Reversal of akinesia in experimental parkinsonism by GABA antagonist microinjections in the pedunculopontine nucleus

Abstract

Recent studies, mainly in animals, have shown that the pedunculopontine nucleus (PPN) in the upper brainstem has extensive connections with several motor centres in the CNS. This structure has also been implicated in the akinesia seen in patients with Parkinson's disease. Here we demonstrate that microinjection of gamma-aminobutyric acid (GABA) receptor A antagonist substance, bicuculline, into the PPN of non-human primates (n = 2) rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in significant improvement of akinesia. The effect of bicuculline microinjection in the PPN matches that of oral administration of L-dopa. This finding opens up new possibilities in the management of akinesia, the most intractable symptom of advanced Parkinson's disease.

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

“…Since increases in bursty and oscillatory activity in the STN are associated with inphase increases in oscillatory activity in the SNpr in the lesioned rat , the results from this study suggest that PPN neurons are more influenced by trough-locked inhibitory input from the SNpr resulting in predominantly peak-locked PPN firing out of phase with firing in the MCx. These results also corroborate observations in PD patients and evidence from parkinsonian non-human primates that suggest that the PPN is over-inhibited in PD (Nandi et al, 2002;Jenkinson et al, 2004;Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007).…”

“…Low frequency stimulation, generally thought to drive neuronal activity, is found to be most therapeutically effective when stimulating the PPN in PD patients (Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007) and studies in non-human primates suggest that the PPN is overinhibited in PD (Kojima et al, 1997;Munro-Davies et al, 1999;Matsumura and Kojima, 2001;Nandi et al, 2002;Jenkinson et al, 2004). Our results also suggest that the PPN is dominated by inhibitory oscillatory input from the SNpr in the parkinsonian brain.…”

“…Non-human primate and patient data suggest that the PPN is overinhibited in PD. While excitotoxic lesions of the PPN in normal primates cause akinesia (Kojima et al, 1997;Munro-Davies et al, 1999;Matsumura and Kojima, 2001), lowfrequency (2.5-10 Hz) stimulation (Jenkinson et al, 2004) or pharmacological disinhibition (Nandi et al, 2002) of the PPN can dramatically improve motor behavior in parkinsonian MPTP-lesioned primates. Stimulation in the 10-25 Hz range, generally thought to drive local neuronal activity, is also effectively used in the PPN to ameliorate motor symptoms in PD patients (Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007).…”

Lesion of the centromedian thalamic nucleus in MPTP‐treated monkeys

“…Nevertheless, past experiences showing a robust effect of STN or PPN lesions similarly used two monkeys. 42,43,48 We are therefore obliged to conclude that selective lesion of the CM projection to the basal ganglia in MPTP-treated monkeys is unlikely capable of improving the parkinsonian state or eliminating levodopa-induced dyskinesias.…”

“…Nevertheless, past experiences showing a robust effect of STN or PPN lesions similarly used two monkeys. 42,43,48 We are therefore obliged to conclude that selective lesion of the CM projection to the basal ganglia in MPTP-treated monkeys is unlikely capable of improving the parkinsonian state or eliminating levodopa-induced dyskinesias.The negative findings presented here should not discard a putative role of the CM in movement control. The parkinsonian and dyskinetic states are relatively simple functional situations seen as opposite poles of abnormal motor behaviors.…”