7-Nitroindazole, a nitric oxide synthase inhibitor, has anxiolytic-like properties in exploratory models of anxiety

Abstract

The action of the novel nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI) was studied in different exploratory models of anxiety. In the rat plus-maze test, 7-NI potently increased time spent on open arms and percentage of open arm visits in a dose dependent manner with the minimal effective dose of 40 mg/kg. 7-NI caused an anxiolytic-like effect in the rat social interaction test. The minimal dose increasing social interaction time was 20 mg/kg. However, the drug also produced a clear sedative effect occurring even at smaller doses (10 mg/kg) in the open field test. 7-NI also showed an anxiolytic-like profile in the mouse light-dark compartment test and in the elevated plus-maze test, but the doses required were higher (80-120 mg/kg) than in rat models. Also, the sedative effect occurred at these doses in open field. We failed to demonstrate any effect of L-arginine either in the rat elevated plus-maze test or in the open field test at doses up to 600 mg/kg IP. These results indicate that there are no major interspecies differences between rats and mice in respect of action of 7-NI. The clear anxiolytic-like action of the nitric oxide synthase inhibitor in four different models shows that nitric oxide is involved in the process of anxiety and that NOS could be a new target in developing anxiolytic drugs.

Stimulation of P2Y1 Receptors Causes Anxiolytic-like Effects in the Rat Elevated Plus-maze: Implications for the Involvement of P2Y1 Receptor-Mediated Nitric Oxide Production

“…However, in both studies the anxiolytic-like response occurred only in a small dose range at lower doses, whereas at higher doses anxiogeniclike effects became apparent. In the present study, a weak but significant anxiolytic effect of L-arginine alone was observed, whereas other authors failed to show any anxiolytic effects of L-arginine on the elevated plus-maze (Yildiz et al, 2000, Volke et al, 1997. Possible reasons for these incompatible findings may consist in a different basal tonus of fear in the animals used and in different application routes.…”

Inhibition of neuronal nitric oxide reduces anxiety-like responses to pair housing

“…The biological substrates of social interactions, anxiety, and their interaction remain unclear. One chemical system that may be of interest is nitric oxide (NO) because inhibition of neuronal nitric oxide alters social [13,29] and anxiety-like behaviours [9,11,35,45].…”

Nitric Oxide Synthase Inhibitors Attenuate Phencyclidine-Induced Disruption of Prepulse Inhibition

“…A review of preclinical research examining pharmacological effects of NOS inhibitors reveals conflicting results. While some studies have reported that NOS inhibitors share behavioral effects with NMDA antagonists, including anxiolytic, anticonvulsant, and neuroprotective effects (Nagafusi et al 1995;Volke et al 1997), other studies have found that NOS inhibitors either do not mimic (Stewart et al 1994;Wiley et al 1995Wiley et al , 1997 andրor attenuate (Deutsch et al 1996;Johansson et al 1997) the effects of NMDA antagonists. For example, recent studies have shown that NOS inhibitors block the effects of PCP-like NMDA antagonists on "popping" behavior in mice (Deutsch et al 1996) and locomotor activity and prepulse inhibition of the acoustic startle response in rats (Johansson et al 1997).…”

“…Consistent with the dual role of nitric oxide at NMDA receptors, previous research has shown that, although drugs that inhibit nitric oxide (NOS inhibitors) share some behavioral effects with NMDA antagonists, they also may attenuate other behaviors associated with NMDA antagonism. Shared properties include anxiolytic effects, memory impairment, and phencyclidine (PCP)-like discriminative stimulus effects (Chapman et al 1992;Jewett et al 1996;Volke et al 1997). In contrast, Deutsch et al (1996) found that NOS inhibitors blocked "popping" behavior in mice that was induced by the PCP-like noncompetitive NMDA antagonist, dizocilpine.…”

“…Shared properties include anxiolytic effects, memory impairment, and phencyclidine (PCP)-like discriminative stimulus effects (Chapman et al 1992;Jewett et al 1996;Volke et al 1997). In contrast, Deutsch et al (1996) found that NOS inhibitors blocked "popping" behavior in mice that was induced by the PCP-like noncompetitive NMDA antagonist, dizocilpine.…”