GABA‐mimetic drugs enhance apomorphine‐induced contralateral turning in rats with unilateral nigrostriatal dopamine denervation: Implications for the therapy of Parkinson's disease

Abstract

The underlying mechanisms responsible for advanced Parkinson's disease's becoming refractory to dopamimetic therapies are unclear. Postmortem brain studies indicate that patients with Parkinson's disease have decreased basal ganglia gamma-aminobutyric acid (GABA) function in addition to profound striatal dopamine (DA) deficiencies. In experimental animals, GABA-utilizing striatal and nigral projection neurons appear to mediate motor behaviors arising from the stimulation of striatal DA receptors by agonists. We have examined the ability of directly and indirectly acting GABA-mimetic drugs to alter turning behavior elicited by administering apomorphine, a DA agonist, to rats with unilateral lesions of dopaminergic nigrostriatal neurons. Low doses of directly acting postsynaptic GABA agonists (progabide, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin--3-01) or a neuronal GABA transport inhibitor (SKF 100330-A) potentiate apomorphine-induced turning. Higher doses of these agents or acute inhibition of GABA catabolism inhibits turning. Our results suggest that low doses of certain GABA mimetics will improve the responses of patients with Parkinson's disease to concurrent DA receptor agonist therapy.

Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson’s Disease? The Potential Role of Zolpidem in the Treatment of Parkinson’s Disease

“…In the late 1980s, some opinion leaders in the field of movement disorders [ 9 ] had suggested that drugs that may specifically enhance GABAergic neurotransmission may be potentially helpful in the treatment of PD, but at that time there was scanty evidence supporting this intriguing hypothesis. In particular, a pilot study had suggested that GABA agonists such as progabide [ 10 ] might be helpful in the treatment of motor symptoms of patients with PD, in agreement with an experimental study in rats showing the effects of progabide [ 11 ] on motor function (turning behaviour) and with previous postmortem findings showing abnormalities in the GABAergic systems of the brain of patients with Parkinson's disease [ 12 ].…”