Adrenergic agents inhibit rapid increases in cerebellar Purkinje cell glutamic acid decarboxylase (GAD67) mRNA levels after climbing fiber lesions or reserpine treatment.
Loss of the inferior olive-climbing fiber input to the cerebellar cortex after treatment with the neurotoxin 3-acetylpyridine (3-AP) has been reported to double the simple spike activity of the cerebellar Purkinje cell and eliminates complex spike activity. This is quickly followed by a three- to fourfold increase in Purkinje cell mRNA for the 67 kDa form of glutamic acid decarboxylase (GAD), a synthetic enzyme for the neurotransmitter GABA. Treatment with the indirectly acting sympathomimetic amphetamine or the direct acting beta 2 adrenergic agonist clenbuterol inhibited the increase in GAD67 mRNA, and this inhibition was blocked by pretreatment with the beta receptor antagonist propranolol. The activity-enhancing effect of 3-AP treatment on cerebellar neurons was confirmed by extracellular recordings. Clenbuterol treatment prevented the increase in neuronal firing without altering lesion induction or the loss of complex spikes, and propranolol treatment produced a partial reversal of the inhibitory effect of clenbuterol on the neuronal firing rate. These results suggest that beta receptor-mediated effects on cerebellar neuronal activity may prevent the increase in mRNA levels, but that firing rate-independent beta-mediated effects on genomic expression may also play a role. A role for noradrenergic systems in modulating GAD67 mRNA is also supported by the finding that reducing endogenous cerebellar norepinephrine levels by treatment with reserpine increased Purkinje cell GAD67 mRNA levels (250% of control), and this also was inhibited by clenbuterol treatment.
Drengler
S M
SM
Department of Pharmacology and Molecular Biology, Finch University of Health Sciences, Chicago Medical School, Illinois 60064, USA.
Lorden
J F
JF
Billitz
M S
MS
Oltmans
G A
GA
D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D002976:Clenbuterol / Q000494:pharmacology; D004594:Electrophysiology; D005968:Glutamate Decarboxylase / Q000235:genetics*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology; D009847:Olivary Nucleus / Q000187:drug effects / Q000473:pathology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology*
D018663:Adrenergic Agents; D009498:Neurotoxins; D011725:Pyridines; D012333:RNA, Messenger; C010835:3-acetylpyridine; D012110:Reserpine; D005968:Glutamate Decarboxylase; D002976:Clenbuterol