aspects of helplessness related to conservation-withdrawal.

Enhancing brain adenosine signaling with the nucleoside transport blocker NBTI (S-(4-nitrobenzyl)-6-theoinosine) mimics the effects of inescapable shock on later shuttle-escape performance in rats.

“…The present data clearly do not support this aspect of the hypothesis and it eventually will have to be modified. The failure to implicate A 1 receptors in the helplessness effect also is consistent with earlier work examining adenosine agonists (Minor at al., 1994b). Pretest administration of the highly selective A 1 agonist R-PIA ( N 6 -[2-phenylisopropyl]-adenosine) was substantially less effective at mimicking the effects of inescapable shocks than was the nonselective (A 1 /A 2 ) agonist NECA (5′-N-ethylcarboximide-adenosine).…”

“…These data are consistent with a number of other findings from this laboratory that implicate a critical role of adenosine signaling in traumatic stress effects and in other animal models of depression. EHNA and NBTI produce a pattern of results that is quite similar to those produced by systemic injection of adenosine receptor agonists (see Minor et al, 1994aMinor et al, , 1994bWoodson et al, 1998). When adenosine receptor agonists are administered to previously restrained rats shortly before escape testing (Minor et al, 1994b), the nonselective (A 1 /A 2 ) adenosine agonist NECA (5Ј-N-ethylcarboxamido adenosine) is about 100 times more effective at mimicking the effects of inescapable shock than is the highly selective A 1 adenosine agonist R-PIA (R(-)-N6-(2-phenylisoproply)adenosine and about 1000 times more effective than the A 1 enantiomer S-PIA (S(ϩ) N6-(2phenylisopropyl)-adenosine).…”

“…The potentiation of the effects of a low dose of NBTI via preexposure to inescapable shock may have resulted from the cumulative effects of drug and stress on extracellular adenosine concentrations at the time of testing such that the total nucleoside concentration exceeded the threshold for impaired escape performance. In this regard, we have observed similar synergistic effects between stress and exogenous adenosine analogs (Minor et al, 1994b) and drugs that block the extracellular degradation of adenosine (Woodson et al, 1998).…”

Enhancing brain adenosine signaling with the nucleoside transport blocker NBTI (S-(4-nitrobenzyl)-6-theoinosine) mimics the effects of inescapable shock on later shuttle-escape performance in rats.

“…The present data clearly do not support this aspect of the hypothesis and it eventually will have to be modified. The failure to implicate A 1 receptors in the helplessness effect also is consistent with earlier work examining adenosine agonists (Minor at al., 1994b). Pretest administration of the highly selective A 1 agonist R-PIA ( N 6 -[2-phenylisopropyl]-adenosine) was substantially less effective at mimicking the effects of inescapable shocks than was the nonselective (A 1 /A 2 ) agonist NECA (5′-N-ethylcarboximide-adenosine).…”

“…These data are consistent with a number of other findings from this laboratory that implicate a critical role of adenosine signaling in traumatic stress effects and in other animal models of depression. EHNA and NBTI produce a pattern of results that is quite similar to those produced by systemic injection of adenosine receptor agonists (see Minor et al, 1994aMinor et al, , 1994bWoodson et al, 1998). When adenosine receptor agonists are administered to previously restrained rats shortly before escape testing (Minor et al, 1994b), the nonselective (A 1 /A 2 ) adenosine agonist NECA (5Ј-N-ethylcarboxamido adenosine) is about 100 times more effective at mimicking the effects of inescapable shock than is the highly selective A 1 adenosine agonist R-PIA (R(-)-N6-(2-phenylisoproply)adenosine and about 1000 times more effective than the A 1 enantiomer S-PIA (S(ϩ) N6-(2phenylisopropyl)-adenosine).…”

“…The potentiation of the effects of a low dose of NBTI via preexposure to inescapable shock may have resulted from the cumulative effects of drug and stress on extracellular adenosine concentrations at the time of testing such that the total nucleoside concentration exceeded the threshold for impaired escape performance. In this regard, we have observed similar synergistic effects between stress and exogenous adenosine analogs (Minor et al, 1994b) and drugs that block the extracellular degradation of adenosine (Woodson et al, 1998).…”

Helplessness and escape performance: Glutamate-adenosine interactions in the frontal cortex.

“…Additionally, Group S–C responded significantly faster than did the other three groups, suggesting that caffeine treatment alone enhanced shuttle performance. This effect of caffeine on performance in control subjects is not characteristic of other work on helplessness and purines (Minor, Chang, & Winslow, 1994; Minor, Winslow, & Chang, 1994). Caffeine-treated rats usually escape slightly (but not significantly) faster than do other controls.…”

“…The adenosine-mediated effect observed in Experiment 1 provides evidence for the hypothesized links among neural overactivation, adenosine neuroregulation, and shuttle-escape performance (Minor, Chang, & Winslow, 1994; Minor, Winslow, & Chang, 1994; Woodson, Minor, & Job, 1998). From this view, shocks delivered during the first few minutes of escape testing result in excessive neural activation and rapid energy expenditure in critical brain areas of rats previously exposed to inescapable shock.…”

Enhancing brain adenosine signaling with the nucleoside transport blocker NBTI (S-(4-nitrobenzyl)-6-theoinosine) mimics the effects of inescapable shock on later shuttle-escape performance in rats.

