Monoamine Reuptake Inhibitors Research Articles

The Role of Glutamatergic Antagonism in the Antidepressant‐like Activity of the Rapid‐Acting Antidepressant RO‐25‐6981 and Its Analogs

The glutamatergic antagonist, RO‐25‐6981, has previously been shown to exert both rapid and sustained antidepressant‐like activity. The purpose of the current study is to delineate its putative antidepressant mechanisms of NR2B‐selective NMDA receptor antagonism and monoamine reuptake transporter inhibition. RO‐25‐6981 and structural analogs with varying degrees of NR2B binding affinity were tested for antidepressant‐like behavior in wild‐type mice and animals deficient in NR2B subunit expression. In the tail suspension test, four RO‐25‐6981 analogs (TR‐2, TR‐4, TR‐5, and TR‐6) were found to exhibit antidepressant‐like activity in wild‐type mice following acute administration (30 mg/kg, i.p., 30 min) with maximal reductions in immobility by approximately half compared to vehicle‐treated controls. By contrast, RO‐25‐6981 (10 mg/kg, i.p., 30 min) reduced immobility by approximately 90%, an effect comparable to that exhibited by the traditional monoaminergic antidepressants fluoxetine and desipramine. However, unlike RO‐25‐6981, TR‐2, TR‐4, TR‐5 and TR‐6 profoundly limited generalized locomotor activity suggesting increased activity in the tail suspension test was related to psychotropic vs. generalized drug effects. In contrast, other TR analogs tested showed no antidepressant‐like activity in the tail suspension test, despite possessing robust NMDA receptor antagonist activity via mid‐ to low‐nanomolar binding affinity at the NR2B subunit. Interestingly, RO‐25‐6981 and TR‐5 exhibited similar antidepressant‐like activity in wild‐type and NR2B‐deficient mice, despite possessing low‐nanomolar NR2B binding. In addition, cellular serotonin transport assays showed functional inhibitory activity of both agents. Taken together, these data suggest that the antidepressant‐like activity of RO‐25‐6981 and its analogs does not correlate with the degree of NMDA receptor antagonism. Furthermore, these data point to monoamine reuptake inhibition contributing to the overall antidepressant‐like activity of RO‐25‐6981 in animal models of mood.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder

The major depressive disorder (MDD) working group of the Psychiatric Genomics Consortium (PGC) has published a genome-wide association study (GWAS) for MDD in 130,664 cases, identifying 44 risk variants. We used these results to investigate potential drug targets and repurposing opportunities. We built easily interpretable bipartite drug-target networks integrating interactions between drugs and their targets, genome-wide association statistics, and genetically predicted expression levels in different tissues, using the online tool Drug Targetor (drugtargetor.com). We also investigated drug-target relationships that could be impacting MDD. MAGMA was used to perform pathway analyses and S-PrediXcan to investigate the directionality of tissue-specific expression levels in patients vs. controls. Outside the major histocompatibility complex (MHC) region, 153 protein-coding genes are significantly associated with MDD in MAGMA after multiple testing correction; among these, five are predicted to be down or upregulated in brain regions and 24 are known druggable genes. Several drug classes were significantly enriched, including monoamine reuptake inhibitors, sex hormones, antipsychotics, and antihistamines, indicating an effect on MDD and potential repurposing opportunities. These findings not only require validation in model systems and clinical examination, but also show that GWAS may become a rich source of new therapeutic hypotheses for MDD and other psychiatric disorders that need new—and better—treatment options.

Venlafaxine stimulates PNN proteolysis and MMP-9-dependent enhancement of gamma power; relevance to antidepressant efficacy.

