GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons

Abstract

Evidence from electrophysiological studies has suggested an inhibitory interaction between GABAergic neurons in substantia nigra pars reticulata and dopaminergic neurons in pars compacta. However, that this inhibitory interaction is due to a projection from pars reticulata to pars compacta has never been demonstrated directly, nor has the GABAergic neuron that mediates the interaction been identified either electrophysiologically or anatomically. To more closely examine interactions between substantia nigra pars reticulata GABA neurons and dopaminergic neurons, single unit extracellular recordings were obtained from antidromically identified nigrostriatal neurons and their response to antidromic activation of nigral GABAergic projection neurons observed. Stimulation of superior colliculus or thalamus produced a short latency inhibition of dopaminergic neurons. This inhibition was blocked by local application of bicuculline but not 2-hydroxysaclofen. Bicuculline caused most dopaminergic neurons to fire in a bursty mode, whereas saclofen caused most dopaminergic neurons to fire in a pacemaker-like mode. The thalamic-evoked inhibition was not affected by kainate lesions of the globus pallidus, but these lesions produced effects on firing pattern identical to those produced by saclofen. These data demonstrate a short latency inhibition of nigral dopaminergic neurons mediated by GABAA receptors that arises from the axon collaterals of pars reticulata projection neurons. We propose a model in which the firing pattern of nigral dopaminergic neurons in vivo is modulated differentially by disinhibition of GABAA inputs arising from pars reticulata projection neuron axon collaterals and disinhibition of pallidonigral GABAergic inputs mediated by GABAB receptors.

Do silent dopaminergic neurons exist in rat substantia nigra in vivo?

“…At least 2 min of spontaneous activity was recorded for each neuron and was analysed off-line, as described previously. 51 The numbers and percentage of spontaneously firing and silent dopaminergic neurons were reported and compared to previous reports ( 2 contingency analysis). Student's two-tailed t-test was used to test for a difference between the number of antidromically activated neurons per track under control conditions and after apomorphine administration in the cells per track experiments.…”

“…All other data were recorded on to magnetic tape for off-line analysis on a Macintosh Quadra 950 equipped with a National Instruments MIO16L multifunction board and custom-designed software, as described previously. 51 …”

“…Although there is a wellknown monosynaptic GABAergic pathway from the striatum to nigral dopaminergic neurons, 5,21,41,46,54 the majority of the striatonigral fibers terminate in the pars reticulata, 5,21,25 which contains GABAergic projection neurons that have been shown to project via axon collaterals to dopaminergic neurons. 12,14,51 Thus, one could argue that the striatal stimulation inhibits reticulata GABAergic neurons, thereby disinhibiting the silent dopaminergic neurons and causing them to fire. Indeed, a reciprocal relation between the spontaneous firing rates of nigral dopaminergic neurons and non-dopaminergic neurons has been observed, 22 and an increase in the spontaneous firing rate of dopaminergic neurons has been reported when the striatum was stimulated at extremely low intensity (20-50 µA, 50 µs duration).…”

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels

“…These conclusions are supported by several recent computational modeling studies of burst firing in dopaminergic neurons (e.g., Canavier, 1999;Amini et al, 1999;Wilson and Callaway, 2000;Medvedev et al, 2003;Komendantov et al, 2004;Kuznetsov et al, 2006). Although the ability of NMDA receptor stimulation to evoke burst firing is well established, the endogenous trigger for ''spontaneous'' burst firing in vivo has not been demonstrated and in vivo, the firing pattern of nigrostriatal neurons is potently modulated by blockade of GABA A receptors (Tepper et al, 1995;Paladini et al, 1999a).…”

“…In urethane-anesthetized animals the most common pattern of activity ($55% of neurons) is a random mode in which the interspike intervals are described by a Poisson-like process. The next most common pattern is a regular, pacemaker-like activity ($30%) and the least common (15%) is a slow bursting pattern (Tepper et al, 1995;Paladini and Tepper, 1999). Bursts in dopaminergic neurons in anesthetized animals are most frequently comprised of 2-8 spikes with increasing interspike intervals ranging from about 40 to well over 100 ms (Bunney et al, 1973;Grace and Bunney, 1984).…”