Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity

Abstract

The influence of subthalamic nucleus (STN) afferents on dopaminergic (DA) neurons of the rat substantia nigra (SN) was investigated. Hemisections of the brain placed between the STN and the SN or located anterior to the STN caused an increase in the firing rate of DA cells without producing significant changes in their firing pattern. In contrast, electrolytic and ibotenic acid lesions of the STN resulted in 93% and 49% reductions, respectively, in the level of burst firing without affecting the firing rate of DA cells recorded in the lateral SN. Furthermore, procedures which interrupted the STN input to the SN produced rapid pacemaker-like firing in 18% of the lateral SN DA neurons recorded. Activation of the STN using single pulses of electrical stimulation caused: 1) a 20-50 msec inhibition of DA cell firing followed by an excitation, which in 35% of DA cells was accompanied by spikes occurring in a burst-like pattern, and 2) a short-latency inhibition lasting 5-25 msec in 75% of non-DA SN zona reticulata (ZR) neurons. On the other hand, stimulation of the STN for 1 minute at 20 Hz resulted in an initial decrease in DA cell burst firing followed by elevated firing rates and increased burst firing by 30-60 minutes after the stimulation. Pharmacological activation of the STN by infusion of bicuculline caused a rapid inhibition of DA cells followed by a two-fold increase in burst firing 6-14 minutes later, whereas SN ZR cells responded with an elevation in firing rate which dissipated in 6-14 minutes. Muscimol-induced STN inhibition produced complimentary biphasic changes in SN neuron firing: 1) an initial increase followed by a decrease in burst firing and firing rate of DA neurons and 2) a rapid inhibition followed by an excitation of ZR cells over a similar time course. Thus, the STN appears to exert a dual action on SN DA cells: 1) initial inhibition possibly mediated through STN excitation of the inhibitory SN ZR projections to DA cells, and 2) a facilitation of burst firing which may be a direct effect of excitatory STN afferents.

The Hippocampus Modulates Dopamine Neuron Responsivity by Regulating the Intensity of Phasic Neuron Activation

“…The finding that a concomitant increase in both the number of high-and low-bursting neurons was observed suggests that quiescent DA neurons are subject to the same tonic regulation as spontaneously active neurons once they are released from GABA-mediated inhibition. Interestingly, PPTg activation induced a similar B2-fold increase in the number of high-bursting DA neurons albeit through a different mechanism, that is, a transition from low to high burst firing resultant from the increased glutamatergic (and possibly cholinergic) tone to the VTA as suggested by previous studies of glutamate afferents and DA neuron burst firing (Lokwan et al, 1999;Smith and Grace, 1992). The present study demonstrates that simultaneous activation of the vSub and PPTg results in a summation of these effects resulting in a B4-fold increase in the number of high-bursting neurons, confirming the interdependence of the GABAergic and glutamatergic inputs to the ventral mesencephalon.…”

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation

“…According to current theories of drug addiction, drugs activate and, via neuroadaptive processes, change dopaminergic neurotransmission in the nucleus accumbens and its related circuitry (32,33) when repeatedly taken. The STN exercises an excitatory influence on the activity of the DA neurons in the ventral midbrain (34). The loss of excitatory input of the STN under DBS may thus lower the basal level of dopaminergic neuron activity in these structures and ultimately alter their reactivity to food and cocaine reward.…”

Subthalamic Nucleus Lesions Enhance the Psychomotor-Activating, Incentive Motivational, and Neurobiological Effects of Cocaine

“…Thus, we hypothesize that STN lesions increase the psychomotor-activating and incentive motivational effects of cocaine and cocaine-induced c-fos expression in the striatum (and perhaps also the therapeutic effects of L-DOPA) by enhancing dopaminergic neurotransmission in the striatum. Indeed, inhibition of the STN with muscimol, as well as disconnection of the STN and substantia nigra, have been shown to enhance the firing rate of dopamine-containing neurons, presumably by removing STN-mediated activation of the inhibitory GABAergic projections from the substantia nigra pars reticulata onto dopamine-containing cells (Smith and Grace, 1992).…”