fg-9041 and gabazine

Medial temporal lobe epilepsy (mTLE)-the most common form of focal epilepsy-is defined by recurrent partial seizures originating within the medial temporal lobe. Such seizures are commonly associated with the anterior hippocampus (as opposed to the posterior hippocampus), and refractory to the currently available anti-epileptic drugs (AED) for about one third of patients. Unfortunately, the mechanisms driving seizure generation and AED efficacy along the longitudinal hippocampal axis remain poorly understood. Recently, several groups investigating differences in excitability along the rodent longitudinal hippocampal axis have demonstrated that CA1 pyramidal neurons from the rodent ventral hippocampus (the rodent homolog of the human anterior hippocampus) are intrinsically more excitable than their dorsal counterparts (the rodent homolog of the human posterior hippocampus). This phenotypic difference is accompanied by significant differences in gene expression along the longitudinal hippocampal axis, which include gene products-such as voltage-gated sodium channel β-subunits-known to influence AED efficacy. Given this phenotypic heterogeneity, and the differential expression of gene products known to influence anti-epileptic drug efficacy, we sought to investigate the efficacy of the classical use-dependent sodium channel blocker, carbamazepine, in CA1 pyramidal neurons across the longitudinal hippocampal axis. Accordingly, we performed whole-cell current-clamp recordings on CA1 pyramidal neurons from acute hippocampal slices prepared from the dorsal and ventral hippocampus, and found that acute exposure to 100 μM carbamazepine induced a significantly greater suppression of repetitive firing for dorsal neurons relative to ventral neurons by inducing profound spike frequency adaptation (SFA). Moreover, we observed a small, but significant depolarization of resting membrane potential (RMP) for dorsal neurons (but not ventral neurons), following exposure to carbamazepine. Together, these observations demonstrate that carbamazepine's effect is concentrated in the dorsal hippocampus, which could provide meaningful insight into the side effect profile of carbamazepine (and related anti-epileptic drugs) in non-epileptic tissue, and inform future work investigating the mechanisms of carbamazepine resistance in epileptic tissue.

Topics: Action Potentials; Animals; Anticonvulsants; Carbamazepine; Correlation of Data; Electric Stimulation; Excitatory Amino Acid Antagonists; GABA Antagonists; Hippocampus; In Vitro Techniques; Male; Neural Inhibition; Patch-Clamp Techniques; Pyramidal Cells; Pyridazines; Quinoxalines; Rats; Rats, Sprague-Dawley

Auditory cortex (AC) layer 5B (L5B) contains both corticocollicular neurons, a type of pyramidal-tract neuron projecting to the inferior colliculus, and corticocallosal neurons, a type of intratelencephalic neuron projecting to contralateral AC. Although it is known that these neuronal types have distinct roles in auditory processing and different response properties to sound, the synaptic and intrinsic mechanisms shaping their input-output functions remain less understood. Here, we recorded in brain slices of mouse AC from retrogradely labeled corticocollicular and neighboring corticocallosal neurons in L5B. Corticocollicular neurons had, on average, lower input resistance, greater hyperpolarization-activated current (Ih), depolarized resting membrane potential, faster action potentials, initial spike doublets, and less spike-frequency adaptation. In paired recordings between single L2/3 and labeled L5B neurons, the probabilities of connection, amplitude, latency, rise time, and decay time constant of the unitary EPSC were not different for L2/3→corticocollicular and L2/3→corticocallosal connections. However, short trains of unitary EPSCs showed no synaptic depression in L2/3→corticocollicular connections, but substantial depression in L2/3→corticocallosal connections. Synaptic potentials in L2/3→corticocollicular connections decayed faster and showed less temporal summation, consistent with increased Ih in corticocollicular neurons, whereas synaptic potentials in L2/3→corticocallosal connections showed more temporal summation. Extracellular L2/3 stimulation at two different rates resulted in spiking in L5B neurons; for corticocallosal neurons the spike rate was frequency dependent, but for corticocollicular neurons it was not. Together, these findings identify cell-specific intrinsic and synaptic mechanisms that divide intracortical synaptic excitation from L2/3 to L5B into two functionally distinct pathways with different input-output functions.

