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Dopamine neurons in the ventral tegmental area (VTA) have been implicated in rewarded behaviors, including intracranial self-stimulation (ICSS). We demonstrate, in unrestrained rats, that the discharge activity of a homogeneous population of presumed VTA GABA neurons, implicated in cortical arousal, increases before ICSS of the medial forebrain bundle (MFB). These findings suggest that VTA GABA neurons may be involved in the attentive processes related to brain stimulation reward (BSR).

Although mesolimbic dopamine (DA) transmission has been implicated in behavioral and cortical arousal, DA neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are not significantly modulated by anesthetics or the sleep-wake cycle. However, VTA and SN non-DA neurons evince increased firing rates during active wakefulness (AW) and rapid eye movement (REM) sleep, relative to quiet wakefulness. Here we describe the effects of movement, select anesthetics, and the sleep-wake cycle on the activity of a homogeneous population of VTA GABA-containing neurons during normal sleep and after 24 hr sleep deprivation. In freely behaving rats, VTA GABA neurons were relatively fast firing (29 +/- 6 Hz during AW), nonbursting neurons that exhibited markedly increased activity during the onset of discrete movements. Adequate anesthesia produced by administration of chloral hydrate, ketamine, or halothane significantly reduced VTA GABA neuron firing rate and converted their activity into phasic 0.5-2.0 sec ON/OFF periods. VTA GABA neuron firing rate decreased 53% during slow-wave sleep (SWS) and increased 79% during REM, relative to AW; however, the discharging was not synchronous with electrocortical alpha wave activity during AW, delta wave activity during SWS, or gamma wave activity during REM. During deprived SWS, there was a direct correlation between increased VTA GABA neuron slowing and increased delta wave power. These findings indicate that the discharging of VTA GABA neurons correlates with psychomotor behavior and that these neurons may be an integral part of the extrathalamic cortical activating system.

We have recently identified a homogeneous population of gamma-aminobutyric acid (GABA)-containing neurons in the ventral tegmental area (VTA), an area implicated in the reinforcing properties of alcohol. We evaluated the effects of local and systemic ethanol on VTA GABA neuron spontaneous activity in ethanol naive and chronically treated freely behaving rats and in anesthetized rats. In freely behaving animals, acute i.p. administration of 0.2 to 2.0 g/kg ethanol reduced the firing rate of VTA GABA neurons. Chronic administration of 2.0 g/kg i.p. ethanol enhanced baseline activity of VTA GABA neurons and induced tolerance to ethanol inhibition of their firing rate. In a separate group of freely behaving animals, tolerance to 0.4 to 2.0 g/kg i.p. ethanol-induced inhibition of VTA GABA neuron firing rate was observed following 2 weeks of chronic exposure to ethanol vapors producing intermittent blood alcohol levels of 158 mg/100 ml. In acute studies in halothane-anesthetized animals, ethanol applied locally into the VTA decreased the spontaneous firing rate of VTA GABA neurons, whereas systemic ethanol produced an early inhibition followed by a late excitation at 30 to 60 min after the ethanol injection, suggesting that ethanol modulation of an extrinsic input may excite VTA GABA neurons. Tolerance to local ethanol inhibition of VTA GABA neuron firing rate was produced by 2 weeks of chronic exposure to intermittent ethanol vapors. These results demonstrate the marked sensitivity of these neurons to ethanol and suggest that chronic ethanol administration produces selective adaptive circuit responses within the VTA or in extrategmental structures that regulate VTA GABA neuron activity.

Infection of neonatal Lewis rats with lymphocytic choriomeningitis virus (LCMV) produces distinct retinal, cerebellar, and hippocampal neuropathology. To understand the neurophysiological consequences of LCMV-induced hippocampal pathology, we studied evoked monosynaptic potentials and electro-encephalographic (EEG) activity in the dentate gyrus and CA1 and CA3 subfields of the hippocampus in vivo. Lewis rats were inoculated intracerebrally with LCMV at postnatal day 4. In rats studied 84-107 d postinfection, virus was cleared from the dentate gyrus and the number of dentate granule cells was decreased by 70%. No viral antigen or cell loss was apparent in CA1 or CA3. The hippocampal EEG of LCMV-infected rats 84-102 d postinfection was dominated by continuous theta. Although evoked potentials elicited in CA1 and CA3 by monosynaptic afferent stimulation revealed no differences between sham- and LCMV-infected rats, there was a site-specific dissociation of synaptic [population excitatory postsynaptic potential (pEPSP)] and cellular (population spike) responses and a suppression of GABA-mediated recurrent inhibition in the dentate gyrus of LCMV-infected rats. These findings indicate that GABA-mediated inhibition was markedly decreased in LCMV-infected rats. In support of this, parvalbumin-immunoreactive cell bodies and neuronal processes were decreased in LCMV-infected rats, suggesting that a subpopulation of GABA interneurons was affected. These findings indicate that abnormalities in synaptic function persist after clearance of infectious virus from the central nervous system and suggest that decreased inhibition subsequent to pathological sequence in a subpopulation of GABA interneurons may be implicated in the hyperexcitability of dentate granule cells.

