Biomedical subjects

Scott C Steffensen

Publications and source records attributed to Scott C Steffensen.

5 recordsLinked to original sources

PubMed2006

Contingent and non-contingent effects of heroin on mu-opioid receptor-containing ventral tegmental area GABA neurons.

Opiate activation of mu-opioid receptors (muORs) in the ventral tegmental area (VTA) modulates gamma-aminobutyric acid (GABA) neurotransmission within the mesocorticolimbic dopamine (DA) reward system. We combined in vivo extracellular electrophysiological recordings in anesthetized and freely behaving rats with intracellular Neurobiotin filling and immunocytochemistry to characterize the effects of opiates on VTA GABA neurons, evaluate their discharge activity during opiate self-administration, and identify the cellular sites for opiate activation. We identified a subpopulation of VTA GABA neurons that was characterized by location, spike discharge profile, activation by microelectrophoretic DA, and response to internal capsule (IC) stimulation. Systemic administration of heroin or microelectrophoretic application of the selective muOR agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) reduced VTA GABA neuron firing rate (heroin IC(50) = 0.35 mg/kg) and was blocked by the muOR antagonist naloxone. Heroin also reduced IC-evoked post-stimulus spike discharges, a manifestation of gap-junction-mediated electrical coupling between VTA GABA neurons. The baseline firing rate of VTA GABA neurons significantly increased (239%) following the acquisition of heroin self-administration behavior and transiently increased during each response for heroin (105%), but decreased (49%) following heroin, similar to non-contingent heroin. Electrophysiologically characterized VTA GABA neurons were filled with Neurobiotin and labeled dendrites contained plasmalemmal muOR immunoreactivity. Dually labeled muOR dendrites contained dendrodendritic appositions characteristic of gap junctions. These findings indicate that inhibition of this population of GABAergic neurons by opiates acting on dendritic muORs has implications for modulation of electrical coupling between VTA GABA neurons and dopamine (DA) neurotransmission in the VTA and terminal field regions.

Action Potentials↗

PubMed2006

Dehydroepiandrosterone sulfate and estrone sulfate reduce GABA-recurrent inhibition in the hippocampus via muscarinic acetylcholine receptors.

Several recent studies have established a role for estrogens in ameliorating specific neurodegenerative disorders, mainly those associated with the cholinergic neurons of the basal forebrain and their targets in the cortex and hippocampus. We have previously demonstrated that endogenous and exogenous application of the neurosteroid dehydroepiandrosterone sulfate (DHEAS) markedly reduces GABA-mediated recurrent inhibition and synchronizes hippocampal unit activity to theta rhythm (Steffensen (1995) Hippocampus 5:320-328). In this study, we evaluated the role of muscarinic receptors in mediating the effects of DHEAS and estrone sulfate (ES), the principal circulating estrogen in humans, on short-latency-evoked potential responses, paired-pulse inhibition (PPI), paired-pulse facilitation, and GABA interneuron activity in the dentate gyrus and CA1 subfields of the rat hippocampus. In situ microelectrophoretic application of the muscarinic M2 subtype cholinergic receptor agonist cis-dioxolane, DHEAS, and ES markedly reduced PPI in the dentate and CA1 that was blocked by the M2 receptor antagonist gallamine. Similar to DHEAS, microelectrophoretic administration of ES increased population spike amplitudes, without increasing excitatory transmission, but this effect was not blocked by gallamine. Microelectrophoretic application of cis-dioxolane and ES markedly increased the firing rate of dentate hilar interneurons and CA1 oriens/alveus interneurons and enhanced their synchrony to hippocampal theta rhythm. These findings suggest that select GABA-modulating neurosteroids and neuroactive estrogen sulfates alter septohippocampal cholinergic modulation of hippocampal GABAergic interneurons mediating recurrent, but not feedforward, inhibition of hippocampal principal cell activity.

Action Potentials↗

PubMed2006

Connexin-36 gap junctions mediate electrical coupling between ventral tegmental area GABA neurons.

