Reuptake Blocker Research Articles

Neurochemical Anatomy of Cushing's Syndrome.

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.

The neuropharmacological profile of interval responding during operant tasks.

Responses occurring during intervals of operant tasks have been subdivided as interim, facultative, and terminal, depending on the time between response onset and reward. Although interval responses, also known as adjunctive responses, have been described in pigeons, rats, mice, monkeys, and humans, most experiments have been conducted in rats. We review the neurochemical basis of interval responses and examine the hypothesis that these responses modulate operant performance. Preliminary experiments indicate the involvement of biogenic amines, acetylcholine, and GABA during interval responding associated with operant tasks. In particular, catecholaminergic deafferentation of the basal ganglia modulated interval responses as did the peripheral injection of catecholamine reuptake blockers. Under the influence of amphetamine, interval responding may either increase or decrease, so that a wide range of responses must be selected to gauge drug effects. In non-drugged pigeons and rats, the expression of interval responses facilitates operant training.

Listening to your partner: serotonin increases male responsiveness to female vocal signals in mice.

The context surrounding vocal communication can have a strong influence on how vocal signals are perceived. The serotonergic system is well-positioned for modulating the perception of communication signals according to context, because serotonergic neurons are responsive to social context, influence social behavior, and innervate auditory regions. Animals like lab mice can be excellent models for exploring how serotonin affects the primary neural systems involved in vocal perception, including within central auditory regions like the inferior colliculus (IC). Within the IC, serotonergic activity reflects not only the presence of a conspecific, but also the valence of a given social interaction. To assess whether serotonin can influence the perception of vocal signals in male mice, we manipulated serotonin systemically with an injection of its precursor 5-HTP, and locally in the IC with an infusion of fenfluramine, a serotonin reuptake blocker. Mice then participated in a behavioral assay in which males suppress their ultrasonic vocalizations (USVs) in response to the playback of female broadband vocalizations (BBVs), used in defensive aggression by females when interacting with males. Both 5-HTP and fenfluramine increased the suppression of USVs during BBV playback relative to controls. 5-HTP additionally decreased the baseline production of a specific type of USV and male investigation, but neither drug treatment strongly affected male digging or grooming. These findings show that serotonin modifies behavioral responses to vocal signals in mice, in part by acting in auditory brain regions, and suggest that mouse vocal behavior can serve as a useful model for exploring the mechanisms of context in human communication.

The endogenous cannabinoid and the adrenergic systems in modulation of stress-response

In our modern, fast-paced society, excessive stress (or distress) is a major risk factor for developing a plethora of diseases. There are several neuromediatory systems in the brain that regulate the response to stress, including the adrenergic and endocannabinoid systems. In our experiments, we study the effects of the endocannabinoid system on the restrain stress-induced analgesia (r-SIA). The experiments were done on male Wistar rats. The animals were confined in special restrainers for a period of one hour. The animals were treated with Clonidine (at 4 mg/kg) – a prototypical α2-agonist; Yohimbine – an α2-adrenergic receptor antagonist; Desipramine – a NE reuptake blocker; CB1r agonist anandamide (AEA); CB1r antagonist АМ251 in different combinations. r-SIA was investigated by means of the paw pressure test in order to get a better understanding of the role that the neurotransmitter anandamide plays in the process. The degree to which the levels of r-SIA fluctuated served as an indicator of the degree to which the cannabinoid system and the adrenergic system interacted with one another. Cannabinoids that are administered exogenously were found to reduce levels of r-SIA and modulate the effects of the adrenergic system. These conclusions were reached based on the findings of our research.