Topics: Animals; Animals, Newborn; Auditory Cortex; Auditory Pathways; Excitatory Amino Acid Antagonists; Female; Flavoproteins; GABA Antagonists; In Vitro Techniques; Inferior Colliculi; Male; Mice; Mice, Inbred ICR; Models, Neurological; Nerve Net; Neurons; Patch-Clamp Techniques; Pyridazines; Quinoxalines; Synaptic Potentials; Valine

The cannabinoid receptor type 1 (CB1) and the central nucleus of the amygdala (CeA) are both known to have crucial roles in the processing of fear and anxiety, whereby they appear to be especially involved in the control of fear states. However, in contrast to many other brain regions including the cortical subregions of the amygdala, the existence of CB1 in the CeA remains enigmatic. In this study we show that CB1 is expressed in the CeA of mice and that CB1 in the CeA mediates short-term synaptic plasticity, namely depolarization-induced suppression of excitation (DSE) and inhibition (DSI). Moreover, the CB1 antagonist AM251 increased both excitatory and inhibitory postsynaptic responses in CeA neurons. Local application of AM251 in the CeA in vivo resulted in an acutely increased fear response in an auditory fear conditioning paradigm. Upon application of AM251 in the basolateral nucleus of the amygdala (BLA) in an otherwise identical protocol, no such acute behavioral effects were detected, but CB1 blockade resulted in increased fear responses during tone exposures on the subsequent days. Moreover, we observed that the efficacy of DSE and DSI in the CeA was increased on the day following fear conditioning, indicating that a single tone-shock pairing resulted in changes in endocannabinoid signaling in the CeA. Taken together, our data show the existence of CB1 proteins in the CeA, and their critical role for ensuring short-term adaptation of responses to fearful events, thereby suggesting a potential therapeutic target to accompany habituation-based therapies of post-traumatic symptoms.

Topics: Action Potentials; Adaptation, Psychological; Amygdala; Animals; Behavior, Animal; Cannabinoid Receptor Modulators; Conditioning, Psychological; Electric Stimulation; Endocannabinoids; Excitatory Amino Acid Antagonists; Extinction, Psychological; Fear; GABA Antagonists; Gene Expression Regulation; In Vitro Techniques; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphinic Acids; Piperidines; Propanolamines; Pyrazoles; Pyridazines; Quinoxalines; Receptor, Cannabinoid, CB1; Sensory Receptor Cells; Signal Transduction; Time Factors; Valine

In the mammalian retina, excitatory and inhibitory circuitries enable retinal ganglion cells (RGCs) to signal the occurrence of visual features to higher brain areas. This functionality disappears in certain diseases of retinal degeneration because of the progressive loss of photoreceptors. Recent work in a mouse model of retinal degeneration (rd1) found that, although some intraretinal circuitry is preserved and RGCs maintain characteristic physiological properties, they exhibit increased and aberrant rhythmic activity. Here, extracellular recordings were made to assess the degree of aberrant activity in adult rd1 retinas and to investigate the mechanism underlying such behavior. A multi-transistor array with thousands of densely packed sensors allowed for simultaneous recordings of spiking activity in populations of RGCs and of local field potentials (LFPs). The majority of identified RGCs displayed rhythmic (7-10 Hz) but asynchronous activity. The spiking activity correlated with the LFPs, which reflect an average synchronized excitatory input to the RGCs. LFPs initiated from random positions and propagated across the retina. They disappeared when ionotrophic glutamate receptors or electrical synapses were blocked. They persisted in the presence of other pharmacological blockers, including TTX and inhibitory receptor antagonists. Our results suggest that excitation-transmitted laterally through a network of electrically coupled interneurons-leads to large-scale retinal network oscillations, reflected in the rhythmic spiking of most rd1 RGCs. This result may explain forms of photopsias reported by blind patients, while the mechanism involved should be considered in future treatment strategies targeting the disease of retinitis pigmentosa.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Age Factors; Animals; Carbenoxolone; Cyclooxygenase Inhibitors; Disease Models, Animal; Evoked Potentials, Visual; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Gap Junctions; Glutamic Acid; Glycine; In Vitro Techniques; Light; Male; Meclofenamic Acid; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Neurologic Mutants; Nerve Net; Neural Inhibition; Periodicity; Pyridazines; Quinoxalines; Retinal Degeneration; Retinal Rod Photoreceptor Cells; Sodium Channel Blockers; Statistics as Topic; Tetrodotoxin