“…The present data clearly do not support this aspect of the hypothesis and it eventually will have to be modified. The failure to implicate A 1 receptors in the helplessness effect also is consistent with earlier work examining adenosine agonists (Minor at al., 1994b). Pretest administration of the highly selective A 1 agonist R-PIA ( N 6 -[2-phenylisopropyl]-adenosine) was substantially less effective at mimicking the effects of inescapable shocks than was the nonselective (A 1 /A 2 ) agonist NECA (5′-N-ethylcarboximide-adenosine).…”

“…These data are consistent with a number of other findings from this laboratory that implicate a critical role of adenosine signaling in traumatic stress effects and in other animal models of depression. EHNA and NBTI produce a pattern of results that is quite similar to those produced by systemic injection of adenosine receptor agonists (see Minor et al, 1994aMinor et al, , 1994bWoodson et al, 1998). When adenosine receptor agonists are administered to previously restrained rats shortly before escape testing (Minor et al, 1994b), the nonselective (A 1 /A 2 ) adenosine agonist NECA (5Ј-N-ethylcarboxamido adenosine) is about 100 times more effective at mimicking the effects of inescapable shock than is the highly selective A 1 adenosine agonist R-PIA (R(-)-N6-(2-phenylisoproply)adenosine and about 1000 times more effective than the A 1 enantiomer S-PIA (S(ϩ) N6-(2phenylisopropyl)-adenosine).…”

“…The potentiation of the effects of a low dose of NBTI via preexposure to inescapable shock may have resulted from the cumulative effects of drug and stress on extracellular adenosine concentrations at the time of testing such that the total nucleoside concentration exceeded the threshold for impaired escape performance. In this regard, we have observed similar synergistic effects between stress and exogenous adenosine analogs (Minor et al, 1994b) and drugs that block the extracellular degradation of adenosine (Woodson et al, 1998).…”

Helplessness and escape performance: Glutamate-adenosine interactions in the frontal cortex.

“…Additionally, Group S–C responded significantly faster than did the other three groups, suggesting that caffeine treatment alone enhanced shuttle performance. This effect of caffeine on performance in control subjects is not characteristic of other work on helplessness and purines (Minor, Chang, & Winslow, 1994; Minor, Winslow, & Chang, 1994). Caffeine-treated rats usually escape slightly (but not significantly) faster than do other controls.…”

“…The adenosine-mediated effect observed in Experiment 1 provides evidence for the hypothesized links among neural overactivation, adenosine neuroregulation, and shuttle-escape performance (Minor, Chang, & Winslow, 1994; Minor, Winslow, & Chang, 1994; Woodson, Minor, & Job, 1998). From this view, shocks delivered during the first few minutes of escape testing result in excessive neural activation and rapid energy expenditure in critical brain areas of rats previously exposed to inescapable shock.…”

Enhancing brain adenosine signaling with the nucleoside transport blocker NBTI (S-(4-nitrobenzyl)-6-theoinosine) mimics the effects of inescapable shock on later shuttle-escape performance in rats.

“…The present data clearly do not support this aspect of the hypothesis and it eventually will have to be modified. The failure to implicate A 1 receptors in the helplessness effect also is consistent with earlier work examining adenosine agonists (Minor at al., 1994b). Pretest administration of the highly selective A 1 agonist R-PIA ( N 6 -[2-phenylisopropyl]-adenosine) was substantially less effective at mimicking the effects of inescapable shocks than was the nonselective (A 1 /A 2 ) agonist NECA (5′-N-ethylcarboximide-adenosine).…”

“…These data are consistent with a number of other findings from this laboratory that implicate a critical role of adenosine signaling in traumatic stress effects and in other animal models of depression. EHNA and NBTI produce a pattern of results that is quite similar to those produced by systemic injection of adenosine receptor agonists (see Minor et al, 1994aMinor et al, , 1994bWoodson et al, 1998). When adenosine receptor agonists are administered to previously restrained rats shortly before escape testing (Minor et al, 1994b), the nonselective (A 1 /A 2 ) adenosine agonist NECA (5Ј-N-ethylcarboxamido adenosine) is about 100 times more effective at mimicking the effects of inescapable shock than is the highly selective A 1 adenosine agonist R-PIA (R(-)-N6-(2-phenylisoproply)adenosine and about 1000 times more effective than the A 1 enantiomer S-PIA (S(ϩ) N6-(2phenylisopropyl)-adenosine).…”

“…The potentiation of the effects of a low dose of NBTI via preexposure to inescapable shock may have resulted from the cumulative effects of drug and stress on extracellular adenosine concentrations at the time of testing such that the total nucleoside concentration exceeded the threshold for impaired escape performance. In this regard, we have observed similar synergistic effects between stress and exogenous adenosine analogs (Minor et al, 1994b) and drugs that block the extracellular degradation of adenosine (Woodson et al, 1998).…”

Helplessness and escape performance: Glutamate-adenosine interactions in the frontal cortex.

“…Additionally, Group S–C responded significantly faster than did the other three groups, suggesting that caffeine treatment alone enhanced shuttle performance. This effect of caffeine on performance in control subjects is not characteristic of other work on helplessness and purines (Minor, Chang, & Winslow, 1994; Minor, Winslow, & Chang, 1994). Caffeine-treated rats usually escape slightly (but not significantly) faster than do other controls.…”

“…The adenosine-mediated effect observed in Experiment 1 provides evidence for the hypothesized links among neural overactivation, adenosine neuroregulation, and shuttle-escape performance (Minor, Chang, & Winslow, 1994; Minor, Winslow, & Chang, 1994; Woodson, Minor, & Job, 1998). From this view, shocks delivered during the first few minutes of escape testing result in excessive neural activation and rapid energy expenditure in critical brain areas of rats previously exposed to inescapable shock.…”