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1.
Brain Res ; 906(1-2): 190-7, 2001 Jul 06.
Article in English | MEDLINE | ID: mdl-11430879

ABSTRACT

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).


Subject(s)
Arousal/physiology , Medial Forebrain Bundle/metabolism , Neurons/metabolism , Reward , Self Stimulation/physiology , Ventral Tegmental Area/metabolism , gamma-Aminobutyric Acid/metabolism , Action Potentials/physiology , Animals , Attention/physiology , Behavior, Animal/physiology , Dopamine/metabolism , Electric Stimulation/methods , Male , Medial Forebrain Bundle/cytology , Medial Forebrain Bundle/surgery , Neural Inhibition/physiology , Neurons/cytology , Rats , Rats, Sprague-Dawley , Reaction Time/physiology , Ventral Tegmental Area/cytology
2.
J Neurosci ; 21(5): 1757-66, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11222665

ABSTRACT

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.


Subject(s)
Circadian Rhythm/physiology , Movement/physiology , Neurons/physiology , Ventral Tegmental Area/physiology , gamma-Aminobutyric Acid/metabolism , Action Potentials/physiology , Anesthetics/pharmacology , Animals , Arousal , Electroencephalography , Electromyography , Excitatory Postsynaptic Potentials/physiology , Male , Neurons/cytology , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Sleep/physiology , Sleep Deprivation , Sleep, REM/physiology , Substantia Nigra/cytology , Substantia Nigra/physiology , Ventral Tegmental Area/cytology , Ventral Tegmental Area/drug effects , Wakefulness/physiology
3.
J Pharmacol Exp Ther ; 294(2): 637-47, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10900243

ABSTRACT

Ethanol alters N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid subtype A (GABA(A)) receptor-mediated neurotransmission. We have previously demonstrated that GABA(B) receptor blockade uncovers ethanol enhancement of GABA(A) responses in the hippocampus. Therefore, we evaluated in vivo and in vitro the role of GABA(B) receptors in ethanol-induced inhibition of neuronal activity as well as NMDA responses in the hippocampus, ventral tegmental area (VTA), and nucleus accumbens (NAcc), three brain areas with known sensitivity to low doses of ethanol. In vivo, in situ microelectrophoretic application of ethanol enhanced inhibition of VTA GABA neuron firing rate by the GABA(B) agonist baclofen and reduced inhibition of VTA GABA firing rate by the GABA(A) agonist muscimol. The GABA(B) antagonist CGP35348 blocked baclofen- and ethanol-induced, but not muscimol-induced, reduction of NMDA-activated firing of hippocampal hilar mossy cells, hilar interneurons, and VTA GABA neurons, as well as ethanol inhibition of NMDA receptor-sensitive, amygdala-driven NAcc neurons. We performed in vitro studies in NAcc slices to evaluate the mechanism of GABA(B) receptor-mediated ethanol inhibition of NMDA neurotransmission. In the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the GABA(A) receptor antagonist bicuculline, superfusion of the GABA(B) antagonist CGP55845 blocked ethanol (66 mM) inhibition of evoked NMDA receptor-mediated excitatory postsynaptic potentials. However, CGP55845 did not significantly affect ethanol inhibition of NMDA currents produced by pressure application of NMDA or non-NMDA glutamatergic excitatory postsynaptic potentials evoked in the presence of the bicuculline and the NMDA antagonist DL-2-amino-5-phosphonovalerate. Taken together, these findings suggest that the sensitivity of NMDA receptor-mediated neurotransmission to ethanol is regulated by GABA(B) receptors, possibly at presynaptic sites.


Subject(s)
Brain/drug effects , Central Nervous System Depressants/toxicity , Ethanol/toxicity , N-Methylaspartate/antagonists & inhibitors , Receptors, GABA-B/physiology , Receptors, Presynaptic/physiology , Amygdala/physiology , Animals , Brain/physiology , Central Nervous System Depressants/antagonists & inhibitors , Drug Synergism , Ethanol/antagonists & inhibitors , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , GABA Antagonists/pharmacology , GABA-B Receptor Antagonists , Hippocampus/drug effects , Hippocampus/physiology , Male , Mossy Fibers, Hippocampal/drug effects , Mossy Fibers, Hippocampal/physiology , N-Methylaspartate/pharmacology , Neurons/drug effects , Neurons/physiology , Nucleus Accumbens/drug effects , Nucleus Accumbens/physiology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Receptors, Presynaptic/antagonists & inhibitors , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/physiology
4.
Brain Res ; 847(2): 186-95, 1999 Nov 20.
Article in English | MEDLINE | ID: mdl-10575087