Hypidone hydrochloride (YL-0919) protects mice from meningitis via Sigma1R-STAT1-NLRP3-GSDMD pathway

BackgroundA growing number of studies have found that antidepressants have anti-inflammatory effects while protecting nerves. Hypidone hydrochloride (YL-0919) is a novel highly selective 5-HT reuptake blocker. Our previous studies have demonstrated that YL-0919 exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 can be used to treat inflammatory and infectious diseases remain unknown. In this study, we aimed to verify the anti-inflammatory effect of YL-0919 on bacterial meningitis and further explore the potential molecular mechanisms. MethodsWe performed the experiments on pneumococcal meningitis mice in vivo and S. pneumoniae infected macrophages/microglia in vitro, with or without YL-0919 treatment.Cognitive function was evaluated by open-field task, Morris water maze test, and novel object recognition test. Histopathological staining and immunofluorescence staining were used to detect the pathological damage of meningitis and NLRP3 inflammasome activation in microglia/macrophages. The expression of the STAT1/NLRP3/GSDMD signal pathway was measured by western blots. Proinflammatory cytokines associated with pyroptosis were detected by ELISA. ResultsYL-0919 protected mice from fatal pneumococcal meningitis, characterized by attenuated cytokine storms, decreased bacterial loads, improved neuroethology, and reduced mortality. NLRP3 plays a key role in the regulation of inflammation. When the underlying mechanisms were investigated, we found that YL-0919 inhibited the activation of NLRP3 via STAT1, and thus inhibited macrophages/microglia pyroptosis, resulting in downregulation of proinflammatory cytokines. In addition, Sigma1R was identified as a pivotal receptor that can be engaged by YL-0919 to inhibit NLRP3 activation and pyroptosis pathway in microglia/macrophages. ConclusionsThese results provide new insights into the mechanisms of inflammation regulation mediated by the antidepressant YL-0919. Moreover, targeting the STAT1/NLRP3 pyroptosis pathway is a promising strategy for the treatment of infectious diseases like bacterial meningitis.

Vilazodone, a Selective Serotonin Reuptake Inhibitor with Diminished Impact on Methylphenidate-Induced Gene Regulation in the Striatum: Role of 5-HT1A Receptor.

Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, are frequently combined with medical psychostimulants such as methylphenidate (Ritalin), for example, in the treatment of attention-deficit hyperactivity disorder/depression comorbidity. Co-exposure to these medications also occurs with misuse of methylphenidate as a recreational drug by patients on SSRIs. Methylphenidate, a dopamine reuptake blocker, produces moderate addiction-related gene regulation. Findings show that SSRIs such as fluoxetine given in conjunction with methylphenidate potentiate methylphenidate-induced gene regulation in the striatum in rats, consistent with a facilitatory action of serotonin on addiction-related processes. These SSRIs may thus increase methylphenidate's addiction liability. Here, we investigated the effects of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation. Vilazodone differs from prototypical SSRIs in that, in addition to blocking serotonin reuptake, it acts as a partial agonist at the 5-HT1A serotonin receptor subtype. Studies showed that stimulation of the 5-HT1A receptor tempers serotonin input to the striatum. We compared the effects of acute treatment with vilazodone (10-20mg/kg) with those of fluoxetine (5mg/kg) on striatal gene regulation (zif268, substance P, enkephalin) induced by methylphenidate (5mg/kg), by in situ hybridization histochemistry combined with autoradiography. We also assessed the impact of blocking 5-HT1A receptors by the selective antagonist WAY-100635 (0.5mg/kg) on these responses. Behavioral effects of these drug treatments were examined in parallel in an open-field test. Our results show that, in contrast to fluoxetine, vilazodone did not potentiate gene regulation induced by methylphenidate in the striatum, while vilazodone enhanced methylphenidate-induced locomotor activity. However, blocking 5-HT1A receptors by WAY-100635 unmasked a potentiating effect of vilazodone on methylphenidate-induced gene regulation, thus confirming an inhibitory role for 5-HT1A receptors. Our findings suggest that vilazodone may serve as an adjunct SSRI with diminished addiction facilitating properties and identify the 5-HT1A receptor as a potential therapeutic target to treat addiction.

Chiral Resolution of the Enantiomers of the Slow-Onset Dopamine Reuptake Inhibitor CTDP-32476 and Their Activities.

