Depression involves multilevel abnormalities in monoaminergic transmission, the balance between glutamate and GABA, regulation of the stress axis, and synaptic plasticity. Different targets separately influence mood, reward, cognition, sleep, and stress responses and together form an interconnected research network for antidepressant drugs.

Keywords: depression; monoaminergic system; serotonin; norepinephrine; glutamate; NMDA receptor; AMPA receptor; GABA; HPA axis; synaptic plasticity

1 Functional Basis of Depression-Related Target Networks

1.1 Neurotransmitters and Mood Regulation

Serotonin, norepinephrine, and dopamine participate in the regulation of mood, arousal, motivation, reward, and cognition. Glutamate and GABA constitute the major excitatory and inhibitory neurotransmission systems in the central nervous system, respectively, and together maintain neural-network stability. Depression is not caused by a deficiency of a single neurotransmitter alone but may involve combined changes in neurotransmitter synthesis, release, reuptake, receptor responsiveness, and neural-circuit activity.

1.2 Stress and Neuroendocrine Regulation

Chronic stress can activate the hypothalamic-pituitary-adrenal axis and promote the release of corticotropin-releasing factor, adrenocorticotropic hormone, and glucocorticoids. Prolonged glucocorticoid exposure may affect glucocorticoid receptor-mediated negative-feedback regulation and alter neural activity in brain regions such as the hippocampus, prefrontal cortex, and amygdala.

1.3 Synaptic Plasticity and Neural Networks

Chronic stress and depression-related pathological processes can affect dendritic-spine structure, synaptic-protein expression, neurotrophic-factor signaling, and excitatory-inhibitory balance. Although some antidepressant compounds can rapidly alter neurotransmitter concentrations, sustained behavioral or symptomatic improvement generally requires a longer period, indicating that receptor adaptation, gene expression, and synaptic remodeling are also important components of antidepressant action.

Table 1 Depression-Related Target Systems and Their Major Functions

2 Monoaminergic Systems and Antidepressant Targets

2.1 Monoamine Hypothesis

The monoamine hypothesis proposes that reduced transmission of serotonin, norepinephrine, and dopamine in the central nervous system is associated with some depressive symptoms. Important evidence supporting this hypothesis includes behavioral changes caused by monoamine depletion with Reserpine and the ability of monoamine oxidase inhibitors and tricyclic antidepressant compounds to enhance monoaminergic transmission. Serotonin mainly participates in the regulation of mood, anxiety, sleep, and appetite, norepinephrine is associated with arousal, attention, and stress adaptation, and dopamine participates in reward, motivation, and the experience of pleasure. However, a time lag exists between increased monoamine concentrations and sustained antidepressant effects, indicating that monoamine changes must also be converted into stable functional effects through receptor adaptation, gene expression, and synaptic remodeling.

2.2 Monoamine Oxidase and Neurotransmitter Degradation

Monoamine oxidase mainly includes the MAO-A and MAO-B isoforms. MAO-A preferentially participates in the oxidative metabolism of serotonin and norepinephrine, whereas MAO-B preferentially metabolizes β-phenethylamine and related compounds; dopamine can be metabolized by both MAO-A and MAO-B, with their relative contributions varying among species, brain regions, and cell types. Nonselective and irreversible monoamine oxidase inhibitors such as Tranylcypromine and Iproniazid can reduce monoamine degradation and increase monoamine levels within neurons and the synaptic cleft, but their broad substrate effects may also increase drug and food interactions.

2.3 Monoamine Transporters and Reuptake Inhibition

The serotonin transporter, norepinephrine transporter, and dopamine transporter are responsible for recovering their corresponding neurotransmitters from the synaptic cleft and thereby terminating neural signaling. Tricyclic antidepressant compounds generally inhibit both SERT and NET and may also act on muscarinic acetylcholine receptors, histamine H1 receptors, and α1-adrenergic receptors; selective reuptake inhibitors mainly target specific transporters and can be classified as SSRIs, NRIs, SNRIs, and norepinephrine-dopamine reuptake inhibitors.

2.4 SSRIs, NRIs, and SNRIs

Selective serotonin reuptake inhibitors mainly inhibit SERT and increase synaptic serotonin levels, with representative compounds including Fluoxetine, Fluvoxamine, and Paroxetine. Selective norepinephrine reuptake inhibitors mainly target NET, and Reboxetine is a representative compound. SNRIs such as Duloxetine and Venlafaxine can inhibit both SERT and NET, but different compounds vary in their relative effects on the two transporters, and their pharmacological effects are also influenced by dose, active metabolites, and administration time.

2.5 Atypical and Multimodal Antidepressant Targets

(1) Bupropion

Bupropion mainly regulates norepinephrine and dopamine reuptake and can be used to study catecholaminergic transmission, reward, motivation, anhedonia, and related processes. Its pharmacological mechanism differs from that of antidepressant compounds whose primary target is SERT.

(2) Mirtazapine

Mirtazapine antagonizes presynaptic α2-adrenergic receptors and enhances norepinephrine and serotonin release while also antagonizing 5-HT2, 5-HT3, and histamine H1 receptors. Its multireceptor actions can simultaneously affect mood, anxiety, sleep, and appetite.

(3) Agomelatine

Agomelatine activates the MT1 and MT2 melatonin receptors and antagonizes the 5-HT2C receptor, thereby simultaneously affecting circadian rhythm, sleep, and monoaminergic transmission. Relevant studies need to distinguish the effects produced by melatonin-receptor activation from those produced by 5-HT2C-receptor blockade.

(4) Vortioxetine

In addition to inhibiting SERT, Vortioxetine regulates multiple 5-HT receptors. Its action involves not only increased synaptic serotonin levels but may also affect cognition, neurotransmitter release, and neural-network activity through different receptor subtypes.

Figure 1 Mechanisms of multimodal serotonergic modulation in antidepressant action

3 Glutamatergic Systems and Rapid Antidepressant Mechanisms

3.1 Glutamate Receptors and Excitatory Transmission

Glutamate is the major excitatory neurotransmitter in the central nervous system and acts on ionotropic receptors including NMDA, AMPA, and Kainate receptors, as well as metabotropic glutamate receptors mGluR1-mGluR8. NMDA receptors exhibit both voltage and ligand dependence and participate in calcium influx and synaptic plasticity, whereas AMPA receptors mainly mediate rapid excitatory synaptic transmission. Chronic stress can affect glutamate release, glial uptake, receptor distribution, and dendritic-spine structure, so an overall increase or decrease in glutamate cannot be interpreted simply as an antidepressant effect.

3.2 Ketamine and NMDA Receptors

Ketamine is a noncompetitive NMDA receptor antagonist and can produce relatively rapid antidepressant effects in some research models and clinical settings. Its effects may involve inhibition of NMDA receptors on specific neuronal populations, a transient increase in glutamate release, and enhanced postsynaptic AMPA-receptor transmission. Compounds such as Memantine, Lanicemine, and Traxoprodil, which also act on the NMDA-receptor system, do not exhibit identical antidepressant characteristics, indicating that receptor-subunit selectivity, channel-blocking kinetics, administration method, and downstream synaptic responses all influence the final effect.

3.3 AMPA-BDNF-mTOR Signaling

AMPA receptors are important nodes connecting glutamatergic changes with remodeling of synaptic function. Enhanced AMPA receptor-mediated transmission can promote BDNF-associated signaling and regulate TrkB, mTORC1, Synapsin, and protein-synthesis processes, thereby affecting dendritic spines and synaptic connections. Blocking AMPA receptors can weaken the antidepressant-like effects of some NMDA-receptor modulators, but the contributions of BDNF, Synapsin, and mTOR may differ among brain regions, treatment durations, and models.

3.4 Other Candidate Glutamatergic Targets

Traxoprodil is mainly used to study NMDA receptors containing the GluN2B subunit, Rapastinel positively modulates NMDA-receptor function through a mechanism independent of the glycine coagonist site, and LY341495 is used to block group II metabotropic glutamate receptors. These compounds can be used to analyze relationships between different glutamate-receptor subtypes and AMPA-dependent signaling. When evaluating candidate glutamatergic compounds, receptor currents, glutamate release, synaptic proteins, neural-network activity, and behavioral effects should be measured simultaneously.

4 GABAergic Systems and Excitatory-Inhibitory Balance

4.1 Functional Differences Between GABA Receptors

GABA is the major inhibitory neurotransmitter in the central nervous system. GABA_A receptors are ligand-gated chloride channels that mediate rapid synaptic inhibition, whereas GABA_B receptors are G protein-coupled receptors that produce slower inhibitory effects by regulating potassium channels, calcium channels, and adenylyl cyclase. GABAergic interneurons can also control the excitability of glutamatergic pyramidal neurons and affect monoaminergic neuronal activity, so changes in GABA function may simultaneously influence mood, anxiety, sleep, and stress responses.

4.2 GABA_B Receptor Modulation

GABA_B receptor antagonists such as CGP52432 can produce antidepressant-like behavioral changes in some animal models, suggesting that reducing certain GABA_B receptor-mediated inhibitory effects may enhance neural-network activity. However, GABA_B receptors are present at both presynaptic and postsynaptic sites and can regulate the release of both glutamate and GABA, so their effects are strongly dependent on brain region and cell type. Behavioral changes in forced-swim and tail-suspension tests may also be affected by motor stimulation or sedation, and a reduction in immobility time alone cannot be used to conclude that a compound has antidepressant activity.

5 The HPA Axis and Stress-Related Targets

5.1 CRF1 Receptors and Stress Signaling

Stressful stimuli can promote hypothalamic release of corticotropin-releasing factor, activate pituitary CRF1 receptors, and stimulate adrenocorticotropic hormone secretion, followed by increased adrenal glucocorticoid release. CRF1 receptors are also distributed in central nervous system regions associated with mood and anxiety and can participate in stress-related behavior and autonomic responses. CRF1-receptor antagonists can be used to analyze the relationship between HPA-axis hyperactivation and depression-like behavior, but their effects are influenced by brain region, stress stage, and receptor subtype.

5.2 Glucocorticoid Receptors and Negative Feedback

Glucocorticoids suppress sustained activation of the hypothalamus and pituitary through glucocorticoid receptors and thereby form the negative-feedback mechanism of the HPA axis. Prolonged exposure to high glucocorticoid levels may reduce receptor sensitivity or alter receptor expression, preventing timely termination of the stress response. Glucocorticoid receptor antagonists can be used to study hyperglucocorticoid states and abnormal negative feedback, but their effects depend on the endocrine background of the model and cannot serve as a universal intervention for all depressive phenotypes.

6 Other Potential Antidepressant Targets

6.1 δ-Opioid Receptors

δ-Opioid receptors participate in mood, reward, pain, and stress adaptation. Some δ-opioid receptor agonists exhibit antidepressant-like activity in animal models, but opioid-receptor modulation may also affect analgesia, locomotion, and reward behavior. Therefore, locomotor activity, pain sensitivity, and tolerance should be evaluated simultaneously to avoid misinterpreting analgesia or behavioral stimulation as an antidepressant effect.

6.2 Inflammation-Related Targets

Some patients with depression exhibit increased peripheral inflammatory factors, microglial activation, or immunometabolic abnormalities. Inflammatory signaling can affect tryptophan metabolism, monoamine synthesis, glutamate homeostasis, the HPA axis, and synaptic function and thereby contribute to certain depressive phenotypes. However, inflammation is not a common driving factor in all patients with depression, and anti-inflammatory intervention is more suitable for models or patient subgroups with a clearly defined inflammatory background.

6.3 PDE4-cAMP-CREB Signaling

PDE4 hydrolyzes cAMP and limits PKA-CREB signaling. Inhibition of PDE4 can increase intracellular cAMP levels, promote CREB-associated transcription, and potentially affect BDNF expression, neural plasticity, and inflammatory responses. Rolipram can be used to analyze the relationship between cAMP signaling and antidepressant-like behavior, but PDE4 is broadly involved in neural, immune, and gastrointestinal functions, and relevant studies need to further distinguish the effects of different subtypes, cell types, and brain regions.

7 Research Compounds for Depression-Related Neurotransmitter and Stress Targets

7.1 Monoamine Oxidase and Tricyclic Research Compounds

7.2 Monoamine Reuptake and Multireceptor Modulation Research Compounds

7.3 Glutamate, GABA, and Stress-Signaling Research Compounds

Depression is jointly influenced by neurotransmitter transmission, neuroendocrine regulation, synaptic plasticity, immune inflammation, and related processes. Research on antidepressant targets should integrate molecular activity, neural circuits, behavioral phenotypes, and disease subtypes and should not evaluate the antidepressant potential of a compound solely from a single neurotransmitter concentration or an individual animal-behavior result.

References

[1] Freudenberg F, et al. The Role of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptors in Depression: Central Mediators of Pathophysiology and Antidepressant Activity? Neurosci Biobehav Rev. 2015;52:193-206.

[2] Akinfiresoye L, et al. Antidepressant Effects of AMPA and Ketamine Combination: Role of Hippocampal BDNF, Synapsin, and mTOR. Psychopharmacology (Berl). 2013;230(2):291-298.

[3] Kalueff AV, et al. Role of GABA in Anxiety and Depression. Depress Anxiety. 2007;24(7):495-517.

[4] Pariante CM, et al. Glucocorticoid Receptors in Major Depression: Relevance to Pathophysiology and Treatment. Biol Psychiatry. 2001;49(5):391-404.

For more related articles, please see below:

[1] Antipsychotics and Antidepressants

[2] Paroxetine Hydrochloride

[3] Cholinergic Signaling Modulators

[4] Synthesis and Metabolism of Glutamate and GABA: Core Mechanisms of Neurotransmitters