ABSTRACT

Many of the molecular components constituting the exocytotic machinery responsible for neurotransmitter release have been identified, yet the precise role played by these proteins in synaptic transmission, and their impact on neural function, has not been resolved. The mouse mutation coloboma is a contiguous gene defect that leads to electrophysiological and behavioral deficits and includes the gene-encoding SNAP-25, an integral component of the synaptic vesicle-docking/fusion core complex. The involvement of SNAP-25 in the hyperactive behavior of coloboma mice, which can be ameliorated by the indirect dopaminergic agonist, amphetamine, has been demonstrated by genetic rescue using a SNAP-25 transgene. Coloboma mice also exhibit increased recurrent inhibition, reduced theta rhythm by tail-pinch and reduced long-term potentiation in the hippocampal dentate gyrus that, as the hyperkinesis seen in these mutants suggests, may reflect impaired monoaminergic modulation. We sought to identify neurophysiological correlates of the rescued hyperactivity within hippocampal synaptic circuitry of SNAP-25 transgenic coloboma mutant mice. In contrast to the differences between coloboma and wild-type mice, there was no significant difference in the duration or amplitude of theta rhythmic activity (4-6 Hz) induced by tail-pinch (10 s), afferent-evoked field potentials, or paired-pulse responses recorded in the dentate gyrus of SNAP-25 transgenic coloboma and wild-type mice. Amphetamine (3.0 mg/kg, i.p.) produced disinhibition of dentate paired-pulse responses in both SNAP-25 transgenic and wild-type mice but increased inhibition in non-transgenic coloboma mice. These findings support the hypothesis that alteration of monoaminergic neurotransmission, which can be reversed by the indirect agonist, amphetamine, is particularly sensitive to alterations in the expression of SNAP-25.


Subject(s)
Evoked Potentials/genetics , Hippocampus/metabolism , Hyperkinesis/genetics , Membrane Proteins , Nerve Tissue Proteins/genetics , Synaptic Transmission/genetics , Theta Rhythm , Amphetamine/pharmacology , Animals , Central Nervous System Stimulants/pharmacology , Dopamine/genetics , Dopamine/metabolism , Evoked Potentials/drug effects , Female , Hippocampus/drug effects , Hyperkinesis/metabolism , Male , Mice , Mice, Mutant Strains , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Synaptic Transmission/drug effects , Synaptosomal-Associated Protein 25 , Theta Rhythm/drug effects
5.
J Pharmacol Exp Ther ; 291(3): 1045-53, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10565823

ABSTRACT

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.


Subject(s)
Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Neurons/drug effects , Ventral Tegmental Area/drug effects , gamma-Aminobutyric Acid/physiology , Adaptation, Physiological/drug effects , Administration, Inhalation , Anesthesia , Animals , Central Nervous System Depressants/administration & dosage , Central Nervous System Depressants/blood , Ethanol/administration & dosage , Ethanol/blood , Injections, Intraperitoneal , Male , Microelectrodes , Rats , Rats, Sprague-Dawley , Ventral Tegmental Area/cytology
6.
Am J Pathol ; 154(4): 1181-91, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10233856

ABSTRACT

Chemokines may be important in the control of leukocytosis in inflammatory disorders of the central nervous system. We studied cerebral chemokine expression during the evolution of diverse neuroinflammatory disorders in transgenic mice with astrocyte glial fibrillary acidic protein-targeted expression of the cytokines IL-3, IL-6, or IFN-alpha and in mice with experimental autoimmune encephalomyelitis. Distinct chemokine gene expression patterns were observed in the different central nervous system inflammatory models that may determine the phenotype and perhaps the functions of the leukocytes that traffic into the brain. Notably, high expression of C10 and C10-related genes was found in the cerebellum and spinal cord of GFAP-IL3 mice with inflammatory demyelinating disease and in mice with experimental autoimmune encephalomyelitis. In both these neuroinflammatory models, C10 RNA and protein expressing cells were predominantly macrophage/microglia and foamy macrophages present within demyelinating lesions as well as in perivascular infiltrates and meninges. Intracerebroventricular injection of recombinant C10 protein promoted the recruitment of large numbers of Mac-1(+) cells and, to a much lesser extent, CD4(+) lymphocytes into the meninges, choroid plexus, ventricles, and parenchyma of the brain. Thus, C10 is a prominent chemokine expressed in the central nervous system in experimental inflammatory demyelinating disease that, we show, also acts as a potent chemotactic factor for the migration of these leukocytes to the brain.


