Nitric oxide-active compounds modulate the intensity of glutamate-evoked responses in the globus pallidus of the rat.

AIM: The effects of local applied NO-active compounds on glutamate (GLU)-evoked responses were investigated in globus pallidus (GP) neurons. MAIN METHODS: Extracellularly recorded single units from anesthetized rats were treated with GLU before and during the microiontophoretic application of S-nitrosoglutathione (SNOG), a NO donor, and Nω-nitro-l-arginine methyl ester (L-NAME), a NOS inhibitor. KEY FINDINGS: Most GP cells were excited by SNOG whereas administration of L-NAME induced decrease of GP neurons activity. Nearly all neurons responding to SNOG and/or L-NAME showed significant modulation of their excitatory responses to the administration of iontophoretic GLU. In these cells, the changes induced by NO-active drugs in the magnitude of GLU-evoked responses were used as indicators of NO modulation. In fact, when a NO-active drug was co-iontophoresed with GLU, significant changes in GLU-induced responses were observed: generally, increased magnitudes of GLU-evoked responses were observed during SNOG ejection, whereas the administration of L-NAME decreased responses to GLU. SIGNIFICANCE: The results suggest that the NO-active drugs modulate the response of GP neurons to glutamatergic transmission. Nitrergic modulation of glutamatergic transmission could play an important role in the control of GP bioelectric activity, considered a fundamental key in the BG function.

Evidences of cannabinoids-induced modulation of paroxysmal events in an experimental model of partial epilepsy in the rat.

The anticonvulsant effect of cannabinoids (CB) has been shown to be mediated by the activation of the CB(1) receptor. This study evaluates the anticonvulsant activity of (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1-naphthalenylmethanone (WIN55,212-2, CB agonist) alone or preceded by the administration of N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251, selective CB(1) antagonist) in an experimental in vivo model of complex partial seizures (maximal dentate gyrus activation - MDA) in the rat. WIN55,212-2 (21mgkg(-1)) exerted an anticonvulsant effect, significantly reduced by the pre-treatment with AM251 (1mgkg(-1), 30 min interval). Surprisingly, AM251, administered alone at the same dose, failed to induce any modification in MDA responses. Our data suggest the involvement of the CB system in the inhibitory control of hyperexcitability phenomena in a model of acute partial epilepsy. Although the MDA model per se does not induce a basal activation of CB(1) receptors, as suggested by the lack of efficacy of AM251 when administered alone, the partial suppression of WIN55,212-2-induced effects in rats pre-treated with AM251 allows to hypothesise that the WIN55,212-2-induced antiepileptic effect is strictly linked to an increased CB(1) receptor activation or to the involvement of further receptor subtypes.

In the rat maximal dentate activation model of partial complex epilepsy, the anticonvulsant activity of levetiracetam is modulated by nitric oxide-active drugs.

The effects of nitric oxide-active drugs on the anticonvulsant action of the antiepileptic drug levetiracetam in an experimental model of partial complex seizures named maximal dentate gyrus activation were studied in rats. Levetiracetam was given alone or in combination with 7-nitroindazole, a preferential inhibitor of neuronal nitric oxide synthase, or with L: -arginine, the precursor of nitric oxide synthesis. The maximal dentate activation parameters were the time of latency and the durations of maximal dentate activation and afterdischarge responses. The administration of levetiracetam showed an anticonvulsant effect that was increased when given in combination with 7-nitroindazole. The co-administration of levetiracetam and L: -arginine, which is pro-convulsant, did not significantly modify all the parameters. The present results indicate that the acute administration of levetiracetam, at the lower effective dose, exerts an efficacious inhibitory effect on the severity of maximal dentate activation seizures. Levetiracetam-induced antiepileptic effect is significantly increased by the simultaneous inhibition of neuronal nitric oxide synthase.

Nitric oxide- and cGMP-active compounds affect the discharge of substantia nigra pars reticulata neurons: in vivo evidences in the rat.

The nitric oxide (NO)-active drugs influence on the bioelectric activity of neurons of the pars reticulata of the substantia nigra was studied in urethane-anesthetized rats. A first group of animals was treated with 7-nitro-indazole (7-NI), a preferential inhibitor of neuronal NO synthase. In a second group of rats, electrophysiological recordings were coupled with microiontophoretic administration of Nomega-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor), 3-morpholino-sydnonimin-hydrocloride (SIN-1, a NO donor) and 8-Br-cGMP (a cell-permeable analogue of cGMP, the main second-messenger of NO neurotransmission). 7-NI and L-NAME caused a statistically significant decrease in the firing rate of most of the responsive cells, while application of SIN-1 and 8-Br-CGMP induced statistically significant excitatory effects. The results suggest a NO mediated excitatory modulation of the SNr neurons activity with a possible involvement of the cGMP pathway.