Serotonergic modulation of receptor occupancy in rats treated with l‐DOPA after unilateral 6‐OHDA lesioning

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

“…The present study supported previous experimental findings on animal models of PD (12)(13)(14)(15)(16)(17)(18)(19) and translated them to humans. Using a series of PET imaging assessments with radioligand markers of serotonergic ( 11 C-DASB) and dopaminergic ( 11 C-raclopride) function (Figure 6), we showed that striatal serotonergic terminals contributed to abnormal levodopa-induced short-term increases in synaptic dopamine levels in PD patients with LIDs and that the dampening of the activity of these serotonergic terminals via a 5-HT 1A agonist restored synaptic dopamine to levels similar to those observed in PD stable patients and improved LIDs.…”

“…Striatal dopamine synaptic levels after levodopa administration were not influenced by buspirone pretreatment in the PD stable patient group. Our results are in line with experimental studies showing that 5-HT 1A agonists, including buspirone, are able to reduce or prevent the development of levodopa-induced abnormal involuntary movements in animal models of PD (12)(13)(14)(15)(16)(17)(18)(19). Studies using dyskinetic rats have shown that levodopa-induced abnormal involuntary movements in rats positively correlate with levels of SERT, but not with levels of dopamine transporter, in the striatum (22).…”

“…Removing striatal serotonin (5-HT) afferents, or dampening serotonergic activity with 5-HT receptor type 1A (5-HT 1A ) receptor agonists (including buspirone) or 5-HT receptor type 1B (5-HT 1B ) receptor agonists, attenuated abnormal involuntary movements without increasing parkinsonism (12)(13)(14)(15)(16)(17)(18)(19). However, this mechanism has not been investigated in vivo in PD patients.…”

NLX-112, a novel 5-HT 1A receptor agonist for the treatment of l -DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat

“…In rats that had received L-DOPA (2 mg/kg), DA levels increased to about 400% of basal levels on the lesioned side of the brain, whereas NLX-112 dose-dependently blunted this effect but did not significantly influence DA levels on the intact side of the brain ( Figure 6). This blunting of the peak in DA levels (presumably released by serotonergic neurons) provides a likely mechanism for the suppression of AIMs as discussed previously (Lindgren et al, 2010;Nahimi et al, 2012) and illustrated in Figure 9. It is interesting that the attenuation in maximal DA levels by NLX-112 does not impair the anti-akinetic effect of L-DOPA in the cylinder test (see below and Figure 3).…”

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

“…A typical example is the assessment of interactions between serotonergic and dopaminergic transmission in the disabling treatment-related complication of PD, levodopa (L-DOPA)-induced dyskinesias. Serotonin itself has a minimal role in early compensation in PD, but Carta et al's [9] hypothesis of aberrant dopamine release from serotonergic neurons after uptake of L-DOPA to explain L-DOPA induced dyskinesias was supported by both rodent studies and human PET data [14,40]. PET imaging has also provided evidence that peak-dose dyskinesia is associated with abnormally high striatal dopamine release in L-DOPA-treated patients and lesioned rodents.…”