Anxiolytic Effects of Buspirone and MTEP in the Porsolt Forced SwimTest

Traditionally, a reduction in floating behavior or immobility in the Porsolt forced swimtest is employed as a predictor of anti-depressant efficacy. However, over the pastseveral years, our studies of alcohol withdrawal-induced negative affect consistentlyindicate the coincidence of increased anxiety-related behaviors on various behavioraltests with reduced immobility in the forced swim test. Further, thisbehavioral profile correlates with increased mGlu5 protein expression within limbic brainregions. As the role for mGlu5 in anxiety is well established, we hypothesized that thereduced immobility exhibited by alcohol-withdrawn mice when tested in the forced swim testmight reflect anxiety, possibly a hyper-reactivity to the acute swim stressor. Herein, weevaluated whether or not the decreased forced swim test immobility during alcoholwithdrawal responds to systemic treatment with a behaviorally effective dose of theprototypical anxiolytic, buspirone (5 mg/kg). We also determined the functional relevanceof the withdrawal-induced increase in mGlu5 expression for forced swim test behavior bycomparing the effects of buspirone to a behaviorally effective dose of the mGlu5 negativeallosteric 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 increasesglutamate-related protein expression during early withdrawal. Control animals receivedonly water. At 24-h withdrawal, animals from each drinking condition were subdivided intogroups and treated with an intraperitoneal injection of buspirone, MTEP, or vehicle,30 min prior to the forced swim test. Drug effects on general locomotor activity were alsoassessed. As we reported previously, alcohol-withdrawn animals exhibited significantlyreduced immobility in the forced swim test compared to water controls. Both buspirone andMTEP significantly increased immobility in alcohol-withdrawn animals, with a modestincrease also seen in water controls. No significant group differences were observed forlocomotor activity, indicating that neither anxiolytic was sedating. These results providepredictive validity for increased swimming/reduced immobility in the forced swim test as amodel of anxiety and provide novel evidence in favor of mGlu5 inhibition as an effectivetherapeutic strategy for treating hyper-anxiety during alcohol withdrawal.