Effects of diazepam on behavioural and antinociceptive responses to the elevated plus-maze in male mice depend upon treatment regimen and prior maze experience

Abstract

Recent studies have shown that brief exposure to an elevated plus-maze (EPM) produces non-opioid antinociception in male mice. The present experiments were designed to assess the effects of diazepam on this phenomenon. When acutely administered, low doses (0.5-1.0 mg/kg) of diazepam failed to produce an anxiolytic profile and exerted rather inconsistent effects on EPM-induced elevations in tail-flick latencies. In EPM-experienced mice, chronic treatment with higher doses of diazepam (2-4 mg/kg, 8 days) produced a weak anxiolytic action and inhibited the early phase of EPM antinociception only. However, in EPM-naive mice, 8-day diazepam pretreatment exerted a marked anxiolytic effect and completely eliminated the antinociceptive response to the maze. Together, these data support the view that anxiety is a key factor in certain forms of adaptive pain inhibition and suggest a possible mediational role for benzodiazepine receptors. Our findings also show that prior exposure to the EPM, rather than chronic handling/injection, greatly reduces the anti-anxiety effect of diazepam. Furthermore, since re-exposure to the maze, per se, decreased time spent on the open arms and central platform, a shift in behavioural baseline ("retest anxiogenesis") may have contributed to the weak behavioural effects of diazepam in test-experienced animals. Importantly, as chronic treatment with diazepam did not influence this anxiogenic-like retest profile, our data suggest that a single prior experience of the EPM may radically alter the nature of the anxiety reaction provoked by this test.

The use of the elevated plus maze as an assay of anxiety-related behavior in rodents

“…5,6 ) and mechanisms (e.g., GABA, glutamate, serotonin, hypothalamic-pituitary-adrenal axis neuromodulators, etc. 1,3,[7][8][9][10][11][12] ) underlying anxiety behavior. Indeed, the elevated plus maze has been used as a model of state, unconditioned anxiety for over two decades, and there are now over 2,000 papers related to this topic.…”

The relationship between anxiety and sleep–wake behavior after stressor exposure in the rat

“…The open arm of the EPM is considered anxiogenic, or anxiety inducing; thus, rats exhibiting greater anxiety-related behavior will enter and spend less time in the open arms of the maze (Bertoglio and Carobrez, 2000;Pellow et al, 1985). The percentage of time spent on the open arm is increased and decreased with anxiolytic and anxiogenic substances, respectively (Bertoglio and Carobrez, 2000;Pellow et al, 1985;Rodgers et al, 1992). When used appropriately, the EPM is the most effective and popular animal model to observe and quantify anxiety within the rodent model (Rodgers and Dalvi, 1997).…”

Role of the Dorsomedial Hypothalamus in Mediating the Response to Benzodiazepines on Trial 2 in the Elevated Plus-Maze Test of Anxiety

“…Increases in the percentage of time spent on the open arms and open arm entries indicate an anxiolytic effect, such as caused by benzodiazepines. Surprisingly, rats and mice do not show habituation to anxiety (File 1990;File and Zangrossi 1993;File and Gonzalez 1996;Gonzalez and File 1997;Rodgers et al 1992;Rodgers and Shepherd 1993) or to the elevation in corticosterone (File et al 1994;Holmes et al 1998). Treit et al (1993) have found that on the first exposure to the plus-maze it is the open aspect of the arm, rather than its elevation, that is the main anxiogenic stimulus.…”