Drugs that target monoaminergic transmission represent a first-line treatment for major depression. Though a full understanding of the mechanisms that underlie antidepressant efficacy is lacking, evidence supports a role for enhanced excitatory transmission. This can occur through two non-mutually exclusive mechanisms. The first involves increased function of excitatory neurons through relatively direct mechanisms such as enhanced dendritic arborization. Another mechanism involves reduced inhibitory function, which occurs with the rapid antidepressant ketamine. Consistent with this, GABAergic interneuron-mediated cortical inhibition is linked to reduced gamma oscillatory power, a rhythm also diminished in depression. Remission of depressive symptoms correlates with restoration of gamma power. As a result of strong excitatory input, reliable GABA release, and fast firing, PV-expressing neurons (PV neurons) represent critical pacemakers for synchronous oscillations. PV neurons also represent the predominant GABAergic population enveloped by perineuronal nets (PNNs), lattice-like structures that localize glutamatergic input. Disruption of PNNs reduces PV excitability and enhances gamma activity. Studies suggest that monoamine reuptake inhibitors reduce integrity of the PNN. Mechanisms by which these inhibitors reduce PNN integrity, however, remain largely unexplored. A better understanding of these issues might encourage development of therapeutics that best up-regulate PNN-modulating proteases. We observe that the serotonin/norepinephrine reuptake inhibitor venlafaxine increases hippocampal matrix metalloproteinase (MMP)-9 levels as determined by ELISA and concomitantly reduces PNN integrity in murine hippocampus as determined by analysis of sections following their staining with a fluorescent PNN-binding lectin. Moreover, venlafaxine-treated mice (30mg/kg/day) show an increase in carbachol-induced gamma power in exvivo hippocampal slices as determined by local field potential recording and Matlab analyses. Studies with mice deficient in matrix metalloproteinase 9 (MMP-9), a protease linked to PNN disruption in other settings, suggest that MMP-9 contributes tovenlafaxine-enhanced gamma power. In conclusion, our results support the possibility that MMP-9 activity contributes to antidepressant efficacy through effects on the PNN that may in turn enhance neuronal population dynamics involved in mood and/or memory. Cover Image for this issue: doi: 10.1111/jnc.14498.

Effect of monoamine reuptake inhibition and α1 blockade on respiratory arrest and death following electroshock‐induced seizures in mice

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Although the mechanisms for SUDEP are incompletely understood, seizure-induced respiratory arrest (S-IRA) has been strongly and consistently implicated. A body of evidence indicates that serotonin (5-HT), a modulator of breathing, plays a critical role in SUDEP. Because the 5-HT and norepinephrine (NE) systems interact in many biologic processes and NE is known to modulate breathing and seizures, we hypothesized that NE may play a role in S-IRA and SUDEP. We examined the effects of pharmacologic manipulation of 5-HT and NE on S-IRA and death following maximal electroshock (MES)-induced seizures in adult wild-type (WT) mice, genetically 5-HT neuron-deficient (Lmx1bf/f/p ) mice, and chemically NE neuron-deficient mice. Mice were treated with pharmacologic agents targeting the serotonergic and noradrenergic systems and subjected to seizure induction via MES while breathing was measured via whole-body plethysmography. S-IRA and death was reduced in WT mice with NE reuptake inhibitors (NRIs), reboxetine and atomoxetine, selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the dual 5-HT/NE reuptake inhibitor (SNRI), duloxetine. S-IRA and death was also reduced in Lmx1bf/f/p mice with reboxetine and fluoxetine. The protective effects of the reuptake inhibitors were prevented by the α1 antagonist, prazosin. Citalopram did not reduce S-IRA and death in NE neuron-deficient mice. These data suggest that 5-HT and NE critically interact in the modulation of breathing following a seizure and potentially inform preventive strategies for SUDEP.

Monoaminergic system and depression

Major depressive disorder is a severe, disabling disorder that affects around 4.7% of the population worldwide. Based on the monoaminergic hypothesis of depression, monoamine reuptake inhibitors have been developed as antidepressants and nowadays, they are used widely in clinical practice. However, these drugs have a limited efficacy and a slow onset of therapeutic action. Several strategies have been implemented to overcome these limitations, including switching to other drugs or introducing combined or augmentation therapies. In clinical practice, the most often used augmenting drugs are lithium, triiodothyronine, atypical antipsychotics, buspirone, and pindolol, although some others are in the pipeline. Moreover, multitarget antidepressants have been developed to improve efficacy. Despite the enormous effort exerted to improve these monoaminergic drugs, they still fail to produce a rapid and sustained antidepressant response in a substantial proportion of depressed patients. Recently, new compounds that target other neurotransmission system, such as the glutamatergic system, have become the focus of research into fast-acting antidepressant agents. These promising alternatives could represent a new pharmacological trend in the management of depression.

