Restricted ADP movement in cardiomyocytes: Cytosolic diffusion obstacles are complemented with a small number of open mitochondrial voltage-dependent anion channels.

Adequate intracellular energy transfer is crucial for proper cardiac function. In energy starved failing hearts, partial restoration of energy transfer can rescue mechanical performance. There are two types of diffusion obstacles that interfere with energy transfer from mitochondria to ATPases: mitochondrial outer membrane (MOM) with voltage-dependent anion channel (VDAC) permeable to small hydrophilic molecules and cytoplasmatic diffusion barriers grouping ATP-producers and -consumers.

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-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).

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.

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.

Ethanol inhibits spontaneous activity of central nucleus of the amygdala neurons but does not impair retention in the passive-avoidance task.

Background: Behavioral studies using pharmacological manipulations that increase neuronal activity of the central nucleus of the amygdala (CeA) have implicated the CeA in enhancement of memory modulation. To date, however, there has been a dearth of studies investigating the effect of a drug that decreases CeA activity on memory modulation-a drug that inhibits the neuronal activity of the CeA might be expected to impair memory modulation. To determine whether ethanol inhibits CeA activity and, if so, whether decreased CeA activity is associated with impairment of memory modulation, this study investigated the effect of ethanol on spontaneous single-unit activity of CeA neurons and retention in the passive-avoidance task.

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.

Blockade of alpha2-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 alpha2-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 alpha2-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.

Beta-adrenergic receptor blockade by propranolol enhances retention in a multitrial passive-avoidance procedure.

The effect of beta-adrenergic receptor blockade on retention in a mildly aversive passive-avoidance procedure was investigated. Rats were given passive-avoidance training--1 trial per day for 4 days-and were administered saline, the centrally and peripherally acting beta-adrenergic blocker propranolol (4 or 10 mg/kg ip), or the peripherally acting beta-adrenergic blocker sotalol (4 or 10 mg/kg ip) immediately or 2 hr after the 1st trial. Enhanced retention occurred only with the higher dose (10 mg/kg) of propranolol and only when it was administered immediately after training.

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.

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

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.

Evidence for a selective effect of ethanol on N-methyl-d-aspartate responses: ethanol affects a subtype of the ifenprodil-sensitive N-methyl-d-aspartate receptors.

An extracellular electrophysiological approach was used to determine the effect of ethanol on responses to N-methyl-D-aspartate (NMDA) across several brain regions in urethane-anesthetized rats. The results indicated that, in most brain regions, ethanol inhibited the NMDA-induced increases in firing rate for some, but not all, spontaneously active neurons. Ethanol functioned as an NMDA antagonist for some neurons in the medial septum, red nucleus, deep mesencephalic nucleus, substantia nigra reticulata, ventral tegmental area and cerebellum.

Ethanol alters spatial processing of hippocampal place cells: a mechanism for impaired navigation when intoxicated.

This study describes a new mechanism by which ethanol alters brain function and may impair performance on tasks requiring spatial navigation. Recording electrophysiological activity from single neurons in the awake, freely behaving animal, the present study shows that ethanol impairs the ability of place cells in the hippocampus to process spatial information. The impairment by ethanol in spatial processing of place cells was remarkably similar to the impairment produced by lesions of afferents to the hippocampus, except that the effect of ethanol was reversible.

Acute ethanol impairs spatial memory but not stimulus/response memory in the rat.

The present studies investigate how acutely administered ethanol (ETOH) affects the use of spatial memory. Previous electrophysiological results have shown that acutely administered ETOH alters the firing of hippocampal neurons and that prenatal or chronic exposure to ETOH produces deficits on spatial learning tasks, tasks dependent on the hippocampus. In contrast, it has also been demonstrated that acutely administered ETOH does not impair spatial localization.

Effect of zolpidem on gamma-aminobutyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions.

Previous investigations have suggested a relationship between zolpidem binding within specific brain regions and the ability of ethanol or zolpidem to enhance gamma-aminobutyric acid (GABA)-induced inhibition. The purpose of the present study was to extend our electrophysiological analysis to additional brain sites with high levels of zolpidem binding. In the brain regions chosen, red nucleus and globus pallidus, GABA-induced inhibition was shown to be enhanced by either ethanol or zolpidem on some, but not all, neurons.

Effects of ethanol, MK-801, and chlordiazepoxide on locomotor activity in different rat lines: dissociation of locomotor stimulation from ethanol preference.