GABA, the main inhibitory transmitter in adulthood, early in postnatal development exerts a depolarizing and excitatory action. This effect, which results from a high intracellular chloride concentration ([Cl(-)](i)), promotes neuronal growth and synaptogenesis. During the second postnatal week, the developmental regulated expression of the cation-chloride cotransporter KCC2 accounts for the shift of GABA from the depolarizing to the hyperpolarizing direction. Changes in chloride homeostasis associated with high [Cl(-)](i) have been found in several neurological disorders, including temporal lobe epilepsy. Here, we report that, in adult transgenic mice engineered to express recombinant neutralizing anti-nerve growth factor antibodies (AD11 mice), GABA became depolarizing and excitatory. AD11 mice exhibit a severe deficit of the cholinergic function associated with an age-dependent progressive neurodegenerative pathology resembling that observed in Alzheimer patients. Thus, in hippocampal slices obtained from 6-month-old AD11 (but not wild-type) mice, the GABA(A) agonist isoguvacine significantly increased the firing of CA1 principal cells and, at the network level, the frequency of multiunit activity recorded with extracellular electrodes. In addition, in AD11 mice, the reversal of GABA(A)-mediated postsynaptic currents and of GABA-evoked single-channel currents were positive with respect to the resting membrane potential as estimated in perforated patch and cell attached recordings, respectively. Real-time quantitative reverse transcription-PCR and immunocytochemical experiments revealed a reduced expression of mRNA encoding for Kcc2 and of the respective protein. This novel mechanism may represent a homeostatic response that counterbalances within the hippocampal network the Alzheimer-like neurodegenerative pathology found in AD11 mice.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antibodies, Neutralizing; Biophysics; Bumetanide; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Ion Channel Gating; Isonicotinic Acids; K Cl- Cotransporters; Mice; Mice, Transgenic; Nerve Growth Factor; Neurons; Patch-Clamp Techniques; Pyridazines; Quinoxalines; Receptors, Nicotinic; RNA, Messenger; Sodium Potassium Chloride Symporter Inhibitors; Symporters

Endocannabinoids control hippocampal inhibitory synaptic transmission through activation of presynaptic CB(1) receptors. During depolarization-induced suppression of inhibition (DSI), endocannabinoids are synthesized upon postsynaptic depolarization. The endocannabinoid 2-arachidonoylglycerol (2-AG) may mediate hippocampal DSI. Currently, the best studied pathway for biosynthesis of 2-AG involves the enzyme diacylglycerol lipase (DAGL). However, whether DAGL is necessary for hippocampal DSI is controversial and was not systematically addressed. Here, we investigate DSI at unitary connections between CB(1) receptor-containing interneurons and pyramidal neurons in CA1. We found that the novel DAGL inhibitor OMDM-188, as well as the established inhibitor RHC-80267, did not affect DSI. As reported previously, effects of the DAGL inhibitor tetrahydrolipstatin depended on the application method: postsynaptic intracellular application left DSI intact, while incubation blocked DSI. We show that all DAGL inhibitors tested block slow self-inhibition in neocortical interneurons, which involves DAGL. We conclude that DAGL is not involved in DSI at unitary connections in hippocampus.

Topics: Animals; Animals, Newborn; Benzoxazines; Cyclohexanones; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; GABA Antagonists; Green Fluorescent Proteins; Hippocampus; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Lipoprotein Lipase; Lysine; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Naphthalenes; Neocortex; Neural Inhibition; Neurons; Pyridazines; Quinoxalines; Receptor, Cannabinoid, CB1; Valine