Analysis of fall-related adverse events among older adults using the Japanese Adverse Drug Event Report (JADER) database

BackgroundFalls are a common but serious problem in older adults, and may lead to fractures and bleeding. As many factors, such as medication, aging, and comorbid diseases may simultaneously affect fall-related adverse events (AEs) in older adults, we evaluated the association between fall-related AEs and the use of medication, aging, and comorbid diseases using the Japanese Adverse Drug Event Report (JADER) database.MethodsWe analyzed reports of fall-related AEs associated with α-blockers, diuretics, calcium channel blockers, central nervous system (CNS)-active drugs (opioids, benzodiazepines, hypnotics and sedatives, non-selective monoamine reuptake inhibitors, and selective serotonin reuptake inhibitors (SSRI)) in the JADER database using the reporting odds ratio (ROR). For the definition of falls, we used the Preferred Terms of The Medical Dictionary for Regulatory Activities (MedDRA). We used the association rule mining technique to discover undetected associations, such as potential risk factors.ResultsThe JADER database comprised 430,587 reports between April 2004 and November 2016. The RORs (95% CI) of α-blockers, diuretics, calcium channel blockers, opioids, benzodiazepines, hypnotics and sedatives, non-selective monoamine reuptake inhibitors, and SSRIs were 1.63 (1.27–2.09), 0.74 (0.63–0.86), 1.26 (1.15–1.38), 0.93 (0.80–1.07), 1.83 (1.68–2.01), 1.55 (1.12–2.14), 2.31 (1.82–2.95), and 2.86 (2.49–3.29), respectively. From the lift value in the association rule mining, the number of administered CNS-active drugs and patient age were associated with fall-related AEs. Furthermore, the scores of lift for patients with herpes zoster administered calcium channel blockers or benzodiazepines and patients with dementia administered benzodiazepines were high.ConclusionOur results suggest that the number of administered CNS-active drugs and patient age are both associated with fall-related AEs. We recommend that patients with herpes zoster treated with calcium channel blockers and benzodiazepines be closely monitored for fall-related AEs.

Methcathinone and 3-Fluoromethcathinone Stimulate Spontaneous Horizontal Locomotor Activity in Mice and Elevate Extracellular Dopamine and Serotonin Levels in the Mouse Striatum

Methcathinone (MC) and 3-fluoromethcathinone (3-FMC) are well-known members of the synthetic cathinone derivatives, the second most abused group of novel psychoactive substances (NPS). They are considered as methamphetamine-like cathinones, as they elicit their psychostimulatory effects via inhibition of monoamine uptake and enhanced release. The present study examines the effects of MC and 3-FMC on the spontaneous locomotor activity of mice and extracellular levels of dopamine and serotonin in the mouse striatum. Both MC and 3-FMC produced a dose-dependent increase of horizontal locomotor activity, but no significant changes in rearing behavior were observed. The locomotor stimulation induced by MC and 3-FMC is mediated by activation of dopaminergic neurotransmission, as selective D1-dopamine receptor antagonist, SCH 23390, abolished the effects of both drugs. In line with pharmacological data obtained by previous in vitro studies, MC and 3-FMC produced potent increases of extracellular dopamine and serotonin levels in the mouse striatum. Taken together, results presented within this study confirm previous findings and expand our knowledge on the pharmacology of MC and 3-FMC along with their behavioral effects.

Adherence to and Persistence with Antidepressant Medication during Pregnancy: Does It Differ by the Class of Antidepressant Medication Prescribed?

