In Vivo Electrophysiological Recordings of the Effects of Antidepressant Drugs

Experimental Brain Research (2019) 237:1593–1614 https://doi.org/10.1007/s00221-019-05556-5 REVIEW In vivo electrophysiological recordings of the efects of antidepressant drugs Paul J. Fitzgerald1 · Brendon O. Watson1 Received: 9 October 2018 / Accepted: 6 May 2019 / Published online: 11 May 2019 © The Author(s) 2019 Abstract Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic efects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local feld potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic efects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their efects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit fring patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common fnal efects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar efects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or “neural readout”) of the therapeutic efects of all classes of antidepressants. Keywords MAOi · SSRI · SNRI · Tricyclic · Ketamine · Gamma oscillations Introduction electrophysiological efects on the brain. Here we focus on the importance of electrophysiologic studies of the neuro- In vivo electrophysiology has been crucial for elucidat- biology of these medications and make the argument that ing important properties of many neural systems, yet these increased electrophysiologic study of animals responding electrical approaches have not yet been broadly applied to to antidepressants may deepen our understanding of both the actions of antidepressants. Antidepressant drugs are a these drugs and limbic circuitry more generally. We also standard treatment in a range of neuropsychiatric disorders, seek to communicate both what has been learned already including but not limited to major depression, anxiety dis- and to identify open questions that may be addressable with orders, obsessive–compulsive disorder, and post-traumatic electrophysiologic techniques. Given that the moment-to- stress disorder (Cassano et al. 2002; Locher et al. 2017; moment inner experience of animals and humans is shaped Puetz et al. 2015). In spite of their widespread use and clini- by moment-to-moment neural dynamics best measured elec- cal importance, relatively little is known about their in vivo trophysiologically, it is almost certainly necessary to understand electrophysiologic signaling to understand mood and * Paul J. Fitzgerald mood disorders. Studying changes due to efcacious antide- [email protected] pressants provides an important inroad into understanding * Brendon O. Watson these mood dynamics and brain circuits relating to mood. [email protected] Electrophysiologic recordings in animal models have indeed informed our basic understanding of neuronal sign- 1 Department of Psychiatry, University of Michigan, aling and brain function, ranging from action potential Ann Arbor, MI 48109-5720, USA Vol.:(0123456789)1 3 1594 Experimental Brain Research (2019) 237:1593–1614 generation (Hodgkin and Huxley 1952) and synaptic func- serotonin–norepinephrine reuptake inhibitors (SNRIs), tion (Adrian 1914) to later descriptions of visual process- tricyclic antidepressants (TCAs), monoamine oxidase ing (Hubel and Wiesel 1968), place encoding (O’Keefe and inhibitors (MAOIs), norepinephrine–dopamine reuptake Black 1977) and fear-related circuitry (Milad and Quirk inhibitors (NDRIs), miscellaneous antidepressants, novel 2002). While as a feld we use our understanding of electro- compounds and potential antidepressants, and NMDA physiologic processing to understand many brain functions receptor (NMDAR) antagonists. Throughout the review, in general, we lack a clear conception of how electrophysi- we describe how these recording data synergize with other ologic and usually fast time-scale systems can impact mood techniques, such as in vivo microdialysis and behavioral and psychiatric disease. More recent advances in systems assays, since these additional techniques were also often neuroscience and brain electrophysiology include the addi- used in these studies. As a general rule, the existing studies tions of the importance of larger coordinated assemblies of on monoaminergic drugs appear to have focused on record- neurons (Buzsáki 2010) and the ability of neural oscillations ing in the serotonergic, noradrenergic, and dopaminergic to coordinate both local and long-distance groups of neu- brainstem nuclei, with much less known about their efects rons to more precisely control fow of information (Gray and on prefrontal or sensory cortex. A number of the studies Singer 1989). Little if any such information is commonly include data from subregions of hippocampus, whereas there used in our understanding of how antidepressants might appears to be less known about how antidepressants afect infuence mood- and anxiety-related circuits. amygdala electrophysiology (Beique et al. 1998; Crespi In vivo recording of local feld potentials (LFPs), which 2010; Mnie-Filali et al. 2006) (Marcinkiewcz et al. 2016). are voltage waves in the brain that correspond closely with It is also worth noting that most of these recording studies electroencephalographic (EEG) signals, and single neuron were carried out in anesthetized animals, with a scarcity action potential fring patterns (spiking) is indeed an efec- of awake (and freely moving) experiments. Another theme tive tool for elucidating circuit-specifc neural mechanisms is that studies on monoaminergic drugs have tended to through which antidepressants and other centrally acting focus on single unit fring patterns with less emphasis on drugs produce their therapeutic efects (Blier and El Man- LFPs, whereas the NMDAR antagonist literature shows the sari 2013; Dzirasa et al. 2010; El Mansari et al. 2010; Nagy opposite trend. The latter trend may be due to interest in et al. 2016). When combined with other techniques such as the efects of NMDAR compounds on brain oscillations in in vivo microdialysis and sophisticated behavioral assays, animal models of schizophrenia (Hunt et al. 2015; Kiss et al. in vivo electrophysiology can help shed light on systems- 2011a; Lee et al. 2017). Unless noted otherwise, the experi- level psychopharmacological mechanisms of action and even ments described below refer to rat anesthetized preparations possibly the physiological basis of major depression itself using systemically administered drugs. (Andersson et al. 1995; Belujon et al. 2016; Engin et al. 2008; Linnér et al. 2004). A perhaps underappreciated aspect of antidepressant drug Literature search details research is that it provides basic information on the interaction of monoaminergic subcortical nuclei, including the dor- We conducted a literature search, completed on 7 Octo- sal raphe [which contains serotonin (5-hydroxytryptamine; ber 2017, of the Pubmed database. We used the following 5-HT) neurons], locus coeruleus [norepinephrine (NE) neu- groups of keywords, where quotation marks were used to rons], and ventral tegmental area (VTA) and substantia nigra group an exact phrase of certain terms: (1) “Single + unit/ [dopamine (DA) neurons] (El Mansari et al. 2010; Guiard neuron/cell + recording(s)” + antidepressant(s)/(see LIST et al. 2008). Perhaps every drug reviewed below, including below). (2) “Single + unit/neuron/cell + electrophysiol- ketamine, interacts either directly or indirectly with mono- ogy/electrophysiological” + antidepressant(s)/LIST. (3) aminergic signaling, although this may not constitute the “In vivo/awake + recording(s)” + antidepressant(s)/LIST. principal therapeutic mechanism of action for each drug. (4) “In vivo/awake + electrophysiology/electrophysiologi- Independent of the efects of a given drug, understanding cal” + antidepressant(s)/LIST. (5) “local feld potential(s) the functional interaction of these nuclei with each other and ” + antidepressant(s)/LIST. This LIST comprised the fol- with other brain regions may be essential for understanding lowing terms (appended to the above searches, one term the basis of mood states and other neural phenomena such as at a time): escitalopram, fuoxetine, citalopram, sertraline, alertness and sleep regulation (Espana and Scammell 2011; paroxetine, fuvoxamine, bupropion, reboxetine, duloxetine, Monti and Monti 2007; Samuels and Szabadi 2008). venlafaxine, desvenlafaxine, desipramine, nortriptyline, imi- In this paper we review the antidepressant

Load more