Substantia Nigra Pars Reticulata Neurons Research Articles

Dopamine agonist-mediated rotation in rats with unilateral nigrostriatal lesions is not dependent on net inhibitions of rate in basal ganglia output nuclei

Current models of basal ganglia function predict that dopamine agonist-induced motor activation is mediated by decreases in basal ganglia output. This study examines the relationship between dopamine agonist effects on firing rate in basal ganglia output nuclei and rotational behavior in rats with nigrostriatal lesions. Extracellular single-unit activity ipsilateral to the lesion was recorded in awake, locally-anesthetized rats. Separate rats were used for behavioral experiments. Low i.v. doses of D 1 agonists (SKF 38393, SKF 81297, SKF 82958) were effective in producing rotation, yet did not change average firing rate in the substantia nigra pars reticulata or entopeduncular nucleus. At these doses, firing rate effects differed from neuron to neuron, and included increases, decreases, and no change. Higher i.v. doses of D 1 agonists were effective in causing both rotation and a net decrease in rate of substantia nigra pars reticulata neurons. A low s.c. dose of the D 1/D 2 agonist apomorphine (0.05 mg/kg) produced both rotation and a robust average decrease in firing rate in the substantia nigra pars reticulata, yet the onset of the net firing rate decrease (at 13–16 min) was greatly delayed compared to the onset of rotation (at 3 min). Immunostaining for the immediate-early gene Fos indicated that a low i.v. dose of SKF 38393 (that produced rotation but not a net decrease in firing rate in basal ganglia output nuclei) induced Fos-like immunoreactivity in the striatum and subthalamic nucleus, suggesting an activation of both inhibitory and excitatory afferents to the substantia nigra and entopeduncular nucleus. In addition, D 1 agonist-induced Fos expression in the striatum and subthalamic nucleus was equivalent in freely-moving and awake, locally-anesthetized rats. The results show that decreases in firing rate in basal ganglia output nuclei are not necessary for dopamine agonist-induced motor activation. Motor-activating actions of dopamine agonists may be mediated by firing rate decreases in a small subpopulation of output nucleus neurons, or may be mediated by other features of firing activity besides rate in these nuclei such as oscillatory firing pattern or interneuronal firing synchrony. Also, the results suggest that dopamine receptors in both the striatum and at extrastriatal sites (especially the subthalamic nucleus) are likely to be involved in dopamine agonist influences on firing rates in the substantia nigra pars reticulata and entopeduncular nucleus.

Nigral degeneration following striato-pallidal lesion in tissue type plasminogen activator deficient mice

Tissue type plasminogen activator (tPA) has been suggested as a key factor in excitotoxic neuronal death in the hippocampus. Transneuronal degeneration of the substantia nigra pars reticulata (SNR) neurons after striato-pallidal lesions is attributable to excess excitatory glutamatergic inputs into the SNR following inhibitory GABAergic deafferentation and tPA may contribute to the mechanism of transneuronal degeneration of the SNR. To examine this possibility, we studied pathological changes in the SNR following striato-pallidal lesions produced by electrocoagulation in tPA-deficient mice. There was no difference in the degree of SNR degeneration, or in microglial activation and proliferation in the degenerating SNR of tPA-deficient and control mice. Our results indicate that tPA does not contribute to transneuronal degeneration in the SNR following striato-pallidal lesions in mice.

The effect of α-phenyl- N-tert-butyl nitrone on bioenergetic state in substantia nigra following flurothyl-induced status epilepticus in rats

Status epilepticus (SE), i.e. ongoing seizures of more than 30 min duration, gives rise to bilateral pan-necrotic lesions of the substantia nigra, pars reticulata (SNPR). These are known to be preceded by an initial increase, followed by a depression of metabolic rate, and by failure of the bioenergetic state, suggesting mitochondrial dysfunction. We have previously shown that the spin trap α-phenyl- N-tert-butyl nitrone (PBN) prevents the lesions caused by 45 min of SE from occurring, in spite of ongoing seizure activity. In this article, we demonstrate that PBN, given 30 min before seizure induction, reduces or prevents the decrease in ATP concentration and adenylate energy charge, without significantly reducing the amount of lactate accumulated, or the decrease in intracellular pH (pH i). The results suggest that the spin trap nitrone preserves the structural and functional integrity of SNPR neurons by protecting the mitochondria against oxidative damage.

