Putative neurotoxicity of SKF 38393 and other D1 dopaminergic drugs investigated in rat striatum.
The recently alleged neurotoxicity of the D1 receptor agonist, SKF 38393, was investigated in rat striatum by measuring the enzymes acetylcholinesterase (AChE) and glutamate decarboxylase (GAD). First, unilateral intrastriatal microinjection of the excitotoxin kainic acid (2 micrograms in 1 microliter) was shown to evoke vigorous contraversive circling, followed 1 or 2 weeks later by profound decreases in striatal AChE (24 and 54%), GAD (51 and 75%), and protein (36 and 47%), as well as loss of GAD (45% at 2 weeks) in the ipsilateral substantia nigra. Similar striatal treatments with SKF 38393 (30 micrograms in 0.5-1 microliter), the related benzazepines SKF 82526 (D1 agonist, 30 micrograms in 1 microliter) and SCH 23390 (D1 antagonist, 5 micrograms in 1 microliter), or the phenanthridine D1 agonist CY 208-243 (5 micrograms in 1 microliter) failed to affect the rats' behaviour or their striatal levels of AChE, GAD, and protein. Intrastriatal SKF 38393 (30 micrograms in 0.5 microliter) also had no influence on these enzymes in the substantia nigra. It is concluded that none of the D1 dopaminergic compounds examined here was neurotoxic toward the many different cell groups that contain AChE and/or GAD in the striatum.
Isaac
L
L
Department of Pharmacology, School of Pharmacy, London, England.
Mills
R
R
Fowler
L J
LJ
Starr
B S
BS
Starr
M S
MS
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007267:Injections; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D015259:Dopamine Agents; D009498:Neurotoxins; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000110:Acetylcholinesterase; D005968:Glutamate Decarboxylase; D007608:Kainic Acid