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Dopamine influence in the striatum is essential to motor behavior and may lead to involuntary movements in pathologic conditions. The basic mechanisms lie in differential dopamine responses of medium spiny neurons (MSNs) contributing to striatal output pathways. The relationship between striatal discharge and mobility is thus critical to understanding the actions of dopamine. Using extracellular recordings in severely parkinsonian monkeys, we examined the activity changes of MSNs during different levels of dopamine stimulation. The activity of single MSNs was recorded continuously throughout conditions of parkinsonian disability, its reversal, and the exhibition of involuntary movements after levodopa administration. Parkinsonian disability was associated with robust and widely distributed increases of MSN firing. In the parkinsonian state, dopamine influx produced both increases and decreases in the discharge rate of MSNs. Furthermore, in contrast to the expected net reduction of activity, dopamine-induced recovery of mobility occurred with predominant further increases of neuronal activity. In contrast, involuntary movements were associated with a distinctive inversion of the dopamine responses. The activity increases and decreases associated with the recovery of mobility were subsequently inverted in a number of neurons, and these bidirectional changes created large differences of discharge across MSNs. Thus, a markedly dysregulated state of striatal activity develops after chronic dopamine denervation and, in such a state of MSN activity, dopamine induces altered and disproportionate responses. These findings point to the fundamental role of dopamine-mediated balance of striatal outputs for normal movement.

Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor ΔFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of ΔFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of ΔFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic ΔFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of ΔFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high ΔFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal ΔFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.

Drugs acting at cannabinoid type 1 receptors (CB1) have modulatory effects on glutamate and GABA neurotransmission in basal ganglia; thus, they potentially affect motor behavior in the parkinsonian setting. Preclinical trials with diverse cannabinoid agents have shown varied results, and the precise effects of blocking cannabinoid CB1 receptors remain uncertain. We tested behavioral effects of the selective antagonist 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzenesulfonate (CE) as monotherapy and in combination with l-DOPA in treatment-naive and l-DOPA-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys with moderate and severe parkinsonism. Motor disability and l-DOPA-induced dyskinesias were scored with a standardized scale after subcutaneous drug administration, and plasma levels of l-DOPA were determined by high-performance liquid chromatography/electrochemical detection. CE doses ranged from 0.03 to 1 mg/kg, and l-DOPA methyl ester doses were selected as optimal and suboptimal doses (maximal and 50% of maximal responses, respectively). CE had no intrinsic effects on motor behavior regardless of the degree of parkinsonism (moderate or severe groups) or previous drug exposure (“de novo” or after l-DOPA priming). Initial CE administration did not affect development of l-DOPA antiparkinsonian responses. In coadministration trials, CE, in a dose-dependent manner, increased responses to l-DOPA (suboptimal doses). These effects were seen in both moderate and severely parkinsonian monkeys as a 30% increase of, predominantly, response duration with no effects on l-DOPA pharmacokinetics. CE did not modify levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1 antagonists may enhance the antiparkinsonian action of dopaminomimetics and possibly facilitate the use of lower doses, thereby reducing side effects.

Significance: This study is important because it provides the first account of the electrophysiological activity in the human striatum, and it demonstrates major and distinctive abnormalities of neuronal firing in Parkinson’s disease (PD). Up until now, circuit models of PD were based on striatal changes that were never demonstrated in patients. We compared striatal recordings across patients with PD and other neurological disorders [dystonia and essential tremor (ET)], and correlative findings in nonhuman primates. Therefore, the data provided by the present study significantly contribute to understand the role of striatal mechanisms in basal ganglia circuits and in the pathophysiology of PD. Additionally, the study originally reports altered striatal activity in dystonia and activity compatible with unchanged striatal function in ET.