Subject(s)
Central Nervous System Diseases/metabolism , Cytokines/biosynthesis , Encephalomyelitis, Autoimmune, Experimental/immunology , Leukocytes/immunology , Age Factors , Animals , Central Nervous System Diseases/immunology , Cerebellum/metabolism , Chemokines/biosynthesis , Chemokines/genetics , Chemokines, CC , Chemotaxis/immunology , Cytokines/pharmacology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Gene Expression Regulation/immunology , Glial Fibrillary Acidic Protein/genetics , Interferon-gamma/genetics , Interleukin-3/genetics , Interleukin-6/genetics , Macrophage-1 Antigen/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Organ Specificity , RNA/genetics , RNA/metabolism , Spinal Cord/metabolism
7.
J Neurosci ; 18(19): 8003-15, 1998 Oct 01.
Article in English | MEDLINE | ID: mdl-9742167

ABSTRACT

GABAergic neurons in the ventral tegmental area (VTA) play a primary role in local inhibition of mesocorticolimbic dopamine (DA) neurons but are not physiologically or anatomically well characterized. We used in vivo extracellular and intracellular recordings in the rat VTA to identify a homogeneous population of neurons that were distinguished from DA neurons by their rapid-firing, nonbursting activity (19.1 +/- 1.4 Hz), short-duration action potentials (310 +/- 10 microseconds), EPSP-dependent spontaneous spikes, and lack of spike accommodation to depolarizing current pulses. These non-DA neurons were activated both antidromically and orthodromically by stimulation of the internal capsule (IC; conduction velocity, 2.4 +/- 0.2 m/sec; refractory period, 0.6 +/- 0.1 msec) and were inhibited by stimulation of the nucleus accumbens septi (NAcc). Their firing rate was moderately reduced, and their IC-driven activity was suppressed by microelectrophoretic application or systemic administration of NMDA receptor antagonists. VTA non-DA neurons were recorded intracellularly and showed relatively depolarized resting membrane potentials (-61.9 +/- 1.8 mV) and small action potentials (68.3 +/- 2.1 mV). They were injected with neurobiotin and shown by light microscopic immunocytochemistry to be multipolar cells and by electron microscopy to contain GABA but not the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Neurobiotin-filled dendrites containing GABA received asymmetric excitatory-type synapses from unlabeled terminals and symmetric synapses from terminals that also contained GABA. These findings indicate that VTA non-DA neurons are GABAergic, project to the cortex, and are controlled, in part, by a physiologically relevant NMDA receptor-mediated input from cortical structures and by GABAergic inhibition.


Subject(s)
Neurons, Afferent/physiology , Neurons, Efferent/physiology , Ventral Tegmental Area/cytology , gamma-Aminobutyric Acid/physiology , 2-Amino-5-phosphonovalerate/pharmacology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Biotin/analogs & derivatives , Dopamine/physiology , Electrophysiology , Excitatory Amino Acid Antagonists/pharmacology , Extracellular Space/chemistry , Extracellular Space/enzymology , Male , Microscopy, Electron , Neural Inhibition/physiology , Neurons, Afferent/chemistry , Neurons, Afferent/ultrastructure , Neurons, Efferent/chemistry , Neurons, Efferent/ultrastructure , Nucleus Accumbens/cytology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/analysis , Synapses/chemistry , Synapses/enzymology , Synapses/ultrastructure , Tyrosine 3-Monooxygenase/analysis , gamma-Aminobutyric Acid/analysis
8.
Brain Res ; 716(1-2): 192-6, 1996 Apr 15.
Article in English | MEDLINE | ID: mdl-8738238

ABSTRACT

Ethanol intoxication produces deficits in the acquisition of new information and blocks the induction of hippocampal long-term potentiation (LTP), a candidate neurophysiological correlate for learning and memory. We report that, in adult rats, local application of the dopamine (DA) D1 receptor antagonist SCH-23390 into the lateral septum (LS) blocks ethanol-induced suppression of LTP and alterations of paired-pulse responses in the dentate gyrus. This suggests a primary role for an extra-hippocampal circuit and neurotransmitter system mediating ethanol's ability to suppress LTP.


