Investigation of diazepam efficacy on anxiety-like behavior in hemiparkinsonian rats

• Hemiparkinsonian rats have higher anxiety-like behavior than non-parkinsonian rats.
• Hemiparkinsonian rats have the greatest prevalence of ‘high anxiety’ behavior.
• Diazepam is least efficacious in high anxiety hemiparkinsonian rats.

There is growing recognition that anxiety disorders have a greater impact on quality of life in Parkinson’s disease than motor symptoms. Yet, little is known about the pathophysiology underlying this non-motor symptom in Parkinson’s disease which poses a considerable barrier in developing effective treatment strategies. Here, we administered diazepam to hemiparkinsonian and non-parkinsonian rats and assessed its efficacy in three anxiety behavioral tests. At present, no information about this exists in preclinical research with sparse data in the clinical literature. Moreover, diazepam is an acute anxiolytic which makes this drug a suitable research tool to unmask differences in anxiety-like behavior. Using the unilateral, medial forebrain bundle 6-hydroxydopamine rat model of Parkinson’s disease, we noted that hemiparkinsonian rats had more baseline anxiety-like behavior with 60% of them exhibiting high anxiety (HA) behavior in the elevated plus maze. In contrast, 41% of sham-lesioned rats and 8% of naïve rats exhibited HA behavior. Next, we employed the elevated plus maze and noted that diazepam (1.5 mg/kg) was anxiolytic in low anxiety (LA) sham-lesioned (p = 0.006) and HA sham-lesioned rats (p = 0.016). Interestingly, diazepam was anxiolytic for LA hemiparkinsonian rats (p = 0.017), but not for HA hemiparkinsonian rats (p = 0.174) despite both groups having similar motor impairment and parkinsonian phenotype. Overall, diazepam administration unmasked differences in anxiolytic efficacy between HA hemiparkinsonian rats, LA hemiparkinsonian rats and non-parkinsonian rats. Our data suggests that neuro-circuits involved in anxiety-like behavior may differ within these groups and posits that diazepam may have reduced efficacy in certain individuals with PD anxiety disorders.