Involvement of the sigma1 (sigma1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41.
OBJECTIVE
Tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41) is a potent muscarinic and sigma(1) (sigma (1)) receptor ligand. The sigma (1) receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti-amnesic and antidepressant DRUGS. WE HAVE HERE ANALYSED THE SIGMA (1) COMPONENT IN THE BEHAVIOURAL EFFECTS OF ANAVEX1-41.


METHODS
Binding of ANAVEX1-41 to muscarinic and sigma (1) receptors were measured using cell membranes. Behavioural effects of ANAVEX1-41 were tested in mice using memory (spontaneous alternation, passive avoidance, water-maze) and antidepressant-like activity (forced swimming) procedures.


RESULTS
In vitro, ANAVEX1-41 was a potent muscarinic (M(1)>M(3), M(4)>M(2) with K(i) ranging from 18 to 114 nM) and selective sigma (1) ligand (sigma (1), K(i)=44 nM; sigma (2), K(i)=4 microM). In mice, ANAVEX1-41 failed to affect learning when injected alone (0.03-1 mg kg(-1)), but attenuated scopolamine-induced amnesia with a bell-shaped dose response (maximum at 0.1 mg kg(-1)). The sigma (1) antagonist BD1047 blocked the anti-amnesic effect of ANAVEX1-41 on both short- and long-term memories. Pretreatment with a sigma (1) receptor-directed antisense oligodeoxynucleotide prevented effects of ANAVEX1-41 only in the passive avoidance procedure, measuring long-term memory. ANAVEX1-41 reduced behavioural despair at 30 and 60 mg kg(-1), without involving the sigma (1) receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide.


CONCLUSIONS
ANAVEX1-41 is a potent anti-amnesic drug, acting through muscarinic and sigma (1) receptors. The latter component may be involved in the enhancing effects of the drug on long-term memory processes.
Espallergues
J
J
CNRS, FRE2693, Montpellier, France.
Lapalud
P
P
Christopoulos
A
A
Avlani
V A
VA
Sexton
P M
PM
Vamvakides
A
A
Maurice
T
T
D000647:Amnesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D013550:Swimming; D000097605:Sigma-1 Receptor
D000928:Antidepressive Agents; D005663:Furans; D018727:Muscarinic Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D011976:Receptors, Muscarinic; D017480:Receptors, sigma; D012601:Scopolamine; D000097605:Sigma-1 Receptor; C525028:tetrahydro-N, N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride