Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia

Abstract

The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…Promising neurotransmitter targets are the noradrenergic, serotonergic, GLUergic, and adenosinergic systems [181,185]. Recently, some evidence has been also produced in both animal models and in PD patients suggesting a contributory role of NO signalling in LID [178,179,[186][187][188][189]. Hitherto, the study of NO in the effects of L-DOPA has produced conflicting results.…”

“…Recently, more compelling evidence that an over-activity of NO system could contribute to the pathogenesis of LID has been obtained by using rodent-models of the disease [178,179,186,187]. For example, chronic L-DOPA treatment induced FosB expression in the striatum D1 MSNs and in NOS-positive striatal interneurons in rodent PD-models [178,193].…”

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

“…The impairment of corticostriatal eCB-induced LTD is responsible for the development of cardinal symptoms in PD such as tremor and bradykinesia and also for the appearance of detrimental side effects such as L-DOPA-induced dyskinesia [14,16]. From here, it emerges that striatal eCB-LTD represents a key target for novel therapeutics options in PD ( Figure 2).…”

The serotonin system: a potential target for anti-dyskinetic treatments and biomarker discovery

“…Recently, 5-HT has been closely linked to glutamate signalling in the striatum by inducing long-term depression, an effect that was coupled to the 5-HT1B receptor [11]. These mechanisms might be of particular interest since specific alterations in synaptic plasticity have been associated to LID [12].…”