Effects of 5‐HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents

Abstract

1 The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway activity) were used as a separate test of non-specific drug effects. 2 Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirone, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl}2 aminopropane (DOI), 1,-3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169 369 and cyproheptadine but not by pindolol or a low (0.25mgkg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg'-. 4 Zimeldine burying inhibition was potentiated by ritanserin, ICI 169 369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5 Zimeldine was administered in drinking water at a dose of lOmgkg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels. 6 Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises the possibility of multiple interactions between 5-HT receptor subtypes.

The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

“…The present results support that notion as antidepressants have been shown to reduce marble burying [16,29]. The mechanism behind such an antidepressant-like profile remains unclear, but might include the localization of the receptors to areas such as the hippocampus and amygdala [12], and/or their possible regulation of the activity of serotonergic neurons by interactions with glutamatergic [9] or GABAergic [34] neurons in the raphe nuclei.…”

“…However, the involvement of the 5-HT 2C receptor is controversial as both agonists and antagonists have induced or worsened symptoms of OCD [18,20,31,37]. Studies have also suggested that 5-HT 2A receptor agonism might have beneficial anti-OCD effects [25,29]. Other evidence suggest an involvement of the 5-HT 1A receptor, since agonists at this receptor, specifically, 8-hydroxy-2 (di-n-propylamino)tetralin (8-OH-DPAT) have been shown to reduce OCD-like behavior [19,23].…”

Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites

“…Several studies have linked burying behavior with 5-HT function (Ichimaru et al, 1995), with elevated 5-HT activity causing a decrease in burying behavior (Abe et al, 1998;Njung′e and Handley, 1991a). Increased 5-HT expression in dorsal raphe nucleus of neuromedin B receptor deficient mice, was also found to be associated with a decrease in marble burying (Yamada et al, 2002).…”

“…Marble burying behavior in rodents, thought to be a model of obsessive-compulsive disorder (Njung′e and Handley, 1991b), is sensitive to selective serotonin re-uptake inhibitors (SSRI), the current medication of choice for obsessive compulsive disorder (Njung′e and Handley, 1991a). Several studies have linked burying behavior with 5-HT function (Ichimaru et al, 1995), with elevated 5-HT activity causing a decrease in burying behavior (Abe et al, 1998;Njung′e and Handley, 1991a).…”

Effect of hydroalcoholic extract of leaves ofColocasia esculentaon marble-burying behavior in mice: Implications for obsessive–compulsive disorder

“…Clinical reports indicate that SSRIs and clomipramine are effective in reducing obsessive-compulsive disorder symptoms (Gorman & Kent, 1999). The marbleburying behavior test has been suggested as a useful model for evaluating anti-obsessive-compulsive disorder drugs because no change in the intensity of the marble-burying behavior occurred during repeated testing (this is considered as compulsive behavior) and antidepressants such as tricyclics and SSRIs suppress marble-burying behavior (Millan et al, 2001;Njung'e & Handley, 1991b). Marble-burying behavior is an unconditioned species-specific defensive reaction in rodents, which is not associated with physical danger, and does not habituate upon repeated testing (Njung'e & Handley, 1991a).…”