Subject(s)
Benzazepines/pharmacology , Central Nervous System Depressants/pharmacology , Dopamine Antagonists/pharmacology , Ethanol/pharmacology , Hippocampus/physiology , Long-Term Potentiation/drug effects , Animals , Benzazepines/administration & dosage , Central Nervous System Depressants/antagonists & inhibitors , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Dopamine/physiology , Dopamine Antagonists/administration & dosage , Hippocampus/drug effects , Iontophoresis , Male , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/antagonists & inhibitors
9.
Synapse ; 22(3): 281-9, 1996 Mar.
Article in English | MEDLINE | ID: mdl-9132997

ABSTRACT

Mice heterozygous for the semidominant mutation coloboma (Cm/+) display several distinct pathologies including head bobbing, ophthalmic deformation, and locomotor hyperactivity. The Cm/+ mutation comprises a contiguous gene defect which encompasses deletion of the gene Snap encoding the presynaptic nerve terminal protein SNAP-25 that is an integral component of the synaptic vesicle docking and fusion complex. Indeed, SNAP-25 is required for axonal growth and for the regulated release of neurotransmitters at the synaptic cleft. As an extension of our studies on the behavioral deficits exhibited by these mutants, including evaluation of the hyperkinesis and dopamine-related behavioral pharmacology that might be related to attention-deficit hyperactivity disorder in humans, we have studied spontaneous electroencephalographic and evoked potential recordings in the dentate gyrus of halothane-anesthetized Cm/+ and normal (+/+) littermates to evaluate potential physiological abnormalities of synaptic function in these mice. While sensory activation elicited by brief (10 sec) tail-pinch produced 1-2 min of theta rhythmic activity in +/+ mice, theta induction was markedly reduced in Cm/+ mice. There were no significant differences in dentate afferent-evoked population excitatory postsynaptic potential (pEPSP) slopes, pEPSP facilitation, or population spike (PS) amplitudes; however, paired-pulse inhibition of dentate PS amplitudes was significantly increased in Cm/+ mice. Furthermore, although brief high-frequency stimulation of the perforant path produced robust long-term potentiation (LTP) of synaptic responses in the dentate gyrus of +/+ mice, LTP was attenuated in Cm /+ mice. It has been previously demonstrated that dopamine (DA) neurotransmission is essential for induction of one type of hippocampal theta rhythm and also may modulate hippocampal LTP, suggesting that alterations in DA synaptic transmission may underlie the behavioral abnormalities, in particular the hyperactivity, associated with Cm/+ mutant mice.


Subject(s)
Gene Deletion , Hippocampus/physiology , Membrane Proteins , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/physiology , Neuronal Plasticity/genetics , Neuronal Plasticity/physiology , Animals , Dentate Gyrus/physiology , Electric Stimulation , Electroencephalography , Evoked Potentials/physiology , Extracellular Space/physiology , Female , Long-Term Potentiation/genetics , Long-Term Potentiation/physiology , Male , Mice , Mice, Neurologic Mutants , Neurons, Afferent/physiology , Physical Stimulation , Rats , Synapses/physiology , Synaptosomal-Associated Protein 25 , gamma-Aminobutyric Acid/physiology
11.
J Neurosci ; 16(1): 220-8, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8613788

ABSTRACT

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.


