Abstract
Evidence from structure-activity, molecular biology, ligand binding and behavioral studies has suggested potential differences in the pharmacological effects of indirect dopamine agonists. Striatal dopaminergic neurotransmission is under the regulatory control of GABAergic inputs. The ability of agonists of γ-aminobutyric acidA (GABAA) receptors to enhance stereotyped gnawing was used as a method for dissociating the pharmacological effects of indirect-acting dopamine agonists. Gnawing on corrugated cardboard was studied in C57BL/6J mice. The GABAA agonists, gaboxadol HCl (THIP) and muscimol, were not effective in augmenting gnawing in the presence of the direct-acting dopamine agonists, apomorphine, pergolide, RU 24213 or SKF 38393. In addition, THIP did not enhance the gnawing produced by cocaine, bupropion, GBR 12909 or WIN 35428. In contrast, THIP produced marked augmentation of the gnawing induced by methylphenidate, (+)-amphetamine, methamphetamine, amfonelic acid, indatraline, nomifensine, diclofensine, mazindol and GBR 12935. The qualitative differences in potentiation were not caused by differences in the maximal effect of the drugs alone, inadequate dose or routes of administration, or by differences in duration of action. Neither can the absence of potentiation be accounted for by unique effects of THIP; muscimol was only marginally effective in potentiating the effects of WIN 35428 and bupropion but completely inactive in augmenting the effects of cocaine and GBR 12909. Muscimol was efficacious in augmenting the effects of the drugs for which THIP was active. These results add to a small but growing literature that demonstrates differences in the in vitro and in vivo pharmacological effects of indirect dopamine agonists. The methods used here may help in defining the molecular and neural substrates of these differential effects.
Footnotes
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Send reprint requests to: J. M. Witkin, Ph.D., NIDA Addiction Research Center, 5500 Nathan Shock Drive, Baltimore, MD 21224.
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↵1 The animals used in these studies were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC). In conducting the research described in this report, the investigators adhered to the “Guide for the Care and Use of Laboratory Animals,” as promulgated by the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. Parts of this research were reported in abstract form (Witkin et al., 1995).
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↵2 Present address: Université de Liège, Unité de Psychologie Biologique et Pharmacopsychologie, 5, boulevard du Rectorat (B#32), Sart-Tilman - B-4000 Liège, Belgium.
- Abbreviations:
- CL
- confidence limits
- GABA
- γ-aminobutyric acid
- GBR 12909
- 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenyl-propyl]piperazine dihydrochloride
- GBR 12935
- 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine
- RU 24213
- N-n-propyl-N-phenylethyl-1-phenylethylamine
- SCH 23390
- R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- SKF 38393
- 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
- SKF 82958
- (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- THIP
- Gaboxadol HCl
- WIN 35428
- (−)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane-1,5-naphthalenedisulfonate
- Received January 16, 1997.
- Accepted September 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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