Amphetamine-induced appetitive 50-kHz calls in rats: a marker of affect in mania?

Animal models aimed to mimic mania have in common the lack of genuine affective parameters. Although rodent amphetamine-induced hyperlocomotion is a frequently used behavioral model of mania, locomotor activity is a rather unspecific target for developing new pharmacological therapies, and does not necessarily constitute a cardinal symptom in bipolar disorder (BD). Hence, alternative behavioral markers sensitive to stimulants are required. Since d-amphetamine induces appetitive 50-kHz ultrasonic vocalizations (USV) in rats, we asked whether established or potential antimanic drugs would inhibit this effect, thereby possibly complementing traditional analysis of locomotor activity. Amphetamine-treated rats (2.5 mg/kg) were systemically administered with the antimanic drugs lithium (100 mg/kg) and tamoxifen (1 mg/kg). Since protein kinase C (PKC) activity has been implicated in the pathophysiology of bipolar disorder and the biochemical effects of mood stabilizers, the new PKC inhibitor myricitrin (10, 30 mg/kg) was also evaluated. We demonstrate for the first time that drugs with known or potential antimanic activity were effective in reversing amphetamine-induced appetitive 50-kHz calls. Treatments particularly normalized amphetamine-induced increases of frequency-modulated calls, a subtype presumably indicative of positive affect in the rat. Our findings suggest that amphetamine-induced 50-kHz calls might constitute a marker for communicating affect that provides a useful model of exaggerated euphoric mood and pressured speech. The antimanic-like effects of the PKC inhibitors tamoxifen and myricitrin support the predictive and etiological validity of both drugs in this model and highlight the role of PKC signaling as a promising target to treat mania and psychosis-related disorders.