Pregnant women are often concerned about the impact of medication use on their pregnancy, such as congenital abnormalities. This study examined the rate of adherence to and persistence with antidepressant medications during pregnancy based on the class of antidepressants prescribed. Women who gave birth between 2012 and 2015 in Alberta, Canada; had ≥1 diagnosis of depression within 1 year of preconception in outpatient physician claims, emergency department, or hospitalization administrative data; and were adherent (medication possession ratio ≥80%) to ≥2 consecutive antidepressant prescriptions during the preconception year ( n = 1865) were included in this retrospective cohort study. The rates of adherence and persistence (prescription refill gap ≤30 days) were calculated by antidepressant class and were compared using chi-square tests. During pregnancy, 834 (44.7%; 95% CI, 42.4% to 47.0%) women discontinued antidepressants. Among those continuing antidepressants, the overall rate of adherence was 62.6% (95% CI, 59.4% to 65.7%). The rate differed significantly by medication class ( P < 0.0001), with a rate of 75.1% (95% CI, 68.3% to 80.9%) for serotonin-norepinephrine inhibitors, 60.9% (95% CI, 57.2% to 64.5%) for selective serotonin reuptake inhibitors, 42.8% (95% CI, 19.9% to 69.3%) for nonselective monoamine reuptake inhibitors, and 37.5% (95% CI, 22.5% to 55.4%) for atypical antidepressants. Only, 40.7% (95% CI, 37.5 to 44.1) of women were persistent with antidepressants for the full pregnancy period-the rate differed significantly by medication class ( P < 0.0001). Adherence to and persistence with antidepressants is low during pregnancy and varies by medication class. Low adherence and persistence can interfere with a therapeutic effect of antidepressants, which may contribute to the worsening of depression symptoms.

Hypericum polyanthemum cyclohexane extract potentiates behavioral effects and neurodegeneration induced by nigral infusions of 6-hydroxydopamine in rats

IntroductionParkinson’s Disease (PD) is a progressive neurodegenerative disorder, hallmark of which is loss of nigral dopaminergic neurons. Since a Hypericum polyanthemum extract inhibits monoamine reuptake and some of its constituents present cytotoxic properties, the aim of this study was to evaluate the effect of this extract in an animal PD model. MethodsAdult Wistar rats (110 days old) received 6-hydroxydopamine (6-OHDA) infusions into the right medial forebrain bundle. A cyclohexane extract from aerial parts of H. polyanthemum (POL; 90 mg/kg/administration; gavage) was administered in three different regimens. In Regimens 1 and 2, rats received 3 administrations of POL starting 4 or 24 h after 6-OHDA infusion, respectively. In Regimen 3, these administrations were carried out 1 day before any evaluation of ipsilateral rotational activity induced by methylphenidate (MP, 20 mg/kg, i.p.). MP was administered 10, 45, and 85 days after 6-OHDA infusion in all groups. Nigral tyrosine hydroxylase (TH) immunocontent was evaluated 120 days after 6-OHDA infusion in animals submitted to Regimen 2 only. The effect of POL on apomorphine-induced climbing behavior in non-lesioned adult CF1 mice (60 days old) treated with POL was also evaluated. ResultsRegimen 2 increased MP-induced rotational activity and decreased nigral TH levels in 6-OHDA-lesioned rats. Rotational activity was not altered in regimens 1 and 3. In addition, no change in climbing behavior was observed in non-lesioned mice. ConclusionTogether, these results indicate that, in 6-OHDA-lesioned rats, a cyclohexane H. polyanthemum extract potentiates neurotoxicity and MP-induced motor asymmetry depending on the time of administration. In the short term, it seems to not act directly on mice dopaminergic receptors.

Adherence And Persistence To Antidepressant Medication During Pregnancy: Does It Differ By The Class Of Antidepressant Medication Prescribed?

IntroductionPregnant women are often concerned about the impact of antidepressant medication use on their pregnancy, such as congenital abnormalities. This concern may vary in a way that depends on the class of antidepressant medication prescribed.&#x0D; Objectives and ApproachThis study examined the rate of adherence and persistence to antidepressants based on the class of antidepressants prescribed during pregnancy This is a retrospective cohort study using population-based administrative data in Alberta– linking delivery record, hospitalization data, physician claims data, emergency department data, and prescription medication data. The eligible study population included women with depression who gave birth between 2012-2015, and were adherent (medication possession ratio ≥80%) to ≥ 2 consecutive antidepressant prescriptions during the preconception year (n=1,865). The rates of adherence and persistence (prescription refill gap ≤30 days) were calculated by medication class and were compared using chi-square tests.&#x0D; ResultsDuring pregnancy, 834 (44.7%) women completely stopped taking antidepressants. Among those taking antidepressants, the overall rate of adherence was 62.6% (95% CI: 59.4%, 65.7%). The rate differed significantly by medication class (p&lt;0.0001), with rate of 75.1% (95% CI: 68.3%, 80.9%) for serotonin-norepinephrine inhibitors, 60.9% (95% CI: 57.2%, 64.5%) for selective serotonin reuptake inhibitors, 42.9% (95% CI: 19.9%, 69.2%) for non-selective monoamine reuptake inhibitors, and 37.5% (95% CI: 22.4%, 55.4%) for the atypical antidepressants. Similarly, 40.7%, (95% CI: 37.5, 44.0) of women were persistent to antidepressants up to the full pregnancy period – similar to the adherence pattern, the rate differed significantly by medication class.&#x0D; Conclusion/ImplicationsAdherence to and persistence in using antidepressants is low during pregnancy and it varies by medication class, possessing to the worsening of depression symptoms. This could be improved by conducting more research on drug safety during pregnancy and translating research evidence into treatment decision and correcting mothers’ misperceptions towards antidepressants.