Long-term potentiation (LTP) of parallel fiber-Purkinje cell (PF-PC) synapses in the cerebellum has been suggested to underlie aspects of motor learning. Previous in vitro studies have primarily used low frequency PF stimulation conditioning paradigms to generate either presynaptic PF-PC LTP (4-8 Hz) or postsynaptic PF-PC LTP (1 Hz). Little is known about the conditions that evoke PF-PC LTP in vivo. High frequency stimulation in vivo increases PC responsiveness to peripheral stimuli; however, neither the site of action nor the signaling pathways involved have been examined. Using flavoprotein autofluorescence optical imaging in the FVB mouse in vivo, this report describes that a conditioning stimulation consisting of a high frequency burst of PF stimulation (100 Hz, 15 pulse trains every 3 s for 5 min) evokes a long-term increase in the response to PF stimulation. Following the conditioning stimulation, the response to PF stimulation increases over 20 min to approximately 130% above baseline and this potentiation persists for at least 2 h. Field potential recordings of the responses to PF stimulation show that the postsynaptic component is potentiated but the presynaptic, parallel fiber volley is not. Paired-pulse facilitation does not change after the conditioning stimulation, suggesting the potentiation occurs postsynaptically. Blocking non-NMDA (N-methyl-d-aspartic acid) ionotropic glutamate receptors with DNQX (6,7-dinitroquinoxaline-2,3-dione disodium salt, 50 muM, bath application) during the conditioning stimulation has no effect on the long-term increase in fluorescence. However, blocking subtype I metabotropic glutamate receptors (mGLuR(1)) with LY367385 (200 muM) during the conditioning stimulation abolishes the long-term increase in fluorescence. Blocking GABAergic neurotransmission is not required to evoke this long-term potentiation. Blocking GABA(A) receptors reduces but does not eliminate the long-term potentiation. Therefore, this study demonstrates that high frequency PF stimulation generates long-term potentiation of PF-PC synapses in vivo. This novel form of LTP is generated primarily postsynaptically and is mediated by mGluR(1) receptors.

Topics: Animals; Benzoates; Biophysics; Cerebellar Cortex; Diagnostic Imaging; Dose-Response Relationship, Drug; Electric Stimulation; Excitatory Amino Acid Antagonists; GABA Antagonists; Glycine; Long-Term Potentiation; Male; Mice; Mice, Inbred Strains; Nerve Fibers; Optics and Photonics; Purkinje Cells; Pyridazines; Quinoxalines

In the few days prior to eye-opening in mice, the excitatory drive underlying waves switches from cholinergic to glutamatergic. Here, we describe the unique synaptic and spatiotemporal properties of waves generated by the retina's glutamatergic circuits. First, knockout mice lacking vesicular glutamate transporter type 1 do not have glutamatergic waves, but continue to exhibit cholinergic waves, demonstrating that the two wave-generating circuits are linked. Second, simultaneous outside-out patch and whole-cell recordings reveal that retinal waves are accompanied by transient increases in extrasynaptic glutamate, directly demonstrating the existence of glutamate spillover during waves. Third, the initiation rate and propagation speed of retinal waves, as assayed by calcium imaging, are sensitive to pharmacological manipulations of spillover and inhibition, demonstrating a role for both signaling pathways in shaping the spatiotemporal properties of glutamatergic retinal waves.

Topics: Amino Acid Transport Systems, Acidic; Animals; Animals, Newborn; Aspartic Acid; Calcium; Dihydro-beta-Erythroidine; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; GABA Antagonists; Glutamic Acid; In Vitro Techniques; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; N-Methylaspartate; Neural Inhibition; Nicotinic Antagonists; Patch-Clamp Techniques; Pyridazines; Quinoxalines; Retinal Ganglion Cells; Synapses; Synaptic Transmission; Time Factors; Valine; Vesicular Glutamate Transport Protein 1

