Alpha-2 agonists induce amnesia through activation of the Gi-protein signalling pathway.
The post-receptorial mechanism of the amnesic action of the alpha2-agonists clonidine and guanabenz was investigated in the mouse passive avoidance test. Animals were i.c.v. injected with pertussis toxin (PTX) or with antisense oligonucleotides, complementary to the sequence of the alpha-subunit mRNA of Gi1, Gi2, Gi3, Go1 and Go2 proteins. The administration of PTX (0.25 microg per mouse i.c.v.) reversed the amnesia induced by both alpha2-agonists. Similarly, anti-Gialpha1 (6.25-12.5 microg per mouse i.c.v.), anti-Gialpha3 (3.12-12.5 microg per mouse i.c.v.), anti-Goalpha1 (12.5-25 microg per mouse i.c.v.) antagonised the detrimental effect induced by clonidine and guanabenz. By contrast, pretreatment with anti-Gialpha2 (3.12-25 microg per mouse i.c.v.) and anti-Goalpha2 (12.5-25 microg per mouse i.c.v.) never modified the impairment of memory processes induced by the alpha2-agonists. At the highest effective doses, none of the compounds used impaired motor coordination (rota rod test), nor modified spontaneous motility and inspection activity, (hole board test). These results indicate the involvement of Gi1, Gi3, and Go1, but not Gi2 and Go2, protein subtypes in the transduction mechanism responsible for the induction of amnesia by clonidine and guanabenz.
Galeotti
N
N
Department of Preclinical and Clinical Pharmacology, Viale G. Pieraccini 6, I-50139 Florence, Italy.
Bartolini
A
A
Ghelardini
C
C
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology* / Q000633:toxicity; D000647:Amnesia / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D008297:Male; D051379:Mice; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D003000:Clonidine