Peter E. Simson

Comparison between the effects of ethanol and diazepam on spatial working memory in the rat.

Abstract The present study compared the effects of ethanol and diazepam on a task that allows for the assessment of both spatial working memory and the acquisition of spatial information within each day. During the first trial of each day, subjects were shown the spatial location of a food reward on a six-arm radial-arm maze. During nine subsequent free-choice trials, subjects were reinforced for returning to that same spatial location. The location of the food reward varied across days. Thus, choosing correctly on any given trial required subjects to remember where food had been received during the previous trials of that day. The effects of ethanol and diazepam on working memory were assessed by analyzing the overall number of errors committed during the nine free-choice trials of each day. The effects of ethanol and diazepam on within-day acquisition were assessed by comparing the number of errors committed during the first three trials of each day to the number of errors committed during the last three trials of each day. Ethanol and diazepam both produced dose-dependent increases in working memory errors, and both did so without impairing within-day acquisition. The results of the present study provide further evidence of the similarities between the effects of ethanol and benzodiazepine receptor agonists on learning and memory, and are consistent with the hypothesis that ethanol’s potentiation of GABA at GABAA receptors contributes to the learning and memory impairments produced by ethanol.

Prenatal Exposure to Ethanol Disrupts Spatial Memory: Effect of the Training–Testing Delay Period

The present study investigated how variations in the period of delay between training and testing in the Morris water maze task affect the use of spatial memory in adult rats that were prenatally exposed to ethanol. Previous results utilizing the Morris water maze task have shown that prenatal, or early postnatal, exposure to ethanol produces deficits in the use of spatial memory, a type of memory that is dependent on an intact hippocampus. However, in these prior studies the delay period between the training of animals and the testing of spatial memory is typically fixed at only 1 day. In the current study, which utilized a revised training procedure within the Morris water maze task, the period of delay between training and testing was altered such that it was either 1 day or 3 days. Following the 3-day delay, different levels of prenatal exposure to ethanol impaired the use of spatial memory. In contrast, following the 1-day delay, prenatal exposure to ethanol failed to impair the use of spatial memory. The present study thus shows that prenatal exposure to ethanol differentially affects spatial memory in the Morris water maze task depending on the period of delay between training and testing.

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 β-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 β-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.

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 swims 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.

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.

Dose-sensitive excitation and inhibition of spontaneous amygdala activity by propranolol

The effect of systemically administered propranolol was determined on spontaneous activity of neurons in the central nucleus (CeA) of the amygdala, a brain site implicated in fear-related learning and memory. Extracellular recordings of single units in the CeA were obtained in vivo from rats administered saline or the centrally and peripherally acting beta-adrenergic receptor blocker propranolol (4, 7, 10 mg/kg i.p.). The high dose (10 mg/kg) of propranolol markedly increased spontaneous activity of CeA neurons. In contrast, the low (4 mg/kg) and intermediate (7 mg/kg) doses of propranolol significantly decreased spontaneous CeA activity, with the suppressant effect of propranolol on CeA firing rates weakening as the dosage increased from 4 to 7 mg/kg. These results suggest that (1) spontaneous activity of CeA neurons is tonically influenced by competing excitatory and inhibitory modulatory circuits, and (2) propranolols effect on the two modulatory circuits is dose dependent: the high dose increasing spontaneous CeA activity by preferentially blocking an inhibitory circuit, the low dose decreasing spontaneous CeA activity by preferentially blocking an excitatory circuit, and the intermediate dose weakly suppressing CeA activity by blocking both the excitatory and inhibitory modulatory circuits. Disinhibition of CeA activity by the high dose of propranolol may explain the enhancement of retention observed in the passive-avoidance task when this dose of the drug is administered systemically, and may have implications for the use of propranolol clinically in treating aversive-memory-related anxiety disorders such as posttraumatic stress syndrome.

Blockade of α2-ADRENERGIC receptors markedly potentiates glutamate-evoked activity of locus coeruleus neurons

The locus coeruleus (LC) is a small pontine nucleus with widely distributed efferents that supply the majority of norepinephrine in brain. Evidence from our laboratory has implicated α2-adrenergic receptors on LC neurons in regulating the magnitude of the bursting response of LC neurons to both sensory stimulation and systemically administered drugs. Sub-stimulation of α2-adrenergic receptors in the LC and the resulting hyper-responsiveness of LC neurons is thought to at least partially mediate depression in an animal model. The present study extends previous work in our laboratory by demonstrating that blockade of α2-adrenergic receptors also markedly augments the bursting response of LC neurons to locally – via microiontophoresis-applied glutamate.