An improved synthesis was developed for CDTP-32476, a potent slow-onset dopamine reuptake blocker that may have utility as a treatment for cocaine abuse. The enantiomers of the compound were separated by fractional crystallization with N-acetylleucine enantiomers. An X-ray crystal structure was obtained of the RR enantiomer paired with N-acetyl-d-leucine. Chiral chromatography showed that the resolved enantiomers were pure with little contamination by the other enantiomer. The enantiomers were tested for their ability to block the reuptake of monoamines at their respective transporters and to stimulate locomotor activity in mice. Both enantiomers potently blocked the reuptake of dopamine and stimulated locomotor activity in mice. The RR enantiomer that corresponds to the active RR enantiomer of methylphenidate was slightly more potent at the dopamine reuptake site. The RR enantiomer also was found to be about twice as selective for the dopamine transporter relative to the norepinephrine transporter, which may have clinical implications. A method for designing slow-onset stimulants is proposed since there is increasing evidence that such activity is an important factor in stimulants that may have limited abuse potential.

Effects of two kinds of noradrenergic ADHD medicines on sign-tracking and goal-tracking in male rats.

Sign- and goal-tracking are behaviors seen in many species when a conditioned stimulus and it's corresponding unconditioned stimulus are presented at separate locations, and have been the focus of studies on appetitive conditioned and drug dependence. The neurochemical basis of sign-tracking is of interest for both studies of basic conditioning and addiction. In this work, I examined the role of norepinephrine by employing two noradrenergic drugs used for attention-deficit hyperactivity disorder (ADHD)-(a) atomoxetine, a norepinephrine reuptake blocker, and (b) guanfacine, an α2A-adrenergic receptor agonist. Sprague-Dawley rats were trained using a standard Pavlovian conditioning procedure with a retractable lever as conditioned stimulus and sucrose pellets as unconditioned stimulus. It was found that while atomoxetine reduced both sign- (both doses) and goal-tracking (only at the higher dose), guanfacine did not have any effect on either behavior. While norepinephrine reuptake blocking may be an effective strategy for reducing sign-tracking, manipulation of the α2A-adrenergic receptor appears less viable. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Measurement of Noradrenaline and Serotonin Metabolites With Internal Jugular Vein Sampling: An Indicator of Brain Monoamine Turnover in Depressive Illness and Panic Disorder.

In research spanning three decades we have estimated brain monoamine turnover (approximately equating with synthesis rate) with sampling from the internal jugular veins and measurement of trans-cerebral plasma monoamine metabolite concentration gradients. Here we report indices of brain noradrenaline and serotonin turnover in patients with major depressive illness (MDD) and panic disorder (PD). Brain noradrenaline turnover was assessed from the combined flux into the internal jugular veins of the metabolites dihydroxyphenylglycol (DHPG) and 3-hydroxy-4-methoxyphenylglycol (MHPG), and brain serotonin turnover from the overflow of the primary metabolite, 5-hydroxyindole acetic acid (5HIAA). Comparison was made with matched healthy research participants. In both MD and PD the estimate of brain noradrenaline turnover provided by metabolite overflow was unremarkable. In contrast, in both patient groups the estimate of brain serotonin turnover provided by 5HIAA overflow was increased 3–4-fold (P < 0.01). This neurotransmitter abnormality was normalized in MDD and PD in clinical remission, during selective serotonin reuptake blocker (SSRI) dosing. We cannot be sure if the brain serotonergic abnormality we find in MDD and PD is causal or a correlate. Measurements in PD were not made during a panic attack. The increased estimated serotonin turnover here may possibly be a substrate for panic attacks; serotonergic raphe nuclei participate in anxiety responses in experimental animals. It is puzzling that the findings were identical in MDD and PD, although it may be pertinent that these psychiatric diagnoses are commonly comorbid. It is unlikely that activation of brain serotonergic neurons is driving the sympathetic nervous activation present, which contributes to cardiovascular risk, persistent sympathetic activation in MDD and episodic activation in PD during panic attacks. We have previously demonstrated that the mechanism of activation of human central sympathetic outflow in other contexts (hypertension, heart failure) is activation of noradrenergic brainstem neurons projecting to the hypothalamus and amygdala.

