Localized injections of midazolam into the amygdala and hippocampus induce differential changes in anxiolytic-like motor activity in mice

Abstract

Various strains of mice display a reliable increase in motor activity in response to benzodiazepines given at low to moderate doses. This hyperactivity has been described as both an anxiolytic-associated increase in exploratory activity and a nonspecific stimulant effect controlled by central neural mechanisms separate from those involved in the anxiolytic-like effects. The purpose of the current study was to investigate the neural circuitry underlying the hyperactivity effects of benzodiazepines in mice. Specifically, we examined the relationship between anxiety and motor activity after bilateral intra-amygdala or intra-hippocampal microinjections of the nonselective full benzodiazepine receptor agonist midazolam in C57BL/6 mice. Behavioral measures of anxiety and motor activity in open field were examined in mice given localized injections of 0, 2, 8 or 32 nmol of midazolam directed into the amygdala or hippocampus. Midazolam injected into the amygdala at the low dose produced an anxiolytic-like effect, as reflected by an increase in central open field activity. Higher doses injected into the amygdala produced a motor-depressant action, indicative of a drug-induced sedative effect. Infusions into the hippocampus produced a biphasic effect on motor activity with the two lower doses of midazolam producing a motor-stimulant action and the high dose producing a motor-depressant effect. Hippocampus injections produced no anxiolytic-like effects. The current findings demonstrate that injections of midazolam produced a regional dissociation of the anxiety-related and motor-related parameters and provide evidence that the stimulant and anxiolytic effects of benzodiazepines are independent phenomena regulated by different central mechanisms.

Neuronal overexpression of Glo1 or amygdalar microinjection of methylglyoxal is sufficient to regulate anxiety-like behavior in mice

“…administration of MG for 6 days reduced anxiety-like behavior in the elevated plus maze. The studies presented here build on those of Hambsch et al (2010) by administering MG to the BLA, which is strongly associated with anxiety-like behavior [8,9,11–13]. Taken together with prior studies, our data suggest that Glo1 regulates anxiety-like behavior through neurocircuitry typically associated with anxiety-like behavior.…”

“…Neuroimaging studies have reported differences in amygdala-prefrontal circuitry in patients with anxiety disorders [10]. Additionally, direct injection of midazolam, a positive allosteric modulator at GABA-A receptors (benzodiazepine), into the BLA reduces anxiety-like behavior in mice [11]. However, because Glo1 expression and MG production occur in all tissues and all brain regions, the role of the BLA in mediating the effects of MG on anxiety-like behavior have not been explored.…”

“…The BLA has long been shown to be involved in the regulation of anxiety-like behavior [8,9,11–13]. Because MG is a GABA-A receptor agonist, we hypothesized that direct injection of MG into the BLA would reduce anxiety-like behavior in the OFT.…”

“…Because MG is a GABA-A receptor agonist, we hypothesized that direct injection of MG into the BLA would reduce anxiety-like behavior in the OFT. Thus, we performed bilateral microinjections of vehicle, MG (12μM or 24 μM) or midazolam, a benzodiazepine, as a positive control [11] directly into the BLA (Fig.2A) and then measured anxiety-like behavior in the OFT.…”

Amygdala-Specific Reduction of α1-GABAAReceptors Disrupts the Anticonvulsant, Locomotor, and Sedative, But Not Anxiolytic, Effects of Benzodiazepines in Mice

“…The lateral and basolateral nuclei of the amygdala express high levels of α1-GABA A Rs, and are primary sites involved in many behavioral responses induced by BZs (Hevers and Luddens, 1998; Teuber et al, 1999; Pirker et al, 2000; Smith, 2001; Kaufmann et al, 2003; Kopp et al, 2004; Savic et al, 2005; Heldt and Ressler, 2006; Engin and Treit, 2008). To address these issues, the current study examined the behavioral, pharmacological and compensatory consequences of targeted α1-GABA A Rs deletion in the amygdala of adult mice.…”