Stimulation of GABAB receptors increases the expression of the proenkephalin gene in slice cultures of rat neocortex.
In rat neocortex the proenkephalin gene is expressed in GABAergic interneurons. Immunocytochemistry and in situ hybridisation show only a small number of cells in layers II to VI which express the gene. In organotypic slices of rat neocortex, the GABAA receptor inhibitor bicuculline methiodide enhances the expression of the gene in numerous cells. In the present study, we have investigated how GABA regulates the expression of the proenkephalin gene. The GABAA receptor antagonist bicuculline methiodide and the inhibitor of ligand-gated Cl- channels picrotoxin strongly enhanced the expression of the gene in numerous cells which were arranged in neocortical layers II/III and V/VI. Since bicuculline methiodide can also block Ca(++)-activated K+ channels, the possible involvement of such channels was tested. However, apamin which blocks only Ca(++)-activated K+ channels had no effect on the expression of the proenkephalin gene indicating that the effect of bicuculline methiodide was due to inhibition of GABAA receptors. In addition, the GABAB receptor agonist baclofen increased the neocortical expression of the proenkephalin gene mainly in cells located in layers V/VI of the neocortex. The effect of baclofen was inhibited by the GABAB receptor antagonists CGP35348 and CGP52432. Also muscimol, an agonist at GABAA receptors, enhanced the expression of the proenkephalin gene. This effect was blocked by CGP52432 confirming previous observations that muscimol can also stimulate GABAB receptors. Our results indicate that GABA can regulate the expression of the opioid peptide in neocortical neurons in a bidirectional manner. The expression is suppressed via GABAA and enhanced via GABAB receptors.
Mörl
F
F
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Albert-Strasse 25, 79104 Freiburg, Germany.
Leemhuis
J
J
Lindemeyer
K
K
Grass
N
N
Nörenberg
W
W
Meyer
D K
DK
D000818:Animals; D004745:Enkephalins / Q000096:biosynthesis* / Q000235:genetics*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*
D004745:Enkephalins; D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D011498:Protein Precursors; D018080:Receptors, GABA-B; C029992:proenkephalin