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal–pallidal lesion

Unilateral neurotoxin lesion of rat caudate–putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal–pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl- d-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal–pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal–pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats ( P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl- d-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.

Presynaptic inhibition by dopamine of a discrete component of GABA release in rat substantia nigra pars reticulata.

1. Whole-cell patch clamp recordings were made from substantia nigra pars reticulata (SNr) neurones in rat midbrain slices. Monosynaptic IPSCs were evoked by electrical stimulation of the cerebral peduncle in the presence of the glutamate receptor antagonists CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and AP5 (2-amino-5-phosphonopentanoic acid). 2. IPSCs were predominantly outward at -70 mV (in 124/135 cells), with a reversal potential of -83 mV, a time to peak of 2.6 ms and a decay time constant of 6.5 ms. Faster inward IPSCs were also observed in thirty-five cells, with a time to peak of 1.0 ms, a decay time constant of 2.3 ms, and a reversal potential of -61 mV. Both IPSCs were sensitive to the GABAA receptor antagonists picrotoxin or bicuculline. 3. In cells recorded with Cs+-filled pipettes, the outward IPSC reversal potential was shifted to -76 mV, closer to the estimated Cl- equilibrium potential of -56 mV, while that of the inward IPSC was unchanged at -64 mV. 4. The outward IPSC was reversibly depressed by up to 100 % by dopamine in a concentration-dependent manner with an IC50 of 10.5 microM, while the inward IPSC was relatively insensitive. 5. Dopamine was without effect on cell holding current, or on outward IPSC reversal potential, but it increased paired-pulse IPSC facilitation, consistent with a presynaptic site of action. 6. The D1-like dopamine receptor agonist SKF 38393 (10 microM) depressed the outward IPSC by 43 %, while the D2-like dopamine receptor agonist quinpirole (10 microM) was without effect. 7. It is concluded that GABA-ergic synaptic input onto distal rather than proximal regions of SNr neurones is susceptible to presynaptic inhibition via a D1-like receptor. These inputs are probably from striato-nigral fibres, and their inhibition by dopamine is likely to influence the patterning of basal ganglia output.

Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease.

Microelectrode recording methods for stereotactic localization of the subthalamic nucleus (STN) and surrounding structures are described. These methods accurately define targets for chronic deep brain stimulation in the treatment of Parkinson's disease. Mean firing rates and a burst index were determined for all recorded neurons, and responses to active and passive limb and orofacial movements were tested. STN neurons had a mean firing rate of 37+/-17 Hz (n = 248) and an irregular firing pattern (median burst index, 3.3). Movement-related activity and tremor cells were identified in the STN. Ventral to the STN, substantia nigra pars reticulata neurons had a mean rate of 71+/-23 Hz (n = 56) and a more regular firing pattern (median burst index, 1.7). Short trains (1-2 seconds) of electrical microstimulation of STN could produce tremor arrest but were not found to be useful for localization. Compared with data from normal monkeys our findings suggest that STN neuronal activity is elevated in Parkinson's disease.

N-methyl-D-aspartate receptor blockade attenuates D1 dopamine receptor modulation of neuronal activity in rat substantia nigra.

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA receptors. The present study examined whether N-methyl-D-aspartate (NMDA) receptor antagonists affect the neurophysiological responses of substantia nigra pars compacta (SNpc; dopaminergic) and pars reticulata (SNpr; non-dopaminergic) neurons to a systemically administered D1 dopamine agonist in two animals models of Parkinson's disease, reserpine treatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agonist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine-depleting treatments, suggesting the involvement of multiple mechanisms. SKF 38393 consistently increased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage. Pretreatment with the non-competitive NMDA antagonist MK-801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA antagonist (+/-)-CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38393 in both dopamine-depleted preparations. SKF 38393 consistently inhibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4-7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK-801 (0.1 mg/kg i.v.) or the competitive NMDA antagonist (+)-HA-966 (30 mg/kg i.v.) also effectively attenuated SKF 38393's inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor stimulation to modulate firing rates of both dopaminergic and non-dopaminergic cells in the substantia nigra. Although multiple mechanisms appear to underlie D1-mediated effects on substantia nigra firing rates in reserpine and 6-OHDA-treated rats, these results demonstrate a common dependence on glutamatergic transmission and a permissive role for NMDA receptor activation in the ability of D1 receptor stimulation to both enhance and reduce neuronal activity in the substantia nigra.

