Metabolism of central neurotransmitters during development of tolerance to the anticonvulsant effect of clonazepam and of physical dependence on the drug in dogs.
In previous studies, development of functional tolerance to the anticonvulsant effect of clonazepam and physical dependence on the drug have been demonstrated. In the present study, dogs were treated for 6 weeks with clonazepam 0.5 mg/kg b.i.d. Under methohexital anesthesia, cerebrospinal fluid samples were taken before treatment, at 3 days (acute effect), 4 and 5 weeks (tolerance) after the start of treatment, 2 and 8 days after withdrawal and 5 weeks after the end of treatment as another control. The following transmitters or metabolites were determined: HVA, VMA, 5-HIAA, GABA, PGE2, TXB2 and 6-keto PGF1 alpha. 5-HIAA levels showed a significant rise, indicating an increased activity of the serotonergic system in the brain during development both of tolerance and withdrawal. Dopaminergic activity was not altered during treatment, but was increased after cessation of treatment, as indicated by a significant increase in HVA concentrations.
Department of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, F.R.G.
R
R
Scherkl
A
A
Hashem
E
E
Dreimann
H H
HH
Neumayer
H H
HH
Frey
D015121:6-Ketoprostaglandin F1 alpha / Q000134:cerebrospinal fluid; D000818:Animals; D000927:Anticonvulsants; D001923:Brain Chemistry / Q000187:drug effects*; D002998:Clonazepam / Q000494:pharmacology*; D015232:Dinoprostone / Q000134:cerebrospinal fluid; D004285:Dogs; D004361:Drug Tolerance; D005260:Female; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006897:Hydroxyindoleacetic Acid / Q000138:chemical synthesis; D007276:Injections, Intraventricular; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D012890:Sleep / Q000187:drug effects; D019966:Substance-Related Disorders / Q000503:physiopathology*; D013929:Thromboxane B2 / Q000134:cerebrospinal fluid; D005680:gamma-Aminobutyric Acid / Q000134:cerebrospinal fluid
D000927:Anticonvulsants; D018377:Neurotransmitter Agents; D011453:Prostaglandins; D006897:Hydroxyindoleacetic Acid; D013929:Thromboxane B2; D005680:gamma-Aminobutyric Acid; D015121:6-Ketoprostaglandin F1 alpha; D002998:Clonazepam; D015232:Dinoprostone; D006719:Homovanillic Acid