Anxiogenesis induced by nitric oxide synthase inhibition and anxiolytic effect of melanin-concentrating hormone (MCH) in rat brain.

100

Repeated exposure to stressful conditions is linked to the etiology of affective disorders. The melanin-concentrating hormone-1 receptor (MCHR1) may be a novel mechanism that is involved in the modulation of stress responses and affective states. The role of MCHR1 in neuroendocrine, behavioral, and neurochemical stress, and anxiety-related responses was examined by monitoring the effects of melanin-concentrating hormone (MCH) and the selective MCHR1 antagonist, GW3430, in inbred C57Bl/6NTac and MCHR1-knockout (KO) and wild-type (WT) mice. Intracerebroventricular injection of MCH increased plasma corticosterone, and produced anxiety-related responses in the elevated plus maze. The selective MCHR1 antagonist, GW3430, blocked the neuroendocrine and behavioral effects of MCH and produced anxiolytic-like effects by itself in animal models of anxiety. Moreover, KO mice had an anxiolytic-like phenotype in behavioral models of anxiety, and GW3430 had anxiolytic-like effects in WT, but not KO mice. Lastly, stressor-evoked acetylcholine release within the prefrontal cortex of inbred and WT mice, but not KO mice, was blocked by GW3430. We show that MCH elicits anxiety-like responses and that the effects of a selective MCHR1 antagonist and the phenotype of KO mice are consistent with anxiolyticlike action. Distinct behavioral, physiological, and neurochemical stress, and anxiety-related responses were selectively modulated by the MCHR1, and these actions may involve corticolimbic regulation of stress responsivity and anxiety.

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Melanin-Concentrating Hormone-1 Receptor Modulates Neuroendocrine, Behavioral, and Corticolimbic Neurochemical Stress Responses in Mice

Smith

Davis

Rorick-Kehn

et al. 2005

100

“…A number of research groups have indeed reported that suppression of NO production can induce anxiogenic-like behavior in a variety of animal models of experimental anxiety Vale et al, 1998;Monzon et al, 2001;Pokk and Vali, 2002;Czech et al, 2003). That NO is involved in reduction of anxiety is supported by the observation that administration of the NO donor 3-morpholinosyndnonimine (SIN-1) evoked an anxiolytic-like response in mice in the light/dark exploration test (Li and Quock, 2002).…”

Section: Discussionmentioning

confidence: 99%

Antagonism by NOS Inhibition of the Behavioral Effects of Benzodiazepine and GABAA Receptor Agonists in the Mouse Elevated Plus-Maze

Elfline

Branda

Babich

et al. 2004

Earlier we implicated nitric oxide (NO) in mediation of the behavioral effects of benzodiazepines. Since benzodiazepines work through facilitation of GABAergic inhibitory neurotransmission, this study was designed to determine whether the direct-acting g-aminobutyric acid A (GABA A ) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) evokes behavioral effects similar to those of benzodiazepines and whether behavioral effects of THIP are also NO dependent. When challenged with either chlordiazepoxide or THIP in an elevated plus-maze paradigm, male NIH Swiss mice exhibited a dose-related increase in open-arm activity. The chlordiazepoxide-induced effects were sensitive to antagonism by a benzodiazepine antagonist, and the effects of THIP were blocked by a GABA A receptor antagonist. Pretreatment with the NO synthase (NOS) inhibitor L-N G -nitro arginine antagonized the effects of both chlordiazepoxide and THIP; similar pretreatment with the D-isomer, D-N G -nitro arginine, which is inactive as an NOS inhibitor, was without effect on chlordiazepoxide and THIP. These findings indicate that chlordiazepoxide and THIP evoke similar behavioral effects in mice in the elevated plus-maze through actions on different parts of the GABA A receptor, and that NO appears to play a key role in mediation of the behavioral effects of both chlordiazepoxide and THIP.

“…For example, the NOS inhibitor L-NOARG decreased the exploration of an elevated plus-maze system (De Oliveira et , 1997) and was able to antagonize the anxiolytic-like effects of NO (Caton et al, 1994) as well as of chlordiazepoxide (Quock and Nguyen, 1992). Anxiogenic-like effects were also reported after intra-amygdala or intra-hippocampal injection of L-NOARG (Monzon et al, 2001). On the one hand, eNOS-deficient mice showed an increase in anxietyrelated behavior in the plus-maze in comparison with the wild-type controls (Frisch et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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

Kittner

Franke

Fischer

et al. 2002

(ADPbS), the P2X 1,3 receptor agonist a,b-methylene ATP (a,bmeATP), the unspecific P2 receptor antagonist pyridoxalphosphate-6-azopheny l-2 0 ,4 0 -disulfonic acid (PPADS), and the specific P2Y 1 receptor antagonist N 6 -methyl-2 0 -deoxyadenosine-3 0 ,5 0 -bisphosphate (MRS 2179) on the elevated plus-maze behavior of the rat were investigated. All tested compounds were given intracerebroventricularly (0.5 ml). ADPbS (50 and 500 fmol) produced an anxiolytic-like behavioral profile reflected by an increase of the open arm exploration. The anxiolytic-like effects were antagonized by pretreatment with PPADS (5 pmol) or MRS 2179 (5 pmol). Both compounds caused anxiogenic-like effects when given alone. Furthermore, the anxiolytic-like effects of ADPbS could be antagonized by pretreatment with the nitric oxide synthase (NOS) inhibitor N w -nitro-L-arginine methyl ester (L-NAME). In addition, the anxiogenic-like effects of PPADS were reversed by the pretreatment with L-arginine (500 pmol), which is the natural substrate for NOS, but not by D-arginine (500 pmol), which is not. Immunofluorescence staining revealed the presence of P2Y 1 receptors on neurons in different brain regions such as hypothalamus, amygdala, hippocampus and the periaqueductal gray. Furthermore, the colocalization of P2Y 1 receptors and neuronal NOS (nNOS) on some neurons in these regions could be demonstrated. The highest density of P2Y 1 -and nNOS-immunoreactivity was detected in the dorsomedial hypothalamic nucleus. Taken together, the present results suggest that P2Y 1 receptors are involved in the modulation of anxiety in the rat. The anxiolytic-like effects after stimulation of P2Y 1 receptors seem to be in close connection with the related nitric oxide production.