Subject(s)
Dentate Gyrus/cytology , Dentate Gyrus/virology , Lymphocytic Choriomeningitis/physiopathology , Neurons/physiology , Animals , Antigens, Viral/analysis , Cell Count , Dizocilpine Maleate/pharmacology , Evoked Potentials/physiology , Excitatory Amino Acid Antagonists/pharmacology , Interneurons/chemistry , Lymphocytic choriomeningitis virus/immunology , Male , Membrane Potentials/physiology , Neurons/virology , Parvalbumins/analysis , Rats , Rats, Inbred Lew , Theta Rhythm , Time Factors
12.
Brain Res ; 686(2): 134-42, 1995 Jul 24.
Article in English | MEDLINE | ID: mdl-7583279

ABSTRACT

Electrophoretic administration of the mu selective opioid agonist [D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO) in the dentate gyrus of the hippocampus acutely produces a marked increase in the responsiveness of dentate granule cells to perforant path stimulation. This can be measured by an increase in the primary population spike (PS) amplitude and by disinhibition in the paired-pulse (PP) paradigm. Concomitantly, the spontaneous single unit activity of interneurons is usually inhibited. We have observed that after prolonged (usually 10-20 min) local (electrophoretic) administration of DAMGO, a second, late effect is noted, suggesting acute desensitization. There is a loss of the disinhibition seen in the PP paradigm while the primary PS shows only some increased variability in response to stimulation. Furthermore, in a time course parallel to the loss of disinhibition, single cell activity initially inhibited by DAMGO appears to lose its responsiveness. Pretreatment with kappa or delta opioid agonists, or with GABA agonists and antagonists, does not affect the development of this desensitization suggesting selective involvement of the mu receptor. We further propose a regional specificity within the hippocampus since we are unable to detect evidence of desensitization to opioid in CA1 using the same techniques.


Subject(s)
Enkephalins/pharmacology , Hippocampus/drug effects , Animals , Drug Tolerance , Electrophoresis , Electrophysiology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/administration & dosage , Hippocampus/cytology , Hippocampus/physiology , Male , Muscimol/pharmacology , Neurons/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/agonists , Receptors, Opioid, mu/agonists
13.
Hippocampus ; 5(4): 320-8, 1995.
Article in English | MEDLINE | ID: mdl-8589795

ABSTRACT

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.


Subject(s)
Dehydroepiandrosterone/pharmacology , Hippocampus/physiology , Neural Inhibition/drug effects , Neurons/physiology , Theta Rhythm/drug effects , 3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Androstenedione/pharmacology , Animals , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Dihydrotestosterone/analogs & derivatives , Dihydrotestosterone/pharmacology , Enzyme Inhibitors/pharmacology , Evoked Potentials/drug effects , Evoked Potentials/physiology , Extracellular Space/drug effects , Hippocampus/drug effects , Iontophoresis , Male , Rats , Rats, Sprague-Dawley , Synaptic Transmission/drug effects , gamma-Aminobutyric Acid/physiology
14.
Brain Res Mol Brain Res ; 25(3-4): 286-96, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7808228

ABSTRACT

We isolated a cDNA clone, named BSPL, that encodes a brain-specific dipeptidyl peptidase-like protein with 30% identity and 50% similarity to CD26, a lymphocyte membrane antigen involved in T-cell activation. BSPL lacks, however, the catalytic residue responsible for peptidase activity. The expression of BSPL is widespread throughout the CNS but restricted to neurons under normal conditions. Twenty-four hours after injection of kainic acid into the hippocampus, a dramatic increase in the concentration of BSPL mRNA was detected by in situ hybridization in the CA3 region of the injected hemisphere as compared with the contralateral hemisphere or sham-injected animals. An increase in the steady-state level of BSPL mRNA concentration was also found following tetanic stimulation of the perforant path to produce LTP in granule cells of the dentate gyrus. Hybridization signals could be detected in dendritic processes of pyramidal neurons and in some glial cells upon either type of stimulation. These data suggest that BSPL may be involved in synaptic plasticity.


Subject(s)
Dipeptidyl Peptidase 4/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases , Hippocampus/metabolism , Nerve Tissue Proteins/genetics , RNA, Messenger/genetics , Synapses/physiology , Amino Acid Sequence , Animals , Base Sequence , Cell Membrane/physiology , Cloning, Molecular , Electric Stimulation , Genetic Code , Kainic Acid , Male , Molecular Sequence Data , RNA, Messenger/isolation & purification , Rats , Rats, Sprague-Dawley
15.
Neuropharmacology ; 33(8): 963-75, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7845552

ABSTRACT

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.


