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

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Parkinson disease (PD) is caused by degeneration of neuronal, particularly dopaminergic, cells in the substantia nigra pars compacta (Dauer & Przedborski, 2003). The loss of dopaminergic input interferes with the overall transmitter availability in the striatum leading to an imbalance of transmitter systems including glutamate, gamma‐aminobutyric acid, and acetylcholine (ACh) (Calabresi, Picconi, Parnetti, & Di, 2006). The strong branching of striatal cholinergic interneurons (ChIs), the large population of medium spiny neurons (MSNs), and the high expression of dopamine receptors underline the particular importance of the cholinergic and dopaminergic transmitter system (Lim, Kang, & McGehee, 2014). They modulate each other directly via metabotropic muscarinic receptors (on MSNs) and dopaminergic receptors (on ChIs) and indirectly via autoreceptor activation and altered glutamatergic and GABAergic transmission (Kljakic, Janickova, Prado, & Prado, 2017). In the case of dopamine depletion as observed in PD, reduced cholinergic autoreceptor function contributes to the abundance in ACh (Ding et al., 2006). Therefore, the increased activation of metabotropic acetylcholine receptors (AChRs) (accompanied by elevated GABAergic and changed glutamatergic receptor activation) alters the signal transduction of MSNs as the main striatal output, which is already less modulated by dopamine. Besides strategies to compensate dopamine deficits, attempts have been made to restore the transmitter balance—for instance, by antagonizing ACh. As an example, it was recently shown that the ablation of ChIs, the main source of striatal ACh (Oldenburg & Ding, 2011), diminished the risk of induced dyskinesia in L‐DOPA–treated hemiparkinsonian mice (Won, Ding, Singh, & Kang, 2014).
A promising strategy to functionally antagonize striatal cholinergic neurotransmission is local application of botulinum neurotoxin A (BoNT‐A), which blocks the release from presynaptic terminals via degradation of the synaptosomal‐associated proteins of 25 kDa (Dong et al., 2006; Verderio et al., 2006). BoNT‐A is already in use, particularly in symptomatic therapies of drooling in PD (Egevad, Petkova, & Vilholm, 2014) and in disorders of cholinergic hyperactivity (e.g., dystonia, hyperhidrosis, strabismus, blepharospasm) (Lim & Seet, 2010).
We have previously investigated a potential therapeutic application of BoNT‐A in the 6‐hydroxydopamine (6‐OHDA) model of PD (Wree et al., 2011). In this model, unilateral injection of 6‐OHDA into the medial forebrain bundle (MFB) leads to rapid degeneration of nigrostriatal neurons (Meredith, Sonsalla, & Chesselet, 2008), asymmetry in forelimb use (Schallert, Fleming, Leasure, Tillerson, & Bland, 2000), and drug‐induced rotations (Ungerstedt & Arbuthnott, 1970). On the molecular level, the loss of nigrostriatal dopamine input causes an imbalance of dopaminergic and cholinergic neurotransmission in the caudate–putamen (CPu). The degeneration of nigrostriatal terminals is also reflected in reduced concentrations of proteins associated with dopamine production and transport (tyrosine hydroxylase and dopamine transporters [DATs]; Sun et al., 2011), whereas the long‐lasting impact of 6‐OHDA on proteins related to ACh is not yet clear. For instance, while Ma et al. (2014) reported a decrease in striatal choline acetyltransferase concentration following 6‐OHDA infusions, no changes could be observed by Pezzi, Checa, & Alberch (2005). We used the 6‐OHDA model to test the efficacy of a single intrastriatal administration of BoNT‐A. We found significant improvements in motor impairment for up to 6 months after BoNT‐A application (Wree et al., 2011). Histologically, a remarkable number of varicosities were observed at neuronal processes, while the overall quantity of striatal neurons, ChIs, and tyrosine hydroxylase levels remained unchanged (Itakura et al., 2014; Mehlan et al., 2016; Wree et al., 2011). The number of varicosities declined over time, while remaining varicosities exhibited permanently elevated volumes (Mehlan et al., 2016). There were no changes in cognitive abilities or in striatal volume at the BoNT‐A injection site (Antipova et al., 2013; Holzmann et al., 2012).

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