An ontogenic study of receptor mechanisms by which acute administration of low-doses of methamphetamine suppresses DOI-induced 5-HT2A-receptor mediated head-twitch response in mice

BackgroundMethamphetamine (MA) is a non-selective monoamine releaser and thus releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) from corresponding nerve terminals into synapses. DOI ((±)-2, 5-dimethoxy-4-iodoamphetamine) is a direct-acting serotonergic 5-HT2A/C receptor agonist and induces the head-twitch response (HTR) via stimulation of 5-HT2A receptor in mice. While more selective serotonin releasers such as d-fenfluramine evoke the HTR, monoamine reuptake blockers (e.g., cocaine) suppress the DOI-evoked HTR via indirect stimulation of serotonergic 5-HT1A- and adrenergic ɑ2-receptors. Since the induction of HTR by DOI is age-dependent, we investigated whether: (1) during development MA can evoke the HTR by itself, and (2) acute pretreatment with either the selective 5-HT2A receptor antagonist EMD 281014 or low-doses of MA can: (i) modulate the DOI-induced HTR in mice across postnatal days 20, 30 and 60, and (ii) alter the DOI-induced c-fos expression in mice prefrontal cortex (PFC). To further explore the possible modulatory effect of MA on DOI-induced HTR, we investigated whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors by corresponding selective antagonists (WAY 100635 or RS 79948, respectively), can prevent the effect of MA on DOI-induced HTR during aging.ResultsAlthough neither EMD 281014 nor MA by themselves could evoke the HTR, acute pretreatment with either EMD 281014 (0.01, 0.05 and 0.1 mg/kg, i.p.) or MA (1, 2.5, 5 mg/kg, i.p.), dose-dependently suppressed the DOI-induced HTR across ages. While WAY 100635 significantly reversed the inhibitory effect of MA in 20- and 30-day old mice, RS 79948 failed to significantly counter MA’s inhibitory effect. Moreover, DOI significantly increased c-fos expressions in several PFC regions. EMD 281014 prevented the DOI-induced increases in c-fos expression. Despite the inhibitory effect of MA on DOI-induced HTR, MA alone or in combination with DOI, significantly increased c-fos expression in several regions of the PFC.ConclusionThe suppressive effect of MA on the DOI-evoked HTR appears to be mainly due to functional interactions between the HTR-inducing 5-HT2A receptor and the inhibitory 5-HT1A receptor. The MA-induced increase in c-fos expression in different PFC regions may be due to MA-evoked increases in synaptic concentrations of 5-HT, NE and/or DA.

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.

Acetaldehyde Excitation of Lateral Habenular Neurons via Multiple Cellular Mechanisms.

Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but attenuated by the antagonists of dopamine (DA) receptor (DAR) subtype 1 (SCH23390) and subtype 2 (raclopride), and partly abolished by the pretreatment of DA or DA reuptake blocker (GBR12935; GBR). Moreover, application of ACD initiated a depolarizing inward current (IACD) and enhanced the hyperpolarizing-activated currents in LHb neurons. Bath application of Rp-cAMPs, a selective cAMP-PKA inhibitor, attenuated ACD-induced potentiation of EPSCs and IACD Finally, bath application of ZD7288, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channels, attenuated ACD-induced potentiation of firing, EPSCs, and IACD These results show that ACD exerts its aversive property by exciting LHb neurons via multiple cellular mechanisms, and new treatments targeting the LHb may be beneficial for alcoholism.SIGNIFICANCE STATEMENT Acetaldehyde (ACD) has been considered aversive peripherally and rewarding centrally. However, whether ACD has a central aversive property is unclear. Here, we report that ACD excites the lateral habenula (LHb), a brain region associated with aversion and negative valence, through multiple cellular and molecular mechanisms. Intra-LHb ACD produces significant conditioned place aversion. These results suggest that ACD's actions on the LHb neurons might contribute to its central aversive property and new treatments targeting the LHb may be beneficial for alcoholism.