Subject(s)
Hippocampus/cytology , Neurons/drug effects , Opioid Peptides/pharmacology , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer , Analgesics/pharmacology , Animals , Electric Stimulation , Electrophysiology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/pharmacology , Evoked Potentials/drug effects , Hippocampus/drug effects , Interneurons/drug effects , Male , Morphine/pharmacology , Naloxone/pharmacology , Pyrrolidines/pharmacology , Rats , Rats, Sprague-Dawley
16.
Brain Res ; 652(1): 149-53, 1994 Jul 25.
Article in English | MEDLINE | ID: mdl-7953712

ABSTRACT

Transgenic mice expressing the cytokine interleukin-6 exhibit distinctive hippocampal interneuron pathology and behavioral seizures. Electroencephalographic recordings from these mice revealed anomalous hippocampal paroxysmal discharges and suppressed theta rhythm. Analysis of hippocampal field responses evoked by monosynaptic afferent stimulation revealed a site-specific increase in recurrent inhibition in the dentate gyrus. In addition, the cholinergic component of septohippocampal conditioning of dentate-evoked activity was absent in the transgenic mice. These results indicate that overexpression of interleukin-6 selectively disrupts cholinergic transmission by inducing a functional pathophysiology of hippocampal cholinoceptive target neurons.


Subject(s)
Brain Chemistry/physiology , Hippocampus/physiopathology , Interleukin-6/biosynthesis , Animals , Electroencephalography , Electrophysiology , Glial Fibrillary Acidic Protein/biosynthesis , Interleukin-6/genetics , Mice , Mice, Transgenic , Synaptic Transmission/physiology , Theta Rhythm
17.
Synapse ; 17(2): 84-91, 1994 Jun.
Article in English | MEDLINE | ID: mdl-8091305

ABSTRACT

Ethanol selectively alters hippocampal dentate physiology, in part by increasing recurrent inhibition and suppressing long-term potentiation (LTP), a result of ethanol modulation of subcortical inputs. One of these inputs includes the ventral tegmental area (VTA) in the midbrain, whose neurons have been shown to discharge faster following systemic ethanol. To further understand how subcortical inputs regulate hippocampal physiology and their modulation by ethanol, we studied the effects of acute intoxicating levels of ethanol on VTA facilitation of the perforant path to dentate (PPD) responses. Furthermore, to test the role of the VTA on known pharmacological effects of ethanol on hippocampal physiology, we studied the effects of disruption of the VTA-dentate inpute on ethanol actions on recurrent inhibition. Stimulation of the perforant path produced well-characterized evoked responses in the ipsilateral dentate gyrus. Whereas VTA stimulation had no effect on PPD population EPSPs, VTA conditioning markedly increased perforant path-evoked PS amplitudes (140%). The maximum facilitation was observed at VTA conditioning intervals of 30-40 ms. PS amplitudes returned to baseline levels immediately following cessation of VTA conditioning. Intraperitoneal injections of ethanol (1.2 g/kg) markedly decreased VTA facilitation of PPD PS amplitudes. Lesions of the VTA blocked the ethanol-mediated increase in PPD paired-pulse inhibition. These results demonstrate that, to a great extent, the effects of intoxicating doses of ethanol on hippocampal physiology are mediated by remote pharmacological effects on the ventral tegmental area, whose direct or indirect influences on dentate physiology are described.


Subject(s)
Ethanol/pharmacology , Hippocampus/physiology , Ventral Tegmental Area/drug effects , Animals , Electric Stimulation , Evoked Potentials/drug effects , Hippocampus/anatomy & histology , Hippocampus/drug effects , Male , Neural Pathways/drug effects , Rats , Rats, Sprague-Dawley , Ventral Tegmental Area/anatomy & histology , Ventral Tegmental Area/physiology
18.
Alcohol Clin Exp Res ; 17(3): 655-9, 1993 Jun.
Article in English | MEDLINE | ID: mdl-8333597

ABSTRACT

Systemic ethanol increases synaptic inhibition and suppresses long-term potentiation (LTP) in the dentate gyrus of the rat hippocampus. Local application of ethanol directly into the dentate gyrus of anesthetized rats increased the perforant path to dentate feed-forward inhibition, but had no effect on LTP. Local application of ethanol to the medial septum, a subcortical structure with major input to the dentate, increased recurrent inhibition. Selective disruption of septodentate input produced by lesions of the septohippocampal nucleus blocked the effects of systemic ethanol on LTP. These findings are the first to demonstrate that septodentate input is necessary for ethanol to increase recurrent inhibition and suppress LTP in the dentate gyrus and suggest an important role for extrahippocampal modulation of both short- and long-term plasticity in the hippocampus.


