50-kHz ultrasonic vocalizations in hemiparkinsonian rats repeatedly treated with dopaminomimetic drugs as a possible behavioral marker of the affective properties of dopamine-replacing therapy in Parkinson's disease

The current leading therapeutic strategy used to manage Parkinson’s disease (PD) is the so-called dopamine replacement therapy (DRT). However, the prolonged use of DRT is associated with the onset of both motor and non-motor complications. The latter include alterations in the emotional state and iatrogenic psychiatric-like disturbances. As of today, the preclinical investigation of iatrogenic psychiatric-like disturbances in PD is limited, due to a substantial lack of effective experimental models that allow studying the affective properties of dopaminomimetic drugs in parkinsonian animals. In this regard, this study evaluated the emission of 50-kHz ultrasonic vocalizations (USVs), a behavioral marker of positive affect, in rats bearing a unilateral lesion with 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle. Apomorphine (2 or 4 mg/kg, i.p.), L-3,4-dihydroxyphenilalanine (L-DOPA, 6 or 12 mg/kg, i.p.), or pramipexole (2 or 4 mg/kg, i.p.) were administered in a test cage (× 5 administrations) on alternate days. Seven days after treatment discontinuation, rats were re-exposed to the test cage to measure conditioned calling behavior and thereafter received a drug challenge. The total numbers of 50-kHz USVs and the numbers of “flat”, “trill” and “frequency modulated” (FM) calls were scored, to ascertain whether apomorphine, L-DOPA and pramipexole influenced general calling behavior and/or the emission of specific categories of calls that are thought to possess dissimilar behavioral significance. Moreover, the presence of correlations between the numbers of calls emitted and the numbers of contralateral rotations performed was evaluated, to disclose the presence of similarities and/or differences in the effects that apomorphine, L-DOPA and pramipexole elicited on emotional state and motor function. Furthermore, since the nucleus accumbens (NAc) plays a key role in the initiation of 50-kHz USVs in rats, this study evaluated the levels of Zif-268 (a marker of neuronal activation) in the NAc, to further clarify which neuronal circuits regulate the emission of 50-kHz USVs in hemiparkinsonian rats treated with dopaminomimetic drugs. Hemiparkinsonian rats treated with either apomorphine or L-DOPA, but not pramipexole, markedly vocalized during repeated treatment and after drug challenge, and showed conditioned calling behavior. Moreover, apomorphine, L-DOPA and pramipexole elicited different patterns of 50-kHz USV emissions and contralateral rotational behavior, suggesting that 50-kHz USV emissions and rotational behavior are not interchangeable measures in the study of the affective properties of dopaminomimetic drugs. Furthermore, hemiparkinsonian rats treated with either apomorphine or L-DOPA displayed modifications in the emission of categorized calls that varied with the drug, dose, and administration day considered, leaving the question open as to whether it is general calling behavior or the emission of categorized calls that marks the effects of dopaminomimetic drugs on the emotional state of hemiparkinsonian rats. Finally, the results of the present study also suggest that NAc is a brain region involved in the vocal expression of positive affect in hemiparkinsonian rats treated with dopaminomimetic drugs used in the DRT of PD. Taken together, these results suggest that measuring the emission of 50-kHz USVs may be a relevant experimental tool for: i) further characterizing at the preclinical level the effects that dopaminomimetic drugs used in the DRT of PD elicit on the emotional state, and ii) study how these effects may favor the manifestation of behavioral modifications that mimic in experimental rats the behavioral abnormalities featuring the iatrogenic psychiatric-like disturbances that may occur in PD patients.