Communication between neurons in the mammalian brain is primarily through chemical synapses; however, evidence is accumulating in support of electrical synaptic transmission between some neuronal types in the mature nervous system. The authors have recently demonstrated that the gap junction (GJ) blocker quinidine suppresses stimulus-induced and dopamine-evoked coupling of gamma amino butyric acid (GABA) neurons in the ventral tegmental area (VTA) of mature rats (Stobbs et al., 2004). The aim of this study was to evaluate the role of connexin-36 (Cx36) GJs in mediating electrical coupling between VTA GABA neurons in P50-80 rats in vivo and P25-50 rats in vitro. Single stimulation of the internal capsule (IC) evoked VTA GABA neuron spike couplets in mature rats when activated antidromically, and multiple poststimulus spike discharges (PSDs) when activated with brief high-frequency stimulation of the IC (ICPSDs). The Cx36 GJ blocker mefloquine (30 mg/kg) suppressed VTA GABA neuron ICPSDs in mature freely behaving rats. VTA GABA neurons recorded via whole-cell patch clamp in the midbrain slice preparation of P25-50 rats showed robust expression of Cx36 transcripts when tested with single-cell quantitative reverse transcription polymerase chain reaction. In P50-80 rats, Cx36 protein immunoreactivity was evident in the VTA and surrounding structures. Dye-coupling between VTA neurons was observed following Neurobiotin labeling of VTA GABA neurons, as well as with the fluorochrome Alexa Fluor 488 using real-time video fluorescent microscopy. Thus, mature VTA GABA neurons appear to be connected by electrical synapses via Cx36 GJs, whose coupling is enhanced by corticotegmental input and by dopamine.

Animals↗

PubMed2004

Ethanol suppression of ventral tegmental area GABA neuron electrical transmission involves N-methyl-D-aspartate receptors.

Ventral tegmental area (VTA) GABA neurons are critical substrates modulating the mesocorticolimbic dopamine system implicated in natural and drug reward. The aim of this study was to evaluate the effects of ethanol on glutamatergic and GABAergic modulation of VTA GABA neuron electrical synaptic transmission. We evaluated the effects of systemic ethanol (0.05-2.0 g/kg i.p.), the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801; 0.05-0.2 mg/kg i.v.), the connexin-36 gap junction blocker quinidine (5-20 mg/kg i.v.), the fast-acting barbiturate methohexital (Brevital; 5-10 mg/kg i.v.), and the benzodiazepine chlordiazepoxide (Librium; 5-10 mg/kg i.v.), as well as in situ VTA administration of NMDA and the GABA(A) receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule stimulus-induced poststimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, whereas local NMDA enhanced, and the systemic and local GABA(A) receptor modulators did not significantly alter VTA GABA neuron ICPSDs. Ethanol potentiated dizocilpine inhibition of VTA GABA neuron ICPSDs, but not quinidine inhibition. In situ microelectrophoretic application of dopamine markedly enhanced VTA GABA neuron firing rate (131%), spike duration (124%), and spike coupling, which were blocked by systemic quinidine. These findings indicate that VTA GABA neurons are coupled electrically via gap junctions and that the inhibitory effect of ethanol on electrical transmission is primarily via inhibition of NMDA receptor-mediated excitation, not via enhancement of GABA receptor-mediated inhibition. Thus, the rewarding properties of ethanol may result from inhibitory effects on excitatory glutamatergic neurotransmission between electrically coupled networks of midbrain GABA neurons.

Animals↗

PubMed2002

A novel electroencephalographic analysis method discriminates alcohol effects from those of other sedative/hypnotics.

Here we describe a mathematical and statistical signal processing strategy termed event resolution imaging (ERI). Our principal objective was to determine if the acute intoxicating effects of ethanol on spontaneous EEG activity could be discriminated from those of other sedative/hypnotics. We employed ERI to combine and integrate standard analysis methods to learn multiple signal features of time-varying EEG signals. We recorded cortical EEG, electromyographic activity, and motor activity during intravenous administration of saline, ethanol (1.0 g/kg), chlordiazepoxide (10 mg/kg), pentobarbital (6 mg/kg), heroin (0.3 mg/kg), and methamphetamine (2 mg/kg) administered on separate days in six rats. A blind treatment of one of the drugs was readministered to validate the efficacy of ERI analysis. Significant changes in spontaneous EEG activity produced by all five drugs were detected by ERI analysis with a time resolution of 5-10 s. ERI analysis of spontaneous EEG activity also discriminated, with 90-95% accuracy, an ataxic dose of ethanol versus equivalent ataxic doses of chlordiazepoxide or pentobarbital, as well as the effects of saline, a reinforcing dose of heroin, or a locomotor activating dose of methamphetamine. ERI correctly matched the 'blind drug' as ethanol. These findings indicate that ERI analysis can detect the central nervous system effects of various psychoactive drugs and accurately discriminate the electrocortical effects of select sedative/hypnotics, with similar behavioral endpoints, but with dissimilar mechanisms of action.

Acute Disease↗