Anxiolytic Effects of Buspirone and MTEP in the Porsolt Forced Swim Test

Abstract

Traditionally, a reduction in floating behavior or immobility in the Porsolt forced swim test (FST) is employed as a predictor of antidepressant efficacy. However, over the past several years, our studies of alcohol withdrawal-induced negative affect consistently indicate the coincidence of increased anxiety-related behaviors on various behavioral tests with reduced immobility in the FST. Further, this behavioral profile correlates with increased mGlu5 protein expression within limbic brain regions. As the role for mGlu5 in anxiety is well established, we hypothesized that the reduced immobility exhibited by alcohol-withdrawn mice when tested in the FST might reflect anxiety, possibly a hyper-reactivity to the acute swim stressor. Herein, we evaluated whether or not the decreased FST immobility during alcohol withdrawal responds to systemic treatment with a behaviorally-effective dose of the prototypical anxiolytic, buspirone (5 mg/kg). We also determined the functional relevance of the withdrawal-induced increase in mGlu5 expression for FST behavior by comparing the effects of buspirone to a behaviorally effective dose of the mGlu5 negative allosteric modulator MTEP (3 mg/kg). Adult male C57BL/6J mice were subjected to a 14-day, multi-bottle, binge-drinking protocol that elicits hyper-anxiety and increases glutamate-related protein expression during early withdrawal. Control animals received only water. At 24hr withdrawal, animals from each drinking condition were subdivided into groups and treated with an IP injection of buspirone, MTEP, or vehicle, 30min prior to the FST. Drug effects on general locomotor activity were also assessed. As we reported previously, alcohol-withdrawn animals exhibited significantly reduced immobility in the FST compared to water controls. Both buspirone and MTEP significantly increased immobility in alcohol-withdrawn animals, with a modest increase also seen in water controls. No significant group differences were observed for locomotor activity, indicating that neither anxiolytic was sedating. These results provide predictive validity for increased swimming/reduced immobility in the FST as a model of anxiety and provide novel evidence in favor of mGlu5 inhibition as an effective therapeutic strategy for treating hyperanxiety during alcohol withdrawal.

mGlu5-dependent modulation of anxiety during early withdrawal from binge-drinking in adult and adolescent male mice

“…However, the 3 mg/kg MTEP dose was ineffective at attenuating any signs of anxiety-like behavior expressed by the alcohol-withdrawn adults in the present study, including those expressed during the FST. One possible explanation for the discrepancy in FST findings between our reports may relate to the timing of MTEP pretreatment as FST testing occurred approximately 1.5 h post-injection in the present study (as FST was the last assay in the battery), while FST testing occurred 30 min post-injection in our earlier work (FST was the only assay) (Lee et al, 2017a). Thus, the possibility exists that the anxiolytic effectiveness of MTEP in the FST may have dissipated over the course of the longer pretreatment interval or may have been occluded by the prior behavioral testing of the mice in the present study.…”

“…Consistent with a recent study by our group (Lee et al, 2017a), our 2-week, 3-bottle, binge drinking protocol was sufficient to elicit high voluntary alcohol consumption, with both adult and adolescent animals drinking at ‘binge’ levels (BACs ≥80 mg/dl). Also consistent with the literature (Doremus et al, 2005; Spear and Varlinskaya, 2005; SAMHSA, 2008; Vetter et al, 2007), including prior work from our group (Lee et al, 2016, 2017b), adolescent animals consumed significantly higher quantities of alcohol compared to adult drinkers across the 14-day drinking period.…”

“…We demonstrated previously that this behavioral reaction can be reversed by anxiolytic pretreatment (including 3 mg/kg MTEP), arguing that it reflects an anxiety-like response to the swim stressor (Lee et al, 2017a). However, the 3 mg/kg MTEP dose was ineffective at attenuating any signs of anxiety-like behavior expressed by the alcohol-withdrawn adults in the present study, including those expressed during the FST.…”

Prior binge-drinking history promotes the positive affective valence of methamphetamine in mice

“…On average, mice consumed 5.50 ± 0.19 g/kg alcohol in 2-h. Prior studies in our lab and others have correlated these intakes to BACs above 100 mg/dl (Fultz et al, 2017; Lee et al, 2016, 2017a; Rhodes et al, 2005). …”

“…Whether or not this blunted activity reflects alcohol withdrawal-induced lethargy or changes in emotionality cannot be delineated from the design of the present experiment. However, we have amassed considerable evidence indicating that our 2-week binge-drinking paradigm augments negative affect in mice without consistently influencing various measures of locomotor activity (Lee et al, 2016, 2017a,b). Thus, the possibility exists that the increased efficacy of MA to elicit reward in alcohol-experienced mice may relate, in part, to a reversal of the negative affective state produced by alcohol withdrawal.…”