Acetylcholine-dopamine balance hypothesis in the striatum: an update.
The imbalance between cholinergic activity and dopaminergic activity in the striatum causes a variety of neurological disorders, such as Parkinson's disease. During sensorimotor learning, the arrival of a conditioned stimulus reporting a reward evokes a pause response in the firing of the tonically active cholinergic interneurons in targeted areas of the striatum, whereas the same stimulus triggers an increase in the firing frequency of the dopaminergic neurons in the substantia nigra pars compacta. The pause response of the cholinergic interneurons begins with an initial depolarizing phase followed by a pause in spike firing and ensuing rebound excitation. The timing of the pause phase coincides well with the surge in dopaminergic firing, indicating that a dramatic rise in dopamine (DA) release occurs while nicotinic receptors remain unbound by acetylcholine. The pause response begins with dopamine D5 receptor-dependent synaptic plasticity in the cholinergic neurons and an increased GABAergic IPSP, which is followed by a long pause in firing through D2 and D5 receptor-dependent modulation of ion channels. Inactivation of muscarinic receptors on the projection neurons eventually yields endocannabinoid-mediated, dopamine-dependent long-term depression in the medium spiny projection neurons. Breakdown of acetylcholine-dopamine balance hampers proper functioning of the cortico-basal ganglia-thalamocortical loop circuits. In Parkinson's disease, dopamine depletion blocks autoinhibition of acetylcholine release through muscarinic autoreceptors, leading to excessive acetylcholine release which eventually prunes spines of the indirect-pathway projection neurons of the striatum and thus interrupts information transfer from motor command centers in the cerebral cortex.
Aosaki
Toshihiko
T
Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. aosaki@tmig.or.jp
Miura
Masami
M
Suzuki
Takeo
T
Nishimura
Kinya
K
Masuda
Masao
M
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002799:Cholinergic Fibers / Q000378:metabolism / Q000502:physiology*; D003213:Conditioning, Psychological / Q000502:physiology; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007395:Interneurons / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology
D000109:Acetylcholine; D004298:Dopamine