Occlusion of the presynaptic action of cannabinoids in rat substantia nigra pars reticulata by cadmium

Whole-cell patch-clamp recordings were made from substantia nigra pars reticulata (SNR) neurones in rat midbrain slices to characterise the presynaptic action of cannabinoids on GABA neurotransmission and to study the involvement of calcium channels. The cannabinoid agonist WIN55212–2 at 10 μM reduced the amplitudes of GABA A receptor mediated spontaneous postsynaptic currents (IPSCs). This effect was fully reversed by the selective cannabinoid CB1 receptor antagonist SR141716A (20 μM). WIN55212–2 also caused a reduction in the evoked IPSC amplitude, which was associated with a significant increase in the paired pulse ratio over a 50 ms interval. In addition, the reduction in spontaneous IPSC amplitude by WIN55212–2 could be largely occluded by the presence of extracellular Cd 2+ (200 μM). These observations suggest that cannabinoids exert a presynaptic inhibition on GABAergic transmission to SNR neurones via CB1 receptor, an action which involves inhibition of Cd 2+-sensitive presynaptic Ca 2+ channels.

Differential expression of pre- and postsynaptic GABA B receptors in rat substantia nigra pars reticulata neurones

Whole-cell recordings were made from substantia nigra pars reticulata in rat midbrain slices to study the functional expression of pre- and postsynaptic GABA B receptors in GABA output neurones. Baclofen (up to 300 μM) dose-dependently activated a weak current which was insensitive to tetrodotoxin and Ca 2+-free solution but blocked by Ba 2+ and 2-OH-saclofen. The maximum current activated by baclofen (30 μM) was 43.0±4.5 pA ( n=27), representing only 23% of that in dopamine neurones. Baclofen (1–30 μM) also reduced the frequency of the GABA A receptor-mediated miniature inhibitory postsynaptic currents while the distribution of their amplitudes was unaffected. This presynaptic effect of baclofen, prominent at a concentration as low as 1 μM, was sensitive to 2-OH-saclofen and occluded by Cd 2+, but was unaffected by Ba 2+. The results suggest a predominant role of the presynaptic GABA B receptors in substantia nigra pars reticulata. The relative abundance of pre- and postsynaptic GABA B receptor subtypes in this brain region may also be important in mediating the anticonvulsant effect of baclofen in rats.

Presynaptic inhibition of GABAergic inputs to rat substantia nigra pars reticulata neurones by a cannabinoid agonist.

Whole-cell patch-clamp recordings were made from substantia nigra pars reticulata (SNR) neurones in rat midbrain slices to investigate the electrophysiological effects of cannabinoids. The cannabinoid receptor agonist WIN 55212-2 (10 microM) significantly reduced intranigrally evoked and spontaneous inhibitory post-synaptic currents (IPSCs) which were mediated by GABA(A) receptors. The postsynaptic current induced by bath application of GABA was not affected by the presence of WIN 55212-2. The actions of WIN 55212-2 were not mimicked by the inactive enantiomer WIN 55212-3. WIN 55212-2 also hyperpolarized the membrane of SNR neurones in a tetrodotoxin/0-Ca2+-insensitive manner. These data suggest that cannabinoids modulate the activity of SNR neurones by presynaptic inhibition of GABA inputs. They may also exert a direct post-synaptic inhibition on these neurones.

The distribution of neurons in the substantia nigra pars reticulata with input from the motor, premotor and prefrontal areas of the cerebral cortex in monkeys