Several neurosteroids have proconvulsant and memory-enhancing properties and are potent modulators of the gamma-amino butyric acid (GABA) receptor/chloride-ionophore complex. The effects of in situ microelectrophoretic application of the natural sulfate ester of the neurosteroid dehydroepiandrosterone (DHEAS) on evoked field responses and single-unit activity were evaluated in the dentate gyrus and CA1 hippocampal subfield of halothane-anesthetized rats. The effects of endogenous stimulation of DHEAS by in situ micropressure application of Trilostane ((4 alpha, 5 alpha, 17 beta)-4,5-epoxy-3,17-dihydroxyandrost-2-ene-2- carbonitrile (WIN24540)), an inhibitor of 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), the enzyme that metabolizes DHEAS, on evoked responses and cellular activity in the hippocampus were also investigated. In situ microelectrophoretic application of DHEAS or micropressure application of Trilostane into CA1 markedly increased population excitatory postsynaptic potential (pEPSP) slopes and population spike (PS) amplitudes. Neither DHEAS nor Trilostane altered dentate pEPSP slopes or PS amplitudes, but both increased the amplitude of a late component of the pEPSP. Both DHEAS and Trilostane abolished GABA-mediated paired-pulse inhibition in both the dentate and CA1. In addition, both DHEAS and Trilostane markedly increased the spontaneous firing rate of dentate hilar interneurons (INTs: 256% and 185%), CA1 pyramidal cells (PCs: 95% and 105%), and CA1 oriens/alveus (O/A) interneurons (179% and 85%) and synchronized their firing to hippocampal theta rhythm induced by tail-pinch. These findings indicate that exogenous application and endogenous stimulation of DHEAS modulates hippocampal GABA inhibition in a physiologically relevant manner possibly by entraining hippocampal neurons to theta rhythm.

The mechanism by which endogenous opioid peptides regulate neuronal excitability in the dentate gyrus of the hippocampus remains unclear. We studied the neurophysiologic responses to various receptor-selective opioids, given both iontophoretically and systemically, in anesthetized rats. Single unit action potentials and field potential recordings were taken from electrophysiologically classified dentate granule cells (DGCs) or dentate interneurons (INTs). The mu receptor agonist ([D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO)) increased the responsiveness of DGCs to perforant path stimulation, although it did not induce spontaneous activity in DGCs. We did not see this facilitation with systemic morphine sulfate (MS). However, both DAMGO and MS produced similar, primarily inhibitory, effects on INTs. The responsiveness of an individual INT tended to be related to the cell's location in the dentate gyrus, and to a lesser degree, to its baseline spontaneous discharge frequency. U-50488H, a selective kappa receptor agonist, had little effect on either DGCs or INTs. Our results suggest that mu selective opioids have a complex neuropharmacology in this region involving interaction among different types of INTs to produce an effect on the principal output cells.

Acute intoxicating doses of ethanol-producing blood alcohol levels of 120-200 mg% increase paired-pulse (PP) inhibition in the dentate gyrus of anesthetized rats suggesting that ethanol increases recurrent inhibitory processes (Wiesner, J.B., and S.J. Henriksen (1987) Ethanol enhances recurrent inhibition in the dentate gyrus of the hippocampus. Neurosci. Lett. 79:169-173). To further understanding of the neuronal mechanisms underlying this phenomenon, the authors studied the effects of the benzodiazepine (BZ), chlordiazepoxide, and acute intoxicating levels of ethanol on extracellular field potential recordings and single-unit activity in the dentate gyrus and area CA1 of the hippocampus. In the dentate, ethanol had no effect on population excitatory postsynaptic potential (pEPSP) amplitudes or slopes; decreased population spike (PS) amplitudes (25%); increased PP inhibition; decreased dentate granule cell (DGC) spontaneous activity (58%); had no effect on putative interneuron spontaneous activity; and markedly increased post field potential-evoked interneuron discharges (IDs, 218%). Chlordiazepoxide had no effect on pEPSP amplitudes or slopes or PS amplitudes; increased PP inhibition; decreased DGC (62%) and interneuron (72%) spontaneous activity; and markedly decreased IDs (89%). In CA1, ethanol had no effect on pEPSP amplitudes or slopes; decreased PS amplitudes (26%); had no effect on PP responses; decreased pyramidal cell (PC) spontaneous activity (39%); had no effect on interneuron spontaneous activity; and markedly increased IDs (97%). Chlordiazepoxide had no effect on pEPSP amplitudes or slopes or PS amplitudes; had no effect on PP responses; decreased PC spontaneous activity (41%); and had no effect on interneuron spontaneous activity or IDs. The results suggest that the BZs decrease principal cell excitability by postsynaptic facilitation of inhibitory processes, whereas ethanol decreases principal cell excitability indirectly by increasing the excitability of inhibitory interneurons.