Of Duman’s many influential findings, the finding that long-term treatment with antidepressant drugs produces an increase in neurogenesis in the subgranular zone of the adult hippocampus may be one of the most enduring and far-reaching. This novel discovery and his decades of continued research in the field led to a new hypothesis about the mechanism of action of antidepressants, providing a critical step in our understanding of the neurotrophic hypothesis of depression and synaptic plasticity. It is now accepted that antidepressant treatments can oppose and even reverse the effects of stress on the brain and on newly born hippocampal cells, possibly via neurotrophic factors, which Duman had continued to explore. Furthermore, ablation studies have shown preclinically that hippocampal neurogenesis may be necessary for some of the clinical effects of antidepressant drugs. Duman’s laboratory continued to interrogate neurotrophins and synaptic plasticity, demonstrating that newer clinically approved antidepressant compounds also affect neurogenesis and synaptic plasticity. In this review, we summarize Duman’s original findings and discuss the current state of the field of neurogenesis with respect to animal models and human studies and the implications of those findings on the field of drug discovery.

We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

Background and purpose: As a combination of 5‐HT selective reuptake inhibitor (SSRI) with 5‐HT 1A receptor antagonism may yield a rapidly acting antidepressant, WAY‐211612, a compound with both SSRI and 5‐HT 1A receptor antagonist activities, was evaluated in preclinical models. Experimental approach: Occupancy studies confirmed the mechanism of action of WAY‐211612, while its in vivo profile was characterized in microdialysis and behavioural models. Key results: WAY‐211612 inhibited 5‐HT reuptake (K i = 1.5 nmol·L −1 ; K B = 17.7 nmol·L −1 ) and exhibited full 5‐HT 1A receptor antagonist activity (K i = 1.2 nmol·L −1 ; K B = 6.3 nmol·L −1 ; I max 100% in adenyl cyclase assays; K B = 19.8 nmol·L −1 ; I max 100% in GTPγS). WAY‐211612 (3 and 30 mg·kg −1 , po) occupied 5‐HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5‐HT 1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY‐211612 (3–30 mg·kg −1 , po) raised levels of cortical 5‐HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg −1 , s.c.) and a 5‐HT 1A antagonist (WAY‐100635; 0.3 mg·kg −1 , s.c). WAY‐211612 (3.3–30 mg·kg −1 , s.c.) decreased aggressive behaviour in the resident‐intruder model, while increasing the number of punished crossings (3–30 mg·kg −1 , i.p. and 10–56 mg·kg −1 , po) in the mouse four‐plate model and decreased adjunctive drinking behaviour (56 mg·kg −1 , i.p.) in the rat scheduled‐induced polydipsia model. Conclusions and implications: These findings suggest that WAY‐211612 may represent a novel antidepressant.

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.

Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents.

Previous research has suggested that mobilization of neurotrophic factors, such as insulin-like growth factor I (IGF-I), can be involved in the effects of antidepressant treatments. The current experiments showed that IGF-I leads to antidepressant-like effects in the modified rat forced swim test when tested 3 days, but not 1 day, after i.c.v. administration. These effects were sustained longer than the antidepressants paroxetine and desipramine. In addition, blockade of the IGF-I receptor with the IGF-I antagonist JB1 30 min before IGF-I administration prevented the antidepressant-like effects of IGF-I. However, when JB1 was administered 3 days after IGF-I administration and 30 min prior to testing, the antidepressant-like effects of IGF-I were still present suggesting that IGF-1 produces a long-term activation of neural systems involved in the antidepressant response. Because the pattern of antidepressant-like effects of IGF-I resembled those of selective serotonin reuptake inhibitors, the role of serotonin in the behavioral effects of IGF-I was studied. Depletion of serotonin, by the tryptophan hydroxylase inhibitor para-chlorophenylalanine, blocked the antidepressant-like effects of IGF-I. Administration of IGF-I increased basal serotonin levels in the ventral hippocampus and altered the effects of acute citalopram. IGF-I administration did not change hippocampal cell proliferation at the 3-day timepoint when behavioral effects were seen. In addition, IGF-I did not alter the expression of mRNA levels of tryptophan hydroxylase or SERT in the brain stem, or [3H] citalopram binding in the hippocampus or cortex. Thus, IGF-I administration initiates a long-lasting cascade of neurochemical effects involving increased serotonin levels that results in antidepressant-like behavioral effects.