We investigated the distribution of neurons in the substantia nigra pars reticulata (SNr) which received cortical input. The activities of single SNr neurons were studied extracellulary in awake monkeys. SNr neurons showed excitatory and/or inhibitory responses to cortical stimulation. These responses were considered to be mediated by the subthalamic nucleus and striatum, respectively. The neurons receiving inhibitory input from the motor, premotor and supplementary motor areas (Motor-related cortical areas) were located in the lateral part of the SNr, whereas those with input from the medial, dorsal and orbital areas of the prefrontal cortex (PFmdo) were frequently found in the rostro–medial part of this nucleus. SNr neurons with inhibitory input from the ventral periprincipal area (PSv) were mainly distributed in the intermedio–lateral portion, with some degree of overlap with input from other cortical areas. The distribution of the excitatory input was almost similar to that of inhibitory one, but the excitatory input from the PSv was much stronger than that from the PFmdo. Some SNr neurons receiving cortical input were proved to project to the thalamus. Our results support the existence of several parallel organization of the cortico–basal ganglia loop circuits [G.E. Alexander, M.R. DeLong, P.L. Strick, Parallel organization of functionally segregated circuits linking basal ganglia and cortex, Ann. Rev. Neurosci., 9, 1986, pp. 357–381.], but interaction between the loops can not be ignored.

Transsynaptic cell death of neurons following striatopallidal lesions does not occur in substantia nigra pars reticulata in developing rats

In adult rats, combined lesions of the striatum and globus pallidus (GP) cause transsynaptic cell death of neurons in the substantia nigra pars reticulata (SNr) which becomes apparent 1–2 weeks after the lesions. This delayed cell death of SNr neurons has been explained to be caused by over-excitation of SNr neurons which results from an imbalance between excitatory and inhibitory inputs due to two simultaneous events: acceleration of the excitatory input from the disinhibited subthalamic nucleus (STN) and deprivation of the inhibitory input from the striatum. To examine whether the transsynaptic neuronal death in SNr is caused by the same lesions in developing rats, we destroyed the striatum and GP in rats on postnatal days 10 (P10), P15, P20, P25, P30, P35 and P60 by injecting ibotenic acid. We found that cell death did not occur in SNr neurons in rats younger than P20 and that Fos expression induced in STN neurons after these striatopallidal lesions in P10 and P20 rats was lower than that in P30 or P60 rats. These findings suggest that excitation of STN neurons is not enough to cause cell death of SNr neurons in rats younger than P20. Immature functional connection between the cerebral cortex and STN in the early developing animals may contribute to the resistivity of SNr neurons to transsynaptic delayed cell death.

GABA receptor agonist promotes reformation of the striatonigral pathway by transplant derived from fetal striatal primordia in the lesioned striatum.

Striatal lesions are known to cause the anterograde transneuronal degeneration of the substantia nigra pars reticulata (SNr) neurons in consequence to loss of GABAergic inhibitory striatonigral efferents. The present study was undertaken to examine whether long-term intraventricular administration of the GABA agonist muscimol could promote reformation of the striatonigral pathway arising from transplants by rescuing host SNr neurons from transneuronal death in rats with striatal ischemic lesions. Compared to nongrafted rats with striatal lesions, (i) a prominent axonal projection from the transplants to the ipsilateral substantia nigra, (ii) a significant increase in number of survived neurons in the ipsilateral SNr, and (iii) a significant reduction in number of apomorphine-induced turning behaviors were found in grafted animals with muscimol infusion, but not in those without muscimol administration. These findings suggest that preservation of the host target neurons for grafted cells may increase an efficacy of cerebral implants in establishment of the host-graft fiber connections, possibly, leading to functional restoration.

Hemispheric asymmetries in spontaneous firing characteristics of substantia nigra pars reticulata neurons following a unilateral 6-hydroxydopamine lesion of the rat nigrostriatal pathway

Single unit activity of substantia nigra pars reticulata (SNR) neurons was recorded bilaterally in rats subjected to unilateral 6-hydroxydopamine lesions of the ascending mesostriatal dopaminergic pathway, resulting in an almost complete loss of dopaminergic neurons in the ipsilateral SN pars compacta. Firing rate and firing pattern of SNR neurons in lesioned rats were compared with respective data from sham-lesioned rats and naive controls. In lesioned rats, the mean firing rate of SNR neurons at the lesioned side was significantly reduced and there was an increase in the occurrence of bursting activity. In contrast, firing rate in the contralateral SNR was significantly increased without change in the frequency of bursting neurons. This asymmetrical change in spontaneous firing characteristics of SNR neurons following the lesion could be involved in the complex behavioral changes seen in this model of Parkinson's disease.