Mechanisms that control neuronal gain allow for adaptive rescaling to synaptic inputs of varying strengths or frequencies. Here, we show that unitary IPSPs (uIPSPs) modulate gain and unitary EPSP (uEPSP)-action potential coupling in mossy cells (MCs) from rat hippocampal slices. Mossy fibre-evoked uEPSCs were large, facilitated and were suppressed by the group II metabotropic glutamate agonist LY354740. Conversely, uIPSCs were smaller, depressed and were not affected by LY354740, but exerted strong inhibitory control over uEPSP-action potential coupling. The IPSC reversal potential was determined by gramicidin perforated patch recordings to be -65.3 +/- 5.0 mV, lying between the resting membrane potential (-75.3 +/- 1.1 mV) and the action potential threshold (-56.5 +/- 2.4 mV). When applied at theta frequency (10 Hz), uIPSPs increased the offset of the MC input-output response to depolarizing current injection, but also increased gain, maximal firing rate and the slope of the depolarization preceding action potentials. These effects were unchanged by the Ca2+ and HCN channel blockers mibefradil and ZD7288, respectively. The height and maximal slope of MC action potentials during tonic depolarization were also increased by uIPSPs, and the decay of uIPSP conductances injected by dynamic clamp at subthreshold membrane potentials was prolonged by TTX. Application of the muscarinic agonist pilocarpine mimicked the effect of IPSPs on MC maximal firing rate, and action potential height and slope, and this was reversed by the GABA(A) antagonist gabazine. Thus, uIPSPs can increase neuronal gain under hyperexcitable conditions, and this effect is probably due to the de-inactivation of a TTX-sensitive voltage-dependent Na+ conductance.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Animals; Bridged Bicyclo Compounds; Cell Membrane; Electric Capacitance; Electric Impedance; Excitatory Postsynaptic Potentials; Hippocampus; Inhibitory Postsynaptic Potentials; Interneurons; Male; Mossy Fibers, Hippocampal; Neurons; Patch-Clamp Techniques; Pilocarpine; Pyridazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium Channels; Synaptic Transmission; Tetrodotoxin

Extraretinal projections onto neurons in the dorsal lateral geniculate nucleus (dLGN) play an important role in modifying sensory information as it is relayed from the visual thalamus to neocortex. The dLGN receives dopaminergic innervation from the ventral tegmental area; however, the role of dopamine in synaptic transmission in dLGN has not been explored. In the present study, whole cell recordings were obtained to examine the actions of dopamine on glutamatergic synaptic transmission. Dopamine (2-100 microm) strongly suppressed excitatory synaptic transmission in dLGN relay neurons that was evoked by optic tract stimulation and mediated by both N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. In contrast, dopamine did not alter inhibitory synaptic transmission arising from either dLGN interneurons or thalamic reticular nucleus neurons. The suppressive action of dopamine on excitatory synaptic transmission was mimicked by the D(2)-like dopamine receptor agonist bromocriptine (2-25 microm) but not by the D(1)-like receptor agonist SKF38393 (10-25 microm). In addition, the dopamine-mediated suppression was antagonized by the D(2)-like receptor antagonist sulpiride (10-20 microm) but not by the D(1)-like receptor antagonist SCH23390 (5-25 microm). The dopamine-mediated decrease in evoked excitatory postsynaptic current amplitude was accompanied by an increase in the magnitude of paired-pulse depression. Furthermore, dopamine also reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. Taken together, these data suggest that dopamine may act presynaptically to regulate the release of glutamate at the retinogeniculate synapse and modify transmission of visual information in the dLGN.

Topics: Anesthetics, Local; Animals; Animals, Newborn; Bromocriptine; Dopamine; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Geniculate Bodies; In Vitro Techniques; Neurons; Patch-Clamp Techniques; Piperazines; Presynaptic Terminals; Pyridazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Synaptic Transmission; Tetrodotoxin; Visual Pathways

During cortical development, both activity-dependent and genetically determined mechanisms are required to establish proper neuronal connectivity. While activity-dependent transcription may link the two processes, specific transcription factors that mediate such a process have not been identified. We identified the basic helix-loop-helix (bHLH) transcription factor Neurogenic Differentiation 2 (NeuroD2) in a screen for calcium-regulated transcription factors and report that it is required for the proper development of thalamocortical connections. In neuroD2 null mice, thalamocortical axon terminals fail to segregate in the somatosensory cortex, and the postsynaptic barrel organization is disrupted. Additionally, synaptic transmission is defective at thalamocortical synapses in neuroD2 null mice. Total excitatory synaptic currents are reduced in layer IV in the knockouts, and the relative contribution of AMPA and NMDA receptor-mediated currents to evoked responses is decreased. These observations indicate that NeuroD2 plays a critical role in regulating synaptic maturation and the patterning of thalamocortical connections.