Recent studies have identified adaptations of intracellular signaling pathways and target genes that could contribute or modulate the action of antidepressant drugs, as well as exercise-mediated antidepressant responses. Understanding these adaptations, particularly those changes that are common to diverse antidepressant treatments, is important for the development of more potent and specific treatments of depression. There is growing evidence that growth factors may be important mediators of antidepressant responses. Now, VGF (not an acronym), a neuropeptide that has previously been shown to be involved in maintaining organismal energy balance, as well as in mediating hippocampal synaptic plasticity, may be involved in mediating antidepressant responses. These studies use in vivo approaches to link VGF to the anti-depressant- like behavioral effects produced by antidepressant drugs and exercise.

Antidepressant treatments have been proposed to produce their therapeutic effects, in part, through increasing neurotrophin levels in the brain. The current experiments investigated the effects of acute and chronic treatment with different pharmacologic and somatic antidepressant treatments on protein levels of BDNF in several brain regions associated with depression in the rat. Repeated applications (10 days) of electroconvulsive shock (ECS), but not a single treatment (1 day), produced 40-100% increases of BDNF protein in the hippocampus, frontal cortex, amygdala, and brainstem. Chronic (21 days), but not acute (1 day), treatment with the tricyclic antidepressant (TCA) desipramine (10 mg/kg), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg), and the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg) increased BDNF protein levels in the frontal cortex (10-30%), but not in the hippocampus, amygdala, olfactory bulb, and brain stem. To determine whether the regulation of BDNF was unique to antidepressant treatments, drugs used to treat schizophrenia and anxiety were also studied. Chronic administration of the typical antipsychotic haloperidol (1 mg/kg) and the atypical antipsychotic clozapine (20 mg/kg) increased BDNF levels by only 8-10% in the frontal cortex. Haloperidol also elevated BDNF levels in the amygdala, while clozapine decreased BDNF in the olfactory bulb. Acute or chronic treatment with the benzodiazepine chlordiazepoxide (10 mg/kg) did not alter BDNF levels. These results suggest that diverse pharmacologic and somatic antidepressant treatments, as well as antipsychotics, increase levels of BDNF protein in the frontal cortex, even though they have different mechanisms of action at neurotransmitter systems.

There have been significant advances in the treatment of depression since the serendipitous discovery that modulating monoaminergic neurotransmission may be a pathological underpinning of the disease. Despite these advances, particularly over the last 15years with the introduction of selective serotonin and/or norepinephrine reuptake inhibitors (SNRI), there still remain multiple unmet clinical needs that would represent substantial improvements to current treatment regimens. In terms of efficacy there have been improvements in the percentage of patients achieving remission but this can still be dramatically improved and, in fact, issues still remain with relapse. Furthermore, advances are still required in terms of improving the onset of efficacy as well as addressing the large proportion of patients who remain treatment resistant. While this is not well understood, collective research in the area suggests the disease is heterogeneous in terms of the multiple parameters related to etiology, pathology and response to pharmacological agents. In addition to efficacy further therapeutic advances will also need to address such issues as cognitive impairment, pain, sexual dysfunction, nausea and emesis, weight gain and potential cardiovascular effects. With these unmet needs in mind, the next generation of antidepressants will need to differentiate themselves from the current array of therapeutics for depression. There are multiple strategies for addressing unmet needs that are currently being investigated. These range from combination monoaminergic approaches to subtype selective agents to novel targets that include mechanisms to modulate neuropeptides and excitatory amino acids (EAA). This review will discuss the many facets of differentiation and potential strategies for the development of novel antidepressants.

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB αΔ mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB αΔ mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREB αΔ mutant mice. Serotonin depletion decreased neurogenesis in CREB αΔ mutant mice to WT levels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB αΔ mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB αΔ mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREB αΔ mutant mice responded to chronic AD treatment in the NIH paradigm, only CREB αΔ mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment.