Several lines of research have suggested a link between the reward value of a drug and its ability to stimulate locomotion. One goal of the present study was to determine whether ethanol preferentially stimulates locomotor activity in lines of rat that show a preference for ethanol. A secondary goal was to determine the extent to which the benzodiazepine-like and NMDA antagonistic action of ethanol accounted for its effect on locomotor activity.

Neonatal destruction of dopaminergic neurons.

Rats treated as neonates with 6-hydroxydopamine are proposed to model the dopamine deficiency associated with Lesch-Nyhan syndrome (LNS). To understand the neurobiological basis of specific behaviors in LNS, investigations were undertaken in these neonatally lesioned rats. Several new findings resulted from these studies.

Molecular basis for regionally specific action of ethanol on gamma-aminobutyric acidA receptors: generalization to other ligand-gated ion channels.

The present investigation provides evidence that there is neuroanatomical specificity for ethanol enhancement of gamma-aminobutyric acid (GABA)-induced inhibition in mammalian brain and that the expression of a specific GABAA isoreceptor is associated with this regional action of ethanol. Ethanol enhanced responses to iontophoretically applied GABA in the medial septum, inferior colliculus, substantia nigra reticulata, ventral pallidum and the diagonal band of Broca. In contrast to these results, responses to GABA applied to cells in the lateral septum, ventral tegmental area and the hippocampus were not affected by ethanol.

Inhibition of NMDA-evoked electrophysiological activity by ethanol in selected brain regions: evidence for ethanol-sensitive and ethanol-insensitive NMDA-evoked responses.

Our laboratory has previously shown that systemically administered ethanol inhibits NMDA-evoked electrophysiological activity in some, but not all, neurons in the medial septum. In the present report, it was found that ethanol, when applied locally via electro-osmosis, potently inhibited NMDA-evoked neuronal activity in a current-dependent manner in the inferior colliculus and hippocampus. In contrast, locally applied ethanol failed to inhibit NMDA-evoked activity in the lateral septum.

The neuroanatomical specificity of ethanol action on ligand-gated ion channels: a hypothesis.

The studies described will demonstrate that the subunit composition of a GABAA receptor allows ethanol to enhance responses to GABA. Since we have determined that ethanol will influence responses to glycine, nicotine and NMDA in some, but not all, neurons with receptors to these agonists, we hypothesize that specific receptor subtypes of these ligand-gated ion channels will be affected by ethanol.

Augmented sensitivity of D1-dopamine receptors in lateral but not medial striatum after 6-hydroxydopamine-induced lesions in the neonatal rat.

Lesioning of neonatal rats with the neurotoxin 6-hydroxydopamine (6-OHDA) reduced striatal dopamine (DA) levels to 3% of control levels and produced marked increases in the behavioral effects of the selective D1-DA receptor agonist SKF-38393 in these animals when tested as adults. However, no differences were observed, either in basal or D1-DA-stimulated striatal cAMP formation or in forskolin-stimulated or GTP-stimulated cAMP production, between control and lesioned animals. C-fos-like immunoreactivity after SKF-38393 was significantly greater in dorsolateral vs.

Comparison of the D1-dopamine agonists SKF-38393 and A-68930 in neonatal 6-hydroxydopamine-lesioned rats: behavioral effects and induction of c-fos-like immunoreactivity.

Administration of the selective D1-dopamine receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF-38393) to neonatal 6-hydroxydopamine-lesioned rats results in profound behavioral manifestations and induction of striatal c-fos-like immunoreactivity. The full D1-dopamine agonist I,[R,S]1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl-1H-2-benzopyran hydrochloride (A-68930), like SKF-38393, produced a dose-dependent, D1-selective increase in locomotor activity and striatal c-fos-like immunoreactivity. These responses were antagonized by a D1-dopamine antagonist, but not by a D2-dopamine antagonist.

Ethanol potentiates gamma-aminobutyric acid-mediated inhibition in the inferior colliculus: evidence for local ethanol/gamma-aminobutyric acid interactions.

The effect of ethanol on gamma-aminobutyric acid (GABA)-mediated inhibition of neurons of the inferior collicular cortex (IC) was investigated. Systemic administration of 0.5 g/kg ethanol, but not 0.

Dopamine electrophysiology of ventral pallidal/substantia innominata neurons: comparison with the dorsal globus pallidus.

The ventral pallidum/substantia innominata (VP/SI) is an infracommissural extension of the dorsal globus pallidus (GP). Functional studies suggest that the VP/SI is indirectly influenced by dopamine (DA) via inputs from dopaminoceptive regions. However, recent anatomical evidence indicates a direct dopaminergic projection to the VP/SI, but the physiologic and pharmacologic consequences of this input have not been evaluated.