, Volume 231, Issue 13, pp 2567–2577 | Cite as

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

  • Marcela Pereira
  • Roberto Andreatini
  • Rainer K. W. Schwarting
  • Juan C. Brenes
Original Investigation



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.


Mania Bipolar disorder Emotion Dopamine Ultrasonic vocalizations Mood stabilizer Protein kinase C Lithium Tamoxifen Myricitrin 



This work was supported by the grant Schw 559/10-1 from the Deutsche Forschungsgemeinschaft. M. Pereira was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil). R. Andreatini received a researcher fellowship from CNPq. JC Brenes was funded by Deutscher Akademischer Austauschdienst (DAAD, Germany), and the University of Costa Rica.

Conflict of interest

The authors declare no conflicts of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of PharmacologyFederal University of Paraná (UFPR)CuritibaBrazil
  2. 2.Behavioral Neuroscience, Experimental and Biological PsychologyPhilipps-University of MarburgMarburgGermany
  3. 3.Institute for Psychological ResearchUniversity of Costa RicaSan PedroCosta Rica
  4. 4.Neuroscience Research CenterUniversity of Costa RicaSan PedroCosta Rica

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