Stress-dependent opioid and adrenergic modulation of newly retrieved fear memory.

Recent studies on the effect of stress on modulation of fear memory in our laboratory have uncovered endogenous opioid and adrenergic based modulation systems, working in concert, that limit the strengthening or weakening of newly acquired fear memory during consolidation under conditions of mild or intense stress, respectively. The present study sought to determine if similar stress-dependent modulation, mediated by endogenous opioid and adrenergic systems, occurs during reconsolidation of newly retrieved fear memory. Rats underwent contextual fear conditioning followed 24h later by reactivation of fear memory; a retention test was administered the next day. Stress was manipulated by varying duration of recall of fear memory during reactivation. In the first experiment, vehicle or the opioid-receptor blocker naloxone was administered immediately after varied durations (30 or 120 s) of reactivation. The results indicate that (1) reactivation, in the absence of drug, has a marked effect on freezing behavior-as duration of reactivation increases from 30 to 120 s, freezing behavior and presumably fear-induced stress increases and (2) naloxone, administered immediately after 30 s (mild stress) or 120 s (intense stress) of reactivation, enhances or impairs retention, respectively, the next day. In the second experiment, naloxone and the ß-adrenergic blocker propranolol were administered either separately or in combination immediately after 120 s (intense stress) reactivation. The results indicate that separate administration of propranolol and naloxone impairs retention, while the combined administration fails to do so. Taken together the results of the two experiments are consistent with a protective mechanism, mediated by endogenous opioid and adrenergic systems working in concert, that limits enhancement and impairment of newly retrieved fear memory during reactivation in a stress-dependent manner.

Stress-dependent impairment of passive-avoidance memory by propranolol or naloxone.

Previous work has shown that the effect of opioid-receptor blockade on memory modulation is critically dependent upon the intensity of stress. The current study determined the effect of adrenergic-receptor blockade on memory modulation under varied levels of stress and then compared the effect of adrenergic-receptor blockade under intense stress to that of a) opioid-receptor blockade and b) concurrent opioid- and adrenergic-receptor blockade. In the first experiment, the ß-adrenergic-receptor blocker propranolol impaired retention in the passive-avoidance procedure when administered immediately after exposure to intense stress (passive-avoidance training followed by swim stress) but not mild stress (passive-avoidance training alone). In the second experiment, while separate administration of either propranolol or the opioid-receptor blocker naloxone immediately after exposure to intense stress impaired retention, the combined administration of propranolol and naloxone failed to do so. These findings demonstrate that the effect of ß-adrenergic-receptor blockade or opioid-receptor blockade on memory modulation in the passive-avoidance procedure is dependent upon the intensity of stress, and suggest that concurrent inactivation of endogenous adrenergic- and opioid-based memory modulation systems under stressful conditions is protective of memory.

Stress-dependent enhancement and impairment of retention by naloxone: evidence for an endogenous opioid-based modulatory system protective of memory.

The opiate-receptor antagonist naloxone was administered to rats after passive-avoidance training either alone or in combination with forced-swim stress. A retention test revealed that while naloxone enhanced retention when administered alone, it impaired retention when administered in combination with forced-swim stress. The findings provide evidence for a "protective" endogenous opioid-based system that, when not blocked pharmacologically, limits enhancement or impairment of retention under conditions of mild and intense stress, respectively.

NAN-190 potentiates the impairment of retention produced by swim stress.

Exposing rats to stress in the form of forced swim immediately after passive-avoidance training impaired retention. In contrast, exposure to the same stressor 2 h after training failed to impair retention. Systemic administration of the 5-HT1A receptor antagonist NAN-190 (1 mg/kg) immediately after forced swim markedly potentiated the stress-induced impairment of retention. In contrast, NAN-190 failed to affect retention when administered 2 h after forced swim or in forced swim's absence. These findings provide evidence for a NAN-190-sensitive system modulating retention that is 1) activated during a critical period shortly after exposure to swim stress, and 2) protective of memory, thereby limiting the extent to which retention is impaired by experiential stress.

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala.

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.