Lithium decreases 5-HT1A and 5-HT2 receptor and ?2-adrenoreceptor mediated function in mice

Abstract

Lithium administration (LiC1, 10 mmol/kg, SC on day 1, followed by 3 mmol/kg twice daily subsequently) for 14 days to mice produced attenuation of the hypothermic response to injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.5 mg/kg SC). Head twitch responses to the 5-HT-receptor agonist 5-methoxy-N,N-dimethyltryptamine (2.5 mg/kg IP) and to precursor loading with carbidopa (25 mg/kg, IP) and 5-hydroxytryptophan (100 mg/kg IP) were similarly attenuated. By contrast with this reduction of 5-hydroxytryptamine (5-HT) function mediated by the 5-HTIA and 5-HT2 receptor sub-types, repeated lithium administration had no effect on the motor response to a putative 5-HTIB receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)lH indole (RU 24969, 3 mg/kg IP). Alpha2 adrenoceptor function, assessed by the sedation response to elonidine (0.25 mg/kg, IP), was also attenuated by repeated lithium administration. It is proposed that these actions may explain the emergence of lithium as an adjunct to the treatment of refractory depressive illness.

The effects of Ca2+ antagonists and hydralazine on central 5‐hydroxytryptamine biochemistry and function in rats and mice

“…Nevertheless the data on the similarities between lithium and Ca2" antagonists on 5-HT function do provide a possible basis for an explanation as to why Ca2+ antagonists act similarly to antidepressants in various antidepressant screening tests (Mogilnicka et al, 1987;Geoffroy et al, 1988;Czyrak et al, 1989). It is also worth noting that lithium administration results in an attenuation of clonidine-induced hypoactivity (Goodwin et al, 1986a), an effect also produced by the Ca2+ antagonist drugs (Czyrak et al, 1989). Given these similarities between lithium and Ca2+ antagonists it is possible that the effects of Ca2+ antagonists on 5-HT function are through changes in ionic flux and disposition in the CNS.…”

“…Administration of tranylcypromine to lithium pretreated rats results in the appearance of the complete 5-HT-mediated behavioural syndrome and an enhancement of the tranylcypromine/L-tryptophan-induced syndrome (Grahame-Smith & Green, 1974). Furthermore, lithium administration to mice leads to an inhibition of headtwitch behaviour (Goodwin et al, 1986a). The major contrasting action is that repeated lithium administration leads to an enhancement of 8-OH-DPAT-induced behaviour in the rat (Goodwin et al, 1986b) whereas felodipine administration acutely or for 3 days did not alter this response.…”

Clomipramine Enhances the Excitatory Actions of Dorsal Raphe Nucleus Stimulation in Lateral Septal Neurons in the Rat

“…at least on the hippocampus [21,22], whereas 5-HT locally applied to the lateral septal nucleus produces suppression of firing [23], However, CMI pro duced a significant increase in the firing rate in lateral sep tal neurons and enhanced the effects of stimulating the dorsal raphe nucleus. CMI injected systemically produces a blockage of 5-HT uptake in vivo [10] and increases 5-HT levels, mainly in the raphe nuclei [8], a place rich in 5-HT1A receptors [14], the activation of which diminishes 5-HT release [24], An excess of 5-HT in the synaptic cleft produces a decrease in activity of the enzyme tryptophan hydroxylase [25] and in the release of 5-HT [26], In fact. CMI prevents the increase in 5-HT in rats submitted to chronic stress [27], Several 5-HT 1A agonists exert antide pressant actions [28][29][30], but at least their effects on lateral septal nuclei seem to reflect a disinhibitory process by simultaneous actions on 5-HT receptors [31 ].…”

Temperature Regulation in Depression: Functional 5HT1A Receptor Adaptation Differentiates Antidepressant Response

“…Although other systems are also relevant (Banerjee et al, 1977;Koch et al, 2002;Newton et al, 2004;Tiraboschi et al, 2004), some evidence suggests that a component of the delay in response to ADT could be attributable to the time dependent desensitization of 5-HT1A receptors. Serotonin 1A-mediated responses in animals (Goodwin et al, 1986(Goodwin et al, , 1987cGreen, 1987Green, , 1988Hensler et al, 1991;Le Poul et al, 1997;Li et al, 1994;Martin et al, 1992;Mizuta and Segawa, 1988;Sleight et al, 1988), and in humans (Lesch et al, 1990;Rausch et al, 1990) have been shown to undergo adaptive changes with chronic ADT that are not seen with acute ADT. However, no one has explored whether adaptation in 5-HT1A receptor-mediated responses could account for lack of therapeutic effect to a given antidepressant.…”