Abstract
The antidepressant drug amitriptyline is used in the treatment of clinical depression and a variety of neurological conditions such as anxiety, neuropathic pain disorders and migraine. Antidepressants are associated with both therapeutic and untoward effects, and their use in the elderly has tripled since the mid-1990s. Because of this widespread use, we are interested in testing the acute effects of amitriptyline on synaptic transmission at therapeutic concentrations well below those that block voltage-gated calcium channels. We found that 3 μM amitriptyline reduced the frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and reduced quantal content in mice at ages of 7–10 mo. and 23–25 mo., suggesting a presynaptic mechanism of action that does not diminish with age. We employed a reduced synaptic preparation of the basal forebrain (BF) and a new optogenetic aging model utilizing a bacterial artificial chromosome (BAC) transgenic mouse line with stable expression of the channelrhodopsin-2 (ChR2) variant H134R specific for GABAergic neurons [VGAT-ChR2(H134R)-EYFP]. This model enables optogenetic light stimulation of specific GABAergic synaptic terminals across aging. Age-related impairment of circadian behavior was used to confirm predictable age-related changes associated with this model. Our results suggest that low concentrations of amitriptyline act presynaptically to reduce neurotransmitter release and that this action is maintained during aging.
Highlights
Amitriptyline (AMI) is a tricyclic antidepressant used for various neurological disorders such as anxiety, depression, neuropathic pain disorders and migraine (Baldessarini, 2006; Couch et al, 2011; Moore et al, 2015; Urquhart et al, 2018)
The purpose of the present study is to investigate whether therapeutic concentrations of AMI interfere with synaptic transmission in the basal forebrain (BF) using a new synaptic optogenetic model and whether these actions are maintained during aging
We recently demonstrated that the expression of ChR2 in mice carrying the vesicular GABA transporter (VGAT)-ChR2-EYFP transgene is functionally maintained across aging, this mouse line is useful for aging neuroscience (Montgomery et al, in submission)
Summary
Amitriptyline (AMI) is a tricyclic antidepressant used for various neurological disorders such as anxiety, depression, neuropathic pain disorders and migraine (Baldessarini, 2006; Couch et al, 2011; Moore et al, 2015; Urquhart et al, 2018). AMI acts as an antagonist of the serotonin, the α1-adrenergic, the histamine, and the muscarinic acetylcholine receptors (Richelson, 1979; Kachur et al, 1988; Nojimoto et al, 2010; Pandey et al, 2010; Liu et al, 2012). It possesses neurotrophic activity by acting as an agonist of TrkA and TrkB receptor which BDNF activates (Jang et al, 2009). The purpose of the present study is to investigate whether therapeutic concentrations of AMI interfere with synaptic transmission in the basal forebrain (BF) using a new synaptic optogenetic model and whether these actions are maintained during aging
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