216 Functional effects of the monoamine reuptake inhibitor, IPED2015 in both cerebral and erectile tissue in vitro

216 Functional effects of the monoamine reuptake inhibitor, IPED2015 in both cerebral and erectile tissue in vitro

Acute tramadol enhances brain activity associated with reward anticipation in the nucleus accumbens.

Tramadol is an analgesic with monoamine reuptake inhibition and μ-opioid receptor activation. Although tramadol has been widely used for treatment of various pain conditions, there is controversy over the risk of abuse potential. We examined the effects of tramadol on the reward system in humans using functional magnetic resonance imaging (fMRI) to assess the potential of tramadol for drug abuse or dependence. A randomized, double-blind, placebo-controlled, crossover study was conducted for 19 healthy adults under tramadol or placebo. In association with subjective mood questionnaires, monetary incentive delay (MID) task was performed to assess the neural response to reward anticipation during fMRI. Subjective mood measures and blood oxygenation level-dependent (BOLD) signal during gain and loss anticipation were compared between tramadol and placebo. Tramadol significantly reduced anxiety (Z= - 2.513, p = 0.012) and enhanced vigor (Z= - 2.725, p = 0.006) compared with placebo. By Mood Rating Scale, tramadol provoked contented (Z= - 2.316, p = 0.021), relaxed (Z= - 2.236, p = 0.025), and amicable feelings (Z= - 2.015, p = 0.044) as well as increased alertness (Z= - 1.972, p = 0.049) and contentedness domains (Z= - 2.174, p = 0.030) compared with placebo. Several brain regions including nucleus accumbens (NAc) were activated during gain anticipation in the MID task under both tramadol and placebo. Tramadol increased the %BOLD signal change in NAc at +¥500 cue significantly more than the placebo (Z= - 2.295, p = 0.022). Tramadol enhances the reward system and thereby may have abuse potential or precipitate drug abuse in human.

Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self-stimulation and nucleus accumbens dopamine in rats.

Amphetamine maintenance is effective clinically to reduce the consumption of the monoamine uptake inhibitor cocaine but not of the monoamine releaser methamphetamine, and its effectiveness in treating the abuse of other psychostimulants is not known. The mechanisms for differential amphetamine-maintenance effectiveness to treat different types of psychostimulant abuse are also not known. Accordingly, the present study compared the effects of amphetamine maintenance on abuse-related behavioral and neurochemical effects of cocaine, methamphetamine, and the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV) in rats. In behavioral studies, rats were trained to lever press for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. In neurochemical studies, nucleus accumbens (NAc) levels of dopamine (DA) and serotonin (5-HT) were monitored by in vivo microdialysis. Cocaine, methamphetamine, and MDPV each produced dose-dependent ICSS facilitation and increases in NAc DA; cocaine and methamphetamine also increased NAc 5-HT. Amphetamine maintenance (0.32 mg/kg/h × 7 days) produced (1) sustained increases in basal ICSS and NAc DA with no change in NAc 5-HT, (2) blockade of cocaine but not methamphetamine effects on ICSS and NAc DA, and (3) no blockade of cocaine- or methamphetamine-induced increases in NAc 5-HT. Amphetamine maintenance blocked the increases in NAc DA produced by the selective DA uptake inhibitor MDPV, but it did not block MDPV-induced ICSS facilitation. These results show different effects of amphetamine maintenance on behavioral and neurochemical effects of different psychostimulants. The selective effectiveness of amphetamine maintenance to treat cocaine abuse may reflect attenuation of cocaine-induced increases in NAc DA while preserving cocaine-induced increases in NAc 5-HT.

