Role of Gi Proteins in the Antidepressant-like Effect of Amitriptyline and Clomipramine

Abstract

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotides directed against the ␣ subunit of different Gi-proteins (anti-For the past several decades, antidepressant drugs have been widely used in the treatment of clinical depression and other psychiatric disorders. Several distinct pharmacological compounds show therapeutic efficacy. These include monoamine oxidase inhibitors, tricyclic compounds, selective serotonin and norepinephrine reuptake inhibitors, as well as some atypical drugs. Numerous studies have examined the effects of antidepressants on neurotransmitter metabolism, turnover, and receptor sensitivity and several theories on their mechanism of action have been proposed. These include the inhibition of monoamine transporter activity in presynaptic membranes (Schildkraut 1965), downregulation of ␤ -adrenoceptors (Mazzola-Pomietto et al. 1994), alteration at cholinergic, dopaminergic or GABAergic receptors (Henringer and Charney 1987). However, the molecular mechanism of action underlying the therapeutic effect of antidepressants is still unclear.Despite their diversity, these treatments subserve the same final clinical effect. Therefore, the possibility that these diverse agents converge on a single postreceptorial target evoked a great research interest. Since most neurotransmitter receptors and neuromodulators are coupled to intracellular effectors through G-proteins (Birnbaumer 1990), recent studies searching for a com-

Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells

“…It remains unclear as to how amitriptyline-evoked G i/o activation is related to the antidepressive effect of amitriptyline. An in vivo study showed that intracerebroventricular administration of PTX completely prevented the antidepressant-like effect of amitriptyline in the mouse forced swimming test (64). Furthermore, Galeotti et al (64) showed that G i1 , Gi2, G i3 , and G o1 , but not G o2 , play important roles in the antidepressant-like effect of amitriptyline, administering antisense oligonucleotides against the ␣-subunits of the G protein.…”

“…An in vivo study showed that intracerebroventricular administration of PTX completely prevented the antidepressant-like effect of amitriptyline in the mouse forced swimming test (64). Furthermore, Galeotti et al (64) showed that G i1 , Gi2, G i3 , and G o1 , but not G o2 , play important roles in the antidepressant-like effect of amitriptyline, administering antisense oligonucleotides against the ␣-subunits of the G protein. This study confirms the importance of PTX-sensitive G i/o in the effect of antidepressants such as amitriptyline and further elaborates a novel mechanism that could explain the efficacy of antidepressants, increased GDNF production by astrocytes.…”

Contribution of G inhibitory protein alpha subunits in paradoxical hyperalgesia elicited by exceedingly low doses of morphine in mice

“…The sequences of the above ODNs and their characterization are described in a previous paper (Galeotti et al, 2002) and base composition is reported in Table 1. As previously established (Standifer et al, 1996;Sanchez-Blazquez and Garzon, 1998;Galeotti et al, 2002), we used the lowest effective aODN doses (25 μg) to ensure the selectivity of the response in hot plate test. The aODNs, mODNs and dODNs were supplied to mice by i.c.v.…”

Pharmacological Activation Gi/o Protein Increases Glial Cell Line-Derived Neurotrophic Factor Production through Fibroblast Growth Factor Receptor and Extracellular Signal-Regulated Kinase Pathway in Primary Cultured Rat Cortical Astrocytes

“…Previous in vivo studies have demonstrated behavioral response to antidepressants involves increasing GDNF production and PTX-sensitive signaling in the brain. 39,40) The potentiating Gi/o protein signaling efficacy of antidepressant by combination treatment with Gi/o protein activator could boost endogenous GDNF and BDNF production. This would suggest a potential mechanism that could be targeted in the development of novel antidepressant treatments.…”