NO‐mediated cGMP synthesis in cholinergic neurons in the rat forebrain: effects of lesioning dopaminergic or serotonergic pathways on nNOS and cGMP synthesis

Abstract

Nitric oxide synthase (NOS) activity and NO-mediated cGMP synthesis were studied in the rat forebrain of control animals and animals which had received a unilateral lesioning of dopaminergic or serotonergic pathways. Lesioning of the dopaminergic innervation using 6-hydroxydopamine resulted in a 50% decrease in NOS activity in the lesioned frontal cortex and caudate putamen. Lesioning of the serotonergic innervation using 5,7-dihydroxytryptamine had no effect on NOS activity. NO-mediated cGMP accumulation in rat forebrain slices was not affected by 6-hydroxydopamine or 5,7, -dihydroxytryptamine lesioning. Using cGMP immunocytochemistry, it was demonstrated that NO-mediated cGMP synthesis was absent from dopaminergic, serotonergic, GABA-ergic and neuronal NOS-containing nerve fibres. A minor colocalization of cGMP immunoreactivity was found in parvalbumin-containing fibres in the cortex. Extensive colocalization between cGMP immunoreactivity and the acetylcholine transporter was found in all cortical areas and in the caudate putamen. There was no effect of the lesions on this colocalization. These results demonstrate NO-mediated cGMP accumulation in cholinergic fibres in the forebrain of the rat and suggest an anterograde signalling function of NO in cholinergic neuronal systems in the cortex and caudate putamen of the rat.

Phasic Dopaminergic Transmission Increases NO Efflux in the Rat Dorsal Striatum via a Neuronal NOS and a Dopamine D1/5 Receptor-Dependent Mechanism

“…Additionally, we have observed that NO-dependent modulation of striatal neuron activity regulates the activity of DA neurons in the SN via striatonigral feedback pathways (West and Grace, 2000). Moreover, several studies reporting that measures of nNOS activity are depressed in 6-OHDAlesioned animals (de Vente et al, 2000;Sahach et al, 2000;Sancesario et al, 2004) suggest that nitrergic transmission may be compromised in patients with PD. This possibility is substantiated by studies demonstrating that striatal NOSimmunopositive cell numbers and mRNA are significantly depleted in post-mortem Parkinsonian brains (Bockelmann et al, 1994;Eve et al, 1998).…”

“…Thus, behavioral studies have demonstrated that pharmacological blockade of NO signaling decreases basal locomotor activity (Stewart et al, 1994) and behaviors induced by substance P (Mancuso et al, 1994), D 1 and D 2 agonists (Starr and Starr, 1995), NMDA receptor antagonists (Deutsch et al, 1996), and a variety of abused drugs (see below). Interestingly, multiple measures of striatal NOS activity are depressed in 6-OHDAlesioned animals (de Vente et al, 2000;Sancesario et al, 2004) and patients with PD (Bockelmann et al, 1994;Eve et al, 1998), indicating that agents designed to target nitrergic signaling may be useful for the treatment of movement disorders.…”

Ischemic-LTP in Striatal Spiny Neurons of both Direct and Indirect Pathway Requires the Activation of D1-Like Receptors and NO/Soluble Guanylate Cyclase/cGMP Transmission

“…In these conditions we showed that i-LTP did not occur. Accordingly, striatal NOS activity was found to be depressed in 6-OHDA lesioned animals 52,53 and patients with PD. 54,55 Interestingly, our experiments show that i-LTP could be induced when the cGMP analog 8Br-cGMP, was applied in these DA-denervated slices.…”

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

“…In animal 6-OHDA-models of PD nNOS expression is reduced while a proportion of nNOS nerve fibres in the striatum are apparently lost following DAergic deafferentation, resulting in a 50% decrease in NOS activity, and depression of the NO-cGMP pathway [136,137]. In contrast, Gomes et al [37] showed that 6-OHDA lesion induced a significant increase in NOS cell numbers in the ipsilateral dorsal striatum while a decrease was seen in the ipsilateral SNc and contralateral NAc.…”