Reinforcing Potency and Effectiveness of Synthetic Cathinones: Potency versus Selectivity for DAT

Synthetic cathinones found in “bath salts” preparations interact with monoamine transporters and function as either cocaine‐like monoamine uptake inhibitors or amphetamine‐like substrates. Abuse of these synthetic cathinones has resulted in regulation of some cathinones internationally. Modifications to the chemical structure of regulated cathinones (e.g., MDPV) produce a series of new cathinones (e.g., α‐PVP, α‐PPP, MDPBP, and MDPPP) which may not be subject to existing regulations. Although MDPV is a more potent and effective reinforcer than cocaine, little is known about the reinforcing effects of other synthetic cathinones. Thus, this study examined intravenous self‐administration of cocaine, MDPV, α‐PVP, α‐PPP, MDPBP, and MDPPP to test the hypotheses that 1) stimulants with greater potency to inhibit the dopamine transporter (DAT) are more potent reinforcers, and 2) stimulants with greater selectivity for DAT relative to the serotonin transporter (SERT) are more effective reinforcers. Potencies to inhibit monoamine uptake at DAT and SERT were determined using synaptosomes prepared from rat brains. Separate groups of male Sprague‐Dawley rats (n=12 per group) were used to generate full dose‐response curves under a progressive ratio (PR) schedule of reinforcement for α‐PVP, α‐PPP, MDPBP, and MDPPP; full dose‐response curves for MDPV and cocaine were also generated in each rat (n=48). Rank order potency to inhibit DAT was MDPV &gt; α‐PVP ≈ MDPBP &gt; MDPPP ≈ α‐PPP ≈ cocaine, while rank order DAT/SERT selectivity was α‐PVP &gt; α‐PPP &gt; MDPV &gt; MDPBP &gt; MDPPP &gt; cocaine. The potency to inhibit DAT correlated with the potency of each drug to maintain responding (MDPV &gt; α‐PVP ≈ MDPBP &gt; MDPPP ≈ α‐PPP ≈ cocaine). Relative reinforcing effectiveness as determined by comparing the maximum number of infusions obtained for each drug under a PR schedule of reinforcement was α‐PVP &gt; α‐PPP ≈ MDPV &gt; MDPBP ≈ MDPPP &gt; cocaine, which correlated with DAT/SERT selectivity. These data suggest that (1) potency at DAT is an important determinant of the potency of each drug to function as a reinforcer, (2) each of these synthetic cathinones functions as a more effective reinforcer than cocaine, and (3) DAT/SERT selectivity is related to reinforcing effectiveness and may predict the abuse‐related effects of novel synthetic cathinones in humans.Support or Funding InformationThese experiments were supported by NIH grants R01DA039146 (GTC) and T32DA031115 (BMG) and the Intramural Research Programs of NIDA (MHB, KCR) and NIAAA (KCR).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The triple monoamine re-uptake inhibitor DOV 216,303 promotes functional recovery after spinal cord contusion injury in mice

Serotonin, noradrenaline and dopamine are important neuromodulators for locomotion in the spinal cord. Disruption of descending axons after spinal cord injury resulted in reduction of excitatory and neuromodulatory inputs to spinal neurons for locomotion. Receptor agonists or reuptake inhibitors for these neuromodulators have been shown to be beneficial in incomplete spinal cord injury. In this study, we tested a triple re-uptake inhibitor, DOV 216,303, for its ability to affect motor function recovery after spinal cord injury in mice. We impacted C57 mouse spinal cord at the T11 vertebral level and administered vehicle or DOV 216,303 at 10 mg/kg, b.i.d via intraperitoneal injections for 7 days. We monitored motor function with the Basso Mouse Scale for locomotion for 4 weeks. Spinal cords were harvested and histological examinations were performed to assess tissue sparing and lesion severity. Results showed that DOV 216,303-treated mice recovered significantly better than vehicle treated mice starting at 14 days post injury until the end of the survival period. Lesion size of the DOV 216,303 treated mice was also smaller compared to that of vehicle treated mice. This study suggests DOV 216,303 as a potential therapeutic after spinal cord injury warrants further investigation.