Intraventricular administration of GABAA receptor agonist muscimol attenuates the exo‐focal change of the substantia nigra neurons following transient middle cerebral artery occlusion in rats

A therapeutic effect of the selective GABAA receptor agonist muscimol on the ‘exo‐focal postischemic death’ was examined in the substantia nigra pars reticulata (SNr) of rats. Continuous intraventricular infusion of muscimol (muscimol‐infusion group) or saline (control group) was initiated from 24 h after the transient middle cerebral artery occlusion for 2 h. At 3 days postischemia, in accordance to a marked depletion of GABAergic afferent fibers in the ipsilateral substantia nigra, strong immunolabelling for 72 kDa heat shock protein (HSP72) appeared in the SNr neurons of the control rats. In contrast, there was no apparent HSP72 immunoreactivity in the ipsilateral SNr in the muscimol infusion group at this stage. In addition, cell density analysis showed that neuronal cell loss in the ipsilateral SNr was effectively prevented by muscinol infusion, as compared to that in the control group, at 15 days after ischemic insult. Thus, the GABA agonist could relieve the deafferented SNr neurons from the lethal metabolic changes responsible for induction of the stress response, which may occur in the course of exo‐focal postischemic death.

Pre-synaptic effect of the ATP-sensitive potassium channel opener diazoxide on rat substantia nigra pars reticulata neurons

Spontaneous synaptic currents were recorded from visually identified substantia nigra pars reticulata (SNR) neurons in the rat brain slice preparation by whole-cell patch clamp technique. GABA neurons were distinguished from dopamine neurons by their electrophysiological characteristics. In the presence of 20 μM AP5 and CNQX, the spontaneous synaptic currents recorded from GABA neurons were sensitive to bicuculline and reversed polarity at a potential close to the equilibrium potential of Cl −, indicating that they were mediated by GABA A receptors. TTX at 1 μM eliminated action potential-dependent release of GABA from nerve terminals, revealing the miniature inhibitory post-synaptic currents (mIPSCs). The ATP-sensitive potassium channel (K ATP channel) opener diazoxide (30–300 μM) significantly reduced the frequency of the mIPSCs in a dose-dependent manner. However, diazoxide did not affect the average value and the distribution of the mIPSC amplitudes. Thus, this effect of diazoxide was pre-synaptic in nature. The K ATP channel blocker glibenclamide (300 μM) was able to restore the frequency of the mIPSCs. These data suggest that the striatonigral projection, which represents the major inhibitory input controlling SNR GABA neuron activities, possesses presynaptic K ATP channels on the nerve terminals. © 1997 Elsevier Science B.V. All rights reserved.

Taurine inhibits rat substantia nigra pars reticulata neurons by activation of GABA- and glycine-linked chloride conductance

Whole-cell recordings from rat midbrain slices showed that bath application of taurine (30 μM–10 mM) reversibly hyperpolarized and inhibited the firing of substantia nigra pars reticulata neurons. These effects were mediated by an increase in membrane chloride conductance. Taurine cross-desensitized with GABA and glycine. Strychnine competitively antagonized the actions of glycine and taurine but not that of GABA. On the other hand, the responses to taurine and glycine were not sensitive to bicuculaire. These findings suggest that taurine inhibits SNR neurons by opening GABA and glycine linked chloride channels.

Electrophysiological studies of rat substantia nigra neurons in an in vitro slice preparation after middle cerebral artery occlusion

We studied sequential changes in electrophysiological profiles of the ipsilateral substantia nigra neurons in an in vitro slice preparation obtained from the middle cerebral artery-occluded rats. Histological examination revealed marked atrophy and neurodegeneration in the ipsilateral substantia nigra pars reticulata at 14 days after middle cerebral artery occlusion. Compared with the control group, there was no significant change in electrical membrane properties and synaptic responses of substantia nigra pars reticulata neurons examined at one to two weeks after middle cerebral artery occlusion. On the other hand, there was a significant increase in the input resistance and spontaneous firing rate of substantia nigra pars compacta neurons at 13–16 days after middle cerebral artery occlusion. Furthermore, inhibitory postsynaptic potentials evoked by stimulation of the subthalamus in substantia nigra pars compacta neurons was suppressed at five to eight days after middle cerebral artery occlusion. At the same time excitatory postsynaptic potentials evoked by the subthalamic stimulation was increased. Bath application of bicuculline methiodide (50 μM), a GABA A receptor antagonist, significantly increased the firing rate of substantia nigra pars compacta neurons from intact rats. These results strongly suggest that changes in electrophysiological responses observed in substantia nigra pars compacta neurons is caused by degeneration of GABAergic afferents from the substantia nigra pars reticulata following middle cerebral artery occlusion. While previous studies indirectly suggested that hyperexcitation due to deafferentation from the neostriatum may be a major underlying mechanism in delayed degeneration of substantia nigra pars reticulata neurons after middle cerebral artery occlusion, the present electrophysiological experiments provide evidence of hyperexcitation in substantia nigra pars compacta neurons but not in pars reticulata neurons at the chronic phase of striatal infarction.