FDA Approves Qelbree for ADHD

Back to table of contents Previous article Next article Clinical & ResearchFull AccessFDA Approves Qelbree for ADHDTerri D'ArrigoTerri D'ArrigoSearch for more papers by this authorPublished Online:20 May 2021https://doi.org/10.1176/appi.pn.2021.6.12AbstractViloxazine is not a stimulant and is not a controlled substance.In April the Food and Drug Administration (FDA) approved Qelbree (viloxazine extended-release capsules), a selective norepinephrine reuptake inhibitor, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric patients aged 6 to 17 years. Qelbree is not a stimulant and is not a controlled substance.In three separate phase 3 trials involving 1,118 patients aged 6 to 17 years, patients who took Qelbree experienced a greater improvement in ADHD symptoms compared with those who took placebo, as measured by the ADHD Rating Scale and the Clinical Global Impression-Improvement score. Doses during the trials ranged from 100 mg to 400 mg.The recommended starting dose for patients 6 to 11 years old is 100 mg once daily. The recommended starting dose for patients 12 to 17 years old is 200 mg once daily. Dosages for both age groups may be titrated up to 400 mg once daily. Qelbree is taken once daily, and capsules may be broken open and sprinkled on applesauce or swallowed whole.Qelbree may be an option for patients with a history of substance use for whom there may be a concern about using controlled substances like stimulants, says David Rettew, M.D.Valerie HarderDavid Rettew, M.D., the medical director of the Child and Adolescent and Families Division of the Vermont Department of Mental Health and an associate professor of psychiatry and pediatrics at the University of Vermont, said he sees where Qelbree may provide a new treatment option for several patient populations.“One would be the child or adolescent who can’t take stimulant medications due to side effects,” Rettew told Psychiatric News. “Since Qelbree doesn’t have the on/off quality of stimulants where the benefits wear off during the day, there also could be interest in patients and families looking for a more even effect throughout the day. Finally, its use might be considered in individuals with substance use histories where there could be concern about using controlled substances like stimulants.”Qelbree’s label contains a boxed warning that the medication may increase the risk of suicidal thoughts and behaviors. The warning advises health professionals who prescribe Qelbree to monitor patients closely for “clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.”Data from the clinical trials also suggest that the medication may induce manic or mixed episodes in patients with bipolar disorder, and the label cautions that patients should be screened to determine if they are at risk for bipolar disorder.Between 22% and 31% of patients who received Qelbree in the clinical trials experienced an increase in heart rate of at least 20 beats a minute and a 15-point increase in their diastolic blood pressure. The label advises that health professionals should assess their patients’ heart rate and blood pressure prior to initiating treatment and when increasing dosages. However, this may be easier said than done during the pandemic.“Right now, so many medical appointments are being done via telemedicine, and vital signs are more difficult to get,” said Rettew. Rettew noted that viloxazine was marketed as an antidepressant in other countries before being marketed as a treatment for ADHD in the United States.“[Qelbree] therefore has many of the same warnings [as antidepressants], such as the potential for increased suicidal thoughts and activation of mania. Some of the blood pressure and pulse increases have also been found with antidepressants that have norepinephrine reuptake properties such as venlafaxine,” he said. “While the medication is touted as working as a norepinephrine reuptake blocker, there is some research suggesting that it also acts on serotonin, similar to many other antidepressants.”Rettew said he will keep an open mind about Qelbree, but that it would not surprise him if it is seen as similar to another nonstimulant medication for ADHD, Strattera (atomoxetine).“[Strattera] is often pretty well tolerated but there have been some data suggesting that it may not result in as much improvement in core ADHD symptoms as the stimulants. From some of the data from initial trials, it looks like Qelbree could be in the same boat,” Rettew said.“It is also worth noting that all of the ADHD trials [for Qelbree] have been short, just a matter of weeks. Long-term data are really needed, although we do have a long track record of [viloxazine’s] use as an antidepressant.”Rettew is not affiliated with Supernus Pharmaceuticals and was not involved in clinical trials of Qelbree. ■Full prescribing information for Qelbree is posted here. ISSUES NewArchived

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.

Blockade of Catecholamine Reuptake in the Prelimbic Cortex Decreases Top-down Attentional Control in Response to Novel, but Not Familiar Appetitive Distracters, within a Timing Paradigm.