Selective α-Synuclein Knockdown in Monoamine Neurons by Intranasal Oligonucleotide Delivery: Potential Therapy for Parkinson’s Disease

Progressive neuronal death in brainstem nuclei and widespread accumulation of α-synuclein are neuropathological hallmarks of Parkinson's disease (PD). Reduction of α-synuclein levels is therefore a potential therapy for PD. However, because α-synuclein is essential for neuronal development and function, α-synuclein elimination would dramatically impact brain function. We previously developed conjugated small interfering RNA (siRNA) sequences that selectively target serotonin (5-HT) or norepinephrine (NE) neurons after intranasal administration. Here, we used this strategy to conjugate inhibitory oligonucleotides, siRNA and antisense oligonucleotide (ASO), with the triple monoamine reuptake inhibitor indatraline (IND), to selectively reduce α-synuclein expression in the brainstem monoamine nuclei of mice after intranasal delivery. Following internalization of the conjugated oligonucleotides in monoamine neurons, reduced levels of endogenous α-synuclein mRNA and protein were found in substantia nigra pars compacta (SNc), ventral tegmental area (VTA), dorsal raphe nucleus (DR), and locus coeruleus (LC). α-Synuclein knockdown by ∼20%-40% did not cause monoaminergic neurodegeneration and enhanced forebrain dopamine (DA) and 5-HT release. Conversely, a modest human α-synuclein overexpression in DA neurons markedly reduced striatal DA release. These results indicate that α-synuclein negatively regulates monoamine neurotransmission and set the stage for the testing of non-viral inhibitory oligonucleotides as disease-modifying agents in α-synuclein models of PD.

Role of monoaminergic systems and ambient temperature in bath salts constituent 3,4-methylenedioxypyrovalerone (MDPV)-elicited hyperthermia and locomotor stimulation in mice

3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit bath salts products, and in vitro studies implicate monoamine transporters as mediators of its pharmacological effects. Locomotor and thermoregulatory effects of MDPV depend on ambient temperature, so the current studies aimed to gauge the involvement of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in MDPV-induced locomotor stimulation and hyperthermia in the mouse at different ambient temperatures. Mice were pretreated with the selective 5-HT-reuptake inhibitor fluoxetine (3 mg/kg), the NE-reuptake inhibitor desipramine (3 mg/kg), the DA-reuptake inhibitor bupropion (10 mg/kg), or saline, followed by 10 mg/kg MDPV while thermoregulation and locomotor activity were monitored via radiotelemetry. In other studies, mice were pretreated for three days with saline, 100 mg/kg of the tryptophan hydroxylase inhibitor para-chlorophenylalanine (p-CPA), or 100 mg/kg of the tyrosine hydroxylase inhibitor α-methyl-para-tyrosine (α-MPT) before receiving 10 mg/kg MDPV on the fourth day. All manipulations were conducted at both 20 °C and 28 °C ambient temperatures. MDPV increased locomotor activity under both ambient conditions and modestly increased core body temperature at 20 °C; however, neither pretreatment with monoamine reuptake inhibitors nor monoamine synthesis inhibitors significantly altered these effects. At 28 °C, MDPV induced a more pronounced hyperthermic effect which was attenuated by bupropion, desipramine, or fluoxetine pretreatment, but not by the monoamine synthesis inhibitors. These results suggest that MDPV may have a more complex pharmacological profile than suggested by in vitro studies, perhaps extending beyond interactions with monoamine transporters. A more thorough binding profile of MDPV at various brain recognition sites should be developed.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats

“Bath salts” preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., “first-generation” cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., “second-generation” cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Triple reuptake inhibitors: Design, synthesis and structure–activity relationship of benzylpiperidine–tetrazoles

Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine–tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats

Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6h apart) with 5mg/kg CIT, 5mg/kg FLX, 15mg/kg BUP, or saline (SAL) from embryonic day (E) 6–21, and directly to the pups from postnatal day (P) 1–20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted.