Frédérique Menzaghi

Antidepressant-like effects of the subtype-selective nicotinic acetylcholine receptor agonist, SIB-1508Y, in the learned helplessness rat model of depression

Abstract.Rationale: Epidemiological studies of smokers suggest that there is a link between nicotine and depression. Nonetheless, few studies have examined the potential use of nicotinic ligands in the treatment of depression. Objectives: The goal of this study was to evaluate the effects of SIB-1508Y, a novel subtype-selective ligand for high affinity nicotinic acetylcholine receptors (nAChRs), in the learned helplessness model of depression in rats. Methods: In this model, exposure to inescapable footshock produces a lasting deficit in escape responses emitted in a subsequent conditioned avoidance procedure (learned helplessness). The effect of SIB-1508Y on learned helplessness was compared to the clinically used antidepressants, imipramine and fluoxetine, and the non-selective nAChR ligand, nicotine. Results: Similarly to imipramine and fluoxetine, subchronic treatment (5 days) with SIB-1508Y reversed the escape deficit in the learned helplessness model in a dose dependent manner. The effect of SIB-1508Y on learned helplessness was still apparent 1 week following drug administration and was also maintained after 4 weeks of daily administration. In contrast, while nicotine was able to attenuate the learned helplessness deficit, this trend only reached statistical significance after chronic administration. The non-competitive ion channel blocker mecamylamine increased escape failures when administered alone and blocked the effects of SIB-1508Y but not imipramine. SIB-1508Y also produced an increase in avoidance responding, which suggests an enhancement of learning. Conclusion: These results not only suggest a role for nAChRs in the development of a depressive-like syndrome, but also that subtype-selective nAChR agonists, such as SIB-1508Y, may offer a novel therapeutic approach to the treatment of depression.

Conformationally restricted analogues of nicotine and anabasine

A series of conformationally restricted analogues of nicotine has been synthesized and evaluated as agonists of neuronal acetylcholine receptors. Compound 2 (SIB-1663), which selectively activated human recombinant alpha 2 beta 4 and alpha 4 beta 4 nAChRs, was shown to be active in animal models of Parkinsons disease and pain.

Antagonist of nicotinic acetylcholine receptors (nAChR) enhances formalin-induced nociception in rats: tonic role of nAChRs in the control of pain following injury

Following tissue injury, spinal neurons increase in spontaneous activity and in responsiveness to peripheral stimulation. These changes in spinal neurons may underlie abnormal pain behavior. Nicotinic acetylcholine receptor (nAChR) agonists are analgesic when evaluated in animal models of pain, but it is not known if the nAChRs differentially modulate acute and tonic pain. To test this, mecamylamine, a non-subtype selective nAChR antagonist, was systemically injected into rats prior or after hind paw injection of formalin. Formalin injection results in biphasic pain-related behaviors, characterized by a first phase (i.e. acute pain) immediately following formalin injection, then by a second phase (i.e. tonic pain) 15-60 min after formalin injection. Either pre- or post-formalin treatment with mecamylamine decreased phase 1 behaviors and significantly increased phase 2 pain behaviors in a dose-dependent manner. These results suggest that nAChRs may exert opposing effects on acute versus tonic pain and, as such, may have implications for the potential development of nAChR ligands for the treatment of pain.

The antinociceptive effect of intrathecal administration of epibatidine with clonidine or neostigmine in the formalin test in rats.

&NA; The analgesic effect of intrathecal injection of epibatidine, clonidine and neostigmine, compounds that elevate ACh, was examined in the formalin test, a model of post‐injury central sensitization in the rat. The compounds were injected alone and in combination. Intrathecal injection of epibatidine alone did not alter pain behaviors, compared to vehicle‐treated rats. Intrathecal injection of clonidine dose‐dependently reduced tonic pain behaviors (ED50±95% confidence limits=6.7±4.8 &mgr;g). The combination of clonidine and epibatidine (C:E), in the ratio of 26:1, dose‐dependently reduced tonic pain behaviors; and the ED50 of C:E was 1.1±0.98 &mgr;g a significant 6‐fold leftward shift of the dose response curve, compared with clonidine alone. The antinociceptive effect of C:E (26:1) was attenuated by pre‐treatment with the nAChR antagonist mecamylamine. Neostigmine dose‐dependently reduced tonic pain behaviors (ED50=1.5±1.3 &mgr;g). The combination of neostigmine and epibatidine, in a ratio of 8:1, significantly shifted the dose response curve 4‐fold to the left (ED50=0.4±0.3 &mgr;g). The effect is mediated in part by the activation of the nAChR and possibly by the enhanced release of ACh. These data demonstrate significant enhancement of the antinociceptive effects of spinally delivered analgesics by a nAChR agonist, suggesting that this class of compounds may have utility as adjuvants when combined with conventional therapeutics.