Subject(s)
Alcoholic Intoxication/physiopathology , Ethanol/pharmacology , Hippocampus/drug effects , Neural Inhibition/drug effects , Neuronal Plasticity/drug effects , Septal Nuclei/drug effects , Afferent Pathways/drug effects , Afferent Pathways/physiopathology , Animals , Brain Mapping , Cerebral Cortex/drug effects , Cerebral Cortex/physiopathology , Dose-Response Relationship, Drug , Hippocampus/physiopathology , Interneurons/drug effects , Interneurons/physiology , Male , Mental Recall/drug effects , Mental Recall/physiology , Neural Inhibition/physiology , Neuronal Plasticity/physiology , Rats , Rats, Sprague-Dawley , Septal Nuclei/physiopathology
19.
Hippocampus ; 2(2): 201-11, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1308183

ABSTRACT

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.


Subject(s)
Chlordiazepoxide/toxicity , Ethanol/toxicity , Hippocampus/drug effects , Neurons/drug effects , Action Potentials/drug effects , Animals , Electric Stimulation , Evoked Potentials/drug effects , Hippocampus/physiology , Male , Neurons/physiology , Pyramidal Tracts/drug effects , Pyramidal Tracts/physiology , Rats , Rats, Sprague-Dawley , Time Factors
20.
Brain Res ; 538(1): 46-53, 1991 Jan 04.
Article in English | MEDLINE | ID: mdl-1850318

ABSTRACT

The effects of microiontophoretically applied baclofen, bicuculline and phaclofen were studied on evoked field responses, paired-pulse (PP) plasticity and single-unit activity of dentate granule cells (DGCs) and CA1 pyramidal cells (PCs) in anesthetized rats. The GABAB agonist, baclofen, increased population spike (PS) amplitudes in the dentate evoked by perforant path stimulation but decreased PS amplitudes in CA1 evoked by Schaffer collateral stimulation, whereas the GABAA antagonist, bicuculline, increased PS amplitudes in both regions. Neither baclofen nor bicuculline had significant effects on dendritically recorded population excitatory postsynaptic potentials (EPSPs) in the dentate or CA1 evoked by stimulation of their respective afferents. Control PP curves in the dentate revealed a triphasic response of inhibition/potentiation/inhibition, whereas control PP curves in CA1 manifested a biphasic response of inhibition/potentiation of test/conditioned PS amplitudes. Baclofen and bicuculline reversed the early and late phases of PP inhibition in the dentate and the early phase of PP inhibition in CA1. The GABAB antagonist, phaclofen, selectively reversed the effects of baclofen on PP inhibition in both the dentate and CA1. Whereas baclofen had no effect, bicuculline incre sed and phaclofen decreased DGC single-unit spontaneous firing rate, while baclofen decreased and bicuculline and phaclofen increased PC firing rate. These results support and extend studies suggesting that GABAergic feedback inhibition of DGCs and PCs is mediated by postsynaptic GABAA receptors and feedback inhibition of PCs is mediated by postsynaptic GABAB receptors. Our results also provide significant new evidence suggesting that postsynaptic inhibition in the dentate is not regulated by GABAB receptors and that feedback and feedforward inhibition of DGCs and PCs is regulated by presynaptic GABAB receptors located on GABAergic interneurons.


Subject(s)
Baclofen/pharmacology , Bicuculline/pharmacology , Hippocampus/physiology , Pyramidal Tracts/physiology , Action Potentials/drug effects , Animals , Baclofen/administration & dosage , Baclofen/analogs & derivatives , Bicuculline/administration & dosage , Electric Stimulation/methods , Evoked Potentials/drug effects , Hippocampus/drug effects , Interneurons/drug effects , Interneurons/physiology , Iontophoresis , Male , Pyramidal Tracts/drug effects , Rats , Rats, Inbred Strains , Receptors, GABA-A/drug effects , Receptors, GABA-A/physiology , Synapses/drug effects , Synapses/physiology
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