Topics: 2-Amino-5-phosphonovalerate; Amino Acid Sequence; Amino Acids; Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Calcium Channel Blockers; Cells, Cultured; Chelating Agents; Chloramphenicol O-Acetyltransferase; CREB-Binding Protein; Drug Interactions; Egtazic Acid; Electric Stimulation; Embryo, Mammalian; Excitatory Amino Acid Antagonists; GABA Antagonists; Gene Expression; Immunohistochemistry; In Vitro Techniques; Membrane Potentials; Mice; Mice, Knockout; Models, Biological; Nerve Growth Factors; Neural Pathways; Neurons; Neuropeptides; Nimodipine; Patch-Clamp Techniques; Phosphopyruvate Hydratase; Potassium Chloride; Pyridazines; Pyridinium Compounds; Quinoxalines; Receptors, AMPA; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Somatosensory Cortex; Synapses; Thalamus; Transcriptional Activation; Transfection; Vibrissae

Reciprocally connected GABAergic neurons of the globus pallidus (GP) and glutamatergic neurons of the subthalamic nucleus (STN) are a putative generator of pathological rhythmic burst firing in Parkinson's disease (PD). Burst firing of STN neurons may be driven by rebound depolarization after barrages of GABA(A) receptor (GABA(A)R)-mediated IPSPs arising from pallidal fibers. To determine the conditions under which pallidosubthalamic transmission activates these and other postsynaptic GABARs, a parasagittal mouse brain slice preparation was developed in which pallidosubthalamic connections were preserved. Intact connectivity was first confirmed through the injection of a neuronal tracer into the GP. Voltage-clamp and gramicidin-based perforated-patch current-clamp recordings were then used to study the relative influences of GABA(A)R- and GABA(B)R-mediated pallidosubthalamic transmission on STN neurons. Spontaneous phasic, but not tonic, activation of postsynaptic GABA(A)Rs reduced the frequency and disrupted the rhythmicity of autonomous firing in STN neurons. However, postsynaptic GABA(B)Rs were only sufficiently activated to impact STN firing when pallidosubthalamic transmission was elevated or pallidal fibers were synchronously activated by electrical stimulation. In a subset of neurons, rebound burst depolarizations followed high-frequency, synchronous stimulation of pallidosubthalamic fibers. Although GABA(B)R-mediated hyperpolarization was itself sufficient to generate rebound bursts, coincident activation of postsynaptic GABA(A)Rs produced longer and more intense burst firing. These findings elucidate a novel route through which burst activity can be generated in the STN, and suggest that GABARs on STN neurons could act in a synergistic manner to generate abnormal burst activity in PD.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; Animals; Evoked Potentials; Excitatory Amino Acid Antagonists; GABA Antagonists; gamma-Aminobutyric Acid; Globus Pallidus; Lysine; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons; Parkinson Disease; Patch-Clamp Techniques; Picrotoxin; Pyridazines; Quinoxalines; Receptors, GABA-A; Receptors, GABA-B; Subthalamic Nucleus; Synapses; Tetrodotoxin

The dorsal (DRN) and median raphe nuclei (MRN) are two major sources of serotonergic projections to forebrain that are involved in regulation of behavioral state and motor activity, and implicated in affective disorders such as depression and schizophrenia. To investigate afferent influences on serotonergic neurons, this study compared the role of endogenous GABA and glutamate in the DRN and MRN using microdialysis and measurement of locomotor activity in freely behaving rats. Local infusion of the GABA(A) receptor antagonist bicuculline increased serotonin (5-HT) efflux in the DRN but not the MRN. In contrast, infusion of glutamate receptor antagonists produced larger decreases in 5-HT efflux in the MRN compared with the DRN. Moreover, glutamate receptor antagonists attenuated the increase in 5-HT efflux produced by GABA receptor blockade in the DRN. Thus, the disinhibitory effect of GABA blockers could be ascribed in part to an enhanced influence of glutamate. Measurements of locomotor activity indicate that changes in 5-HT were not simply correlated with behavioral activity induced by drug infusion. In summary, the role of inhibitory and excitatory afferents was strikingly different in the DRN and MRN. GABA afferents were the predominant tonic influence on serotonergic neurons in the DRN. In contrast, glutamatergic but not GABAergic afferents had a strong tonic influence on serotonergic neurons in the MRN.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Afferent Pathways; Animals; Bicuculline; Excitatory Amino Acid Antagonists; Extracellular Space; GABA Antagonists; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Male; Motor Activity; Neural Inhibition; Pyridazines; Quinoxalines; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Serotonin