Nitric oxide modulates striatal neuronal activity via soluble guanylyl cyclase: An in vivo microiontophoretic study in rats

Abstract

It is now well established that nitric oxide (NO) acts as a neuromodulator in the central nervous system. To assess the role of NO in modulating striatal activity, single-unit recording was combined with iontophoresis to study presumed spiny projection neurons in urethane-anesthetized male rats. Striatal neurons recorded were essentially quiescent and were therefore activated to fire by the iontophoretic administration of glutamate, pulsed in cycles of 30 sec on and 40 sec off. In this study, iontophoresis of 3-morpholinosydnonimine hydrochloride (SIN 1), a nitric oxide donor, produced reproducible, current-dependent inhibition of glutamate-induced excitation in 12 of 15 striatal neurons, reaching its maximal inhibitory effect (76.2 +/- 5.6% below baseline) during the application of a 100 nA current. Conversely, microiontophoretic application of N-omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, produced clear and reproducible excitation of glutamate evoked firing in 7 of 10 cells (51.4 +/- 2.3%, at 100 nA). To evaluate the involvement of cyclic guanosine monophosphate (cGMP) in the electrophysiological effects produced by the NO donor, the effects of methylene blue, an inhibitor of guanylyl cyclase, on the responses of nine neurons to SIN 1 were tested. In six of nine neurons the effect of SIN 1 was significantly reduced during continuous iontophoretic administration (50 nA) of methylene blue. Taken together, these data show that NO modulates the striatal network and that inhibitory control of the output neurons is involved in this effect. These results also suggest that the effects of nitric oxide on striatal neurons are partially mediated via cGMP.

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…Therefore, NO directly or via a modulation of GLU, ACh and GABA striatal levels excites a subpopulation of MSNs projecting to SN exciting SNc DA cells by inhibiting SNr neurons as suggested by West and Grace [69]. At the same time, SNc neurons could be directly inhibited by another striatal input [73,74] and indirectly by a proportion of SNr neurons, possibly impinging on DA cells that we have shown to be excited by NO [75], limiting the excitatory nicotine effect. Thus, striatal NO might be crucial in permitting and maintaining nicotine action.…”

“…The administration of a NO donor strongly inhibits GLU-induced excitation of the sporadically firing neurons whilst inhibition of the production of endogenous NO produced clear and reproducible excitation of glutamate evoked firing [74,107] (Fig. 2).…”

The Nitric Oxide-Guanylyl Cyclase Signaling Pathway Modulates Membrane Activity States and Electrophysiological Properties of Striatal Medium Spiny Neurons RecordedIn Vivo

“…Additionally, the close proximity of these nitrergic inputs to the dopaminergic and glutamatergic synapses of MSNs (Hidaka and Totterdell, 2001) suggests that NO transmission may play an important role in modulating the responsiveness of MSNs to afferent drive (for review, see West et al, 2002a). In support of this, recent electrophysiological studies have demonstrated that NO-GC signaling modulates corticostriatal synaptic plasticity in vitro (Calabresi et al, 1999a(Calabresi et al, ,b, 2000b and glutamate-induced excitations in vivo (Di Giovanni et al, 2003). NO generation, produced after the activation of corticostriatal pathways, is also critically involved in mediating electrotonic coupling between MSNs (O'Donnell and Grace, 1997).…”

Nitric Oxide Modulation of the Dopaminergic Nigrostriatal System: Focus on Nicotine Action

“…drug type-dependent effects, background redox state of the brain tissue, different NO regulation in different striatal subregions, etc. Nevertheless, we are confident in excluding limitations of the techniques since using a similar approach we have found effects of NO manipulation on the firing activity of other nuclei of the basal ganglia (Di Giovanni et al 2003. Despite the inability of NO to modify basal DA function, the inhibition of NOS completely counteracted the stimulation of DA outflow induced by nicotine.…”

“…At the same time, the inhibitory striatal inputs to the SNc, those that seem not to be dependent on NO, are active as well, limiting the excitatory nicotine effect. Furthermore, due to the sustained DA nicotine overflow higher levels of striatal NO eventually may result in an inhibition of the function of NMDA receptors and a decrease of the activity of MSNs projecting to the SNr/SNc (Choi and Lipton 2000;Di Giovanni et al 2003), thus reducing the activity of indirect excitatory striatonigral pathway.…”