Intrastriatal administration of botulinum neurotoxin A normalizes striatal D₂R binding and reduces striatal D₁R binding in male hemiparkinsonian rats

Abstract

Cerebral administration of botulinum neurotoxin A (BoNT-A) has been shown to improve disease-specific motor behavior in a rat model of Parkinson disease (PD). Since the dopaminergic system of the basal ganglia fundamentally contributes to motor function, we investigated the impact of BoNT-A on striatal dopamine receptor expression using in vitro and in vivo imaging techniques (positron emission tomography and quantitative autoradiography, respectively). Seventeen male Wistar rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and assigned to two treatment groups 7 weeks later: 10 rats were treated ipsilaterally with an intrastriatal injection of 1 ng BoNT-A, while the others received vehicle (n 5 7). All animals were tested for asymmetric motor behavior (apomorphine-induced rotations and forelimb usage) and

Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior

“…Even 12 months after the second BoNT-A application, body weights of BoNT-A- (551 ± 11 g; mean ± SEM) or sham-injected rats (581 ± 14 g) did not differ significantly. Thus, repetitive intrastriatal BoNT-A had no negative effect on the health of the rats, being in line with unaltered measures after the single BoNT-A application [ 12 , 39 ].…”

“…In the striatum, BoNT-A is thought to act in two main directions: ACh release of the tonically active cholinergic interneurons is blocked [ 1 , 4 , 5 ]; and the concentrations of the dopamine D 2 receptor is reduced as shown in hemi-PD rats with D 2 receptor upregulation, as in BoNT-A-injected normal rats [ 38 , 39 ].…”

Experimental Intrastriatal Applications of Botulinum Neurotoxin-A: A Review

“…The 6-hydroxydopamine (6-OHDA) induced unilateral model of hemi-PD in rodents is well established and often used for therapy studies on motor deficits in experimental PD [ 67 , 68 , 69 , 70 , 71 , 72 ]. The group of Wree et al performed unilateral injections of 6-OHDA into the right medial forebrain bundle [ 54 , 58 , 59 , 62 , 63 , 64 ] to provoke a maximum (~90% or more) demise of dopaminergic neurons in the right SNpc [ 67 , 73 ] ( Figure 2 B). In a more incomplete degeneration model of the SNpc, Itakura et al injected 6-OHDA into the CPu [ 65 , 66 ] ( Figure 2 E).…”

“…Wree et al (2011), Antipova et al (2013, 2017), Mann et al (2018a, b) and Wedekind et al (2017) performed apomorphine-induced rotation tests one month after the lesion. Rats were considered to be hemiparkinsonian when they showed at least four apomorphine-induced rotations per minute directed contralateral to the lesion side [ 54 , 58 , 59 , 62 , 63 , 64 ]. Itakura et al (2014a, b) performed a methamphetamine-induced rotation test seven days after the striatal 6-OHDA injection and considered rats as successfully lesioned when they showed at least 1.66 rotations per minute (“50–200 turns within 30 min”) [ 65 , 66 ].…”

Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology

“…PD is characterized by an imbalanced cholinergic hyperactivity in the striatum, due to the loss of dopaminergic neurons of the substantia nigra. Since BoNT/A blocks neurotransmitter release, including acetylcholine (ACh), the toxin was injected directly into the striatum, in animal models of PD [ 32 , 33 , 55 , 56 , 57 ]. In particular, the rodent model of 6-hydroxydopamine (6-OHDA) produces a hemi-parkinsonism.…”