The anticonvulsant gabapentin decreases firing rates of substantia nigra pars reticulata neurons

Gabapentin is a novel anti-epileptic drug which enhances GABA (γ-aminobutyric acid) turnover in certain brain regions, including substantia nigra. However, the functional consequences of GABA turnover increases in response to gabapentin and their potential involvement in the anticonvulsant action of this drug are not known. In the present study, we examined the effects of gabapentin on the extracellular, single unit activity of nondopaminergic (presumably GABAergic) neurons of the substantia nigra pars reticulata in rats. During the recordings, the animals were infused with the narcotic opioid analgesic fentanyl, associated with a skeletal muscle relaxant and artificial ventilation. The spontaneous firing of substantia nigra pars reticulata neurons was determined up to about 2 h after i.v. or i.p. administration of gabapentin at doses of 15–30 mg/kg. After both routes of administration, gabapentin markedly reduced neuronal firing when administered at a dose of 20–30 mg/kg, while 15 mg/kg were ineffective in this regard. The suppressive effect of gabapentin was rapid in onset (2 min after i.v. and about 20 min after i.p. injection), reached peak values of about 70% below predrug baseline after about 45–60 min, and remained at this level for at least 2 h. Vehicle administration had no effect on substantia nigra pars reticulata neurons. The ability of gabapentin to alter substantia nigra pars reticulata firing does correlate with its known ability to increase nigral GABA turnover. Since a substantial body of evidence suggests that the substantia nigra pars reticulata is a critical site at which decrease of neuronal firing by potentiation of GABAergic influences results in protection against various seizure types, the suppressive effect of gabapentin on substantia nigra pars reticulata activity may contribute to the anticonvulsant action of this drug.

Differential Actions of Serotonin, Mediated by 5-HT1Band 5-HT2CReceptors, on GABA-Mediated Synaptic Input to Rat Substantia Nigra Pars Reticulata NeuronsIn Vitro

The ability of serotonin to modulate GABA-mediated synaptic input to substantia nigra pars reticulata (SNr) neurons was investigated with the use of whole-cell patch-clamp recording from slices of rat midbrain. Fast evoked GABA(A) receptor-mediated synaptic currents (IPSCs) were attenuated reversibly approximately 60% by serotonin, which also caused an inward current with reversal potential of -25 mV. This inward current was blocked by the 5-HT2 receptor antagonist ritanserin, whereas the IPSC depression was blocked by the 5-HT1B receptor antagonist pindolol. The amplitude ratio of IPSC pairs (50 msec interpulse interval) was enhanced by serotonin (in ritanserin) and also by the GABA(B) receptor agonist baclofen (which also depressed the IPSC), consistent with a presynaptic site of action in both cases. In contrast, spontaneous tetrodotoxin-sensitive GABA(A) synaptic currents (sIPSCs) were increased in frequency by serotonin (an action that was sensitive to ritanserin, but not pindolol) but reduced in frequency by baclofen. SNr neurons therefore receive inhibitory synaptic input mediated by GABA(A) receptors from at least two distinct sources. One, probably originating from the striatum, may be depressed via presynaptic 5-HT1B and GABA(B) receptors. The second is likely to arise from axon collaterals of SNr neurons themselves and is facilitated by an increase in firing via postsynaptic, somatodendritic 5-HT2C receptor activation, but it is depressed by GABA(B) receptor activation. Thus, serotonin can both depolarize and disinhibit SNr neurons via 5-HT2C and 5-HT1B receptors, respectively, but excitation may be limited by GABA released from axon collaterals.