Specific ablation of central nervous system (CNS) progenitor cells in the brain of live animals is a powerful method to determine the functions of these cells and to reveal novel avenues for the treatment of several CNS-related disorders. To achieve this goal, we generated a line of transgenic rats expressing a bacterial enzyme, Escherichia coli nitroreductase gene (NTR), under control of the nestin promoter. In this system, NTR(+) cells are selectively eliminated upon application of prodrug CB1954, through activation of programmed cell death machineries. At 5 days of age, which is a time when cerebellar development is occurring, transgenic rats bearing the nestin-NTR/green fluorescent protein (GFP) gene are overtly normal and express NTR/GFP in neuronal stem cells, without any toxicity in these cells. The functional consequence of progenitor cell ablation was demonstrated by administering prodrug CB1954 into the cerebellum at this 5-day time point. Stem cell ablation in these neonates resulted in sensorimotor abnormalities, cerebellar degeneration, overall reduction in cerebellar seize, and manifestation of ataxia. In adult rats, GFP expression was not seen in the hippocampal progenitor cells and seen only at very low levels in the lateral ventricles, indicating a different NTR/GFP expression pattern between neonates and adults. In addition, application of CB1954 by intraventricular delivery reduced the number of 5-bromo-2'-deoxyuridine-labeled proliferating cells in the lateral ventricle but not hippocampus of NTR/GFP rats. These findings shows that targeted expression of NTR under a specific promoter might be of significant value in addressing the function of distinct cell population in vivo.

Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs.

The present studies were conducted to determine if increasing central levels of the neurotrophic factor insulin-like growth factor-1 (IGF-I) either directly or indirectly produces anxiolytic and antidepressant-like effects in the mouse. Central levels of IGF-I can be increased directly, by administering IGF-I, or indirectly by blocking the insulin-like growth factor binding proteins (IGFBPs). The IGFBP family has the unique ability to regulate IGF-I levels by sequestering IGF-I into an inactive complex. Therefore, an IGFBP inhibitor increases the level of IGF-I available to bind to its receptor. Intracerebroventricular (icv) administration of the nonspecific IGFBP inhibitor NBI-31772 (10–30 μg) increases the number of punished crossings in the four-plate test and NBI-31772 (0.3–10 μg) increases time spent in the open quadrant of the elevated zero maze (EZM), indicative of anxiolytic-like effects. NBI-31772 (3–30 μg) also decreases immobility time in the tail suspension test, indicative of antidepressant-like effects. Similarly, icv administration of IGF-I (0.1 μg) produces anxiolytic-like effects in the four-plate test and IGF-1 (0.3–1 μg) produces anxiolytic-like effects in the EZM. IGF-I (10 μg) also produces antidepressant-like effects in the tail suspension test. Coadministration of the IGF-I receptor antagonist JB1 with NBI-31772 or IGF-I blocks the anxiolytic-like and antidepressant-like effects of these compounds. These results suggest that NBI-31772 produces behavioral effects by increasing levels of IGF-I that in turn activate the IGF-I receptor. The present studies demonstrate that an IGFBP inhibitor mimics the behavioral effects of IGF-I and that IGFBP inhibition may represent a novel mechanism by which to increase IGF-I to treat depression and anxiety.

Oxytocin (OT) acts as a neuromodulator/neurotransmitter within the central nervous system (CNS) and regulates a diverse range of CNS functions. Notably, evidence from studies in females has revealed an important role for OT in regulating anxiety behavior.

The neuropeptide galanin and its receptors (GAL-R1, GAL-R2, and GAL-R3) are densely localized in areas of the brain thought to regulate stress, fear and anxiety. Several studies suggest a role for galanin in mediating anxiety-like behaviors in rodent models. Here we report that both galanin (0.1 μg, icv) and galnon (0.3, 1.0 and 3.0 mg/kg, ip) show dose-dependent anxiolytic-like activity in the mouse elevated zero maze and four-plate assays. Further, M35 (10 μg, icv), a non-selective galanin receptor antagonist, was able to block galnon’s (0.3 mg/kg, ip) effects in the four-plate model. The in vitro pharmacological basis for these behavioral effects was explored using radioligand binding and a functional calcium mobilization assay. While human galanin was able to displace 125I-galanin in GAL-R1 and human Bowes melanoma cell membranes (Ki = 0.2 nM and 0.17 nM, respectively), galnon only showed affinity for galanin receptors expressed in human Bowes melanoma cells (5.5 μM). Consistent with this finding, galnon only showed functional agonism in Bowes melanoma cells (EC50 = 109 nM). This finding suggests that galnon acts as an agonist at galanin receptors in Bowes melanoma cells but not GALR1 receptors. Taken together, these studies provide further evidence for galaninergic input in anxiety-related behaviors and suggest a functional role for galnon via GAL-R2 or GAL-R3 receptors.