Emotionally charged distracters delay timing behavior. Increasing catecholamine levels within the prelimbic cortex has beneficial effects on timing by decreasing the delay after aversive distracters. We examined whether increasing catecholamine levels within the prelimbic cortex also protects against the deleterious timing delays caused by novel distracters or by familiar appetitive distracters. Rats were trained in a peak-interval procedure and tested in trials with either a novel (unreinforced) distracter, a familiar appetitive (food-reinforced) distracter, or no distracter after being locally infused within the prelimbic cortex with catecholamine reuptake blocker nomifensine. Prelimbic infusion of nomifensine did not alter timing accuracy and precision. However, it increased the delay caused by novel distracters in an inverted-U dose-dependent manner, while being ineffective for appetitive distracters. Together with previous data, these results suggest that catecholaminergic modulation of prelimbic top-down attentional control of interval timing varies with distracter’s valence: prelimbic catecholamines increase attentional control when presented with familiar aversive distracters, have no effect on familiar neutral or familiar appetitive distracters, and decrease it when presented with novel distracters. These findings detail complex interactions between catecholaminergic modulation of attention to timing and nontemporal properties of stimuli, which should be considered when developing therapeutic methods for attentional or affective disorders.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Triple reuptake inhibition of serotonin, norepinephrine, and dopamine increases the tonic activation of α2-adrenoceptors in the rat hippocampus and dopamine levels in the nucleus accumbens

Clinical studies have shown the therapeutic efficacy of an increase in dopamine (DA) transmission in treatment of major depressive disorder (MDD). In the present study, we investigated whether blockade of DA transporters in addition to serotonin (5-HT) and norepinephrine (NE) produced additional adaptations of monoaminergic systems. In vivo electrophysiological recordings were carried out in male anesthetized rats. Vehicle, the 5-HT reuptake inhibitor escitalopram, the NE/DA reuptake blocker nomifensine and their combination (triple reuptake inhibition; TRI) were delivered for 2 or 14 days. Firing activity of NE, 5-HT and DA neurons was assessed. Tonic activation of 5-HT1A receptors and α1- and α2-adrenoceptors was determined in the hippocampus and extracellular DA levels in the nucleus accumbens (NAc). Unlike escitalopram, nomifensine and TRI administration increased the tonic activation of α2-adrenoceptors in the hippocampus despite decreasing NE neuronal firing activity after 2 and 14 days of administration. The firing activity of 5-HT neurons was increased after prolonged nomifensine and TRI regimens, while addition of nomifensine to escitalopram prevented the early 2-day suppression of firing by 5-HT reuptake inhibition. The tonic activation of 5-HT1A receptors was enhanced only with escitalopram. Whereas escitalopram and nomifensine decreased firing activity of DA neurons after a 2-day administration, their combination normalized it to baseline level after 14 days; this was accompanied by a robust increase in extracellular DA levels in the NAc. In summary, these results indicate that TRI increases NE and DA but not 5-HT transmission, suggesting a differential efficacy profile in MDD patients.

The serotonin reuptake blocker citalopram destabilizes fictive locomotor activity in salamander axial circuits through 5-HT1A receptors.

Serotoninergic (5-HT) neurons are powerful modulators of spinal locomotor circuits. Most studies on 5-HT modulation focused on the effect of exogenous 5-HT and these studies provided key information about the cellular mechanisms involved. Less is known about the effects of increased release of endogenous 5-HT with selective serotonin reuptake inhibitors. In mammals, such molecules were shown to destabilize the fictive locomotor output of spinal limb networks through 5-HT1A receptors. However, in tetrapods little is known about the effects of increased 5-HT release on the locomotor output of axial networks, which are coordinated with limb circuits during locomotion from basal vertebrates to mammals. Here, we examined the effect of citalopram on fictive locomotion generated in axial segments of isolated spinal cords in salamanders, a tetrapod where raphe 5-HT reticulospinal neurons and intraspinal 5-HT neurons are present as in other vertebrates. Using electrophysiological recordings of ventral roots, we show that fictive locomotion generated by bath-applied glutamatergic agonists is destabilized by citalopram. Citalopram-induced destabilization was prevented by a 5-HT1A receptor antagonist, whereas a 5-HT1A receptor agonist destabilized fictive locomotion. Using immunofluorescence experiments, we found 5-HT-positive fibers and varicosities in proximity with motoneurons and glutamatergic interneurons that are likely involved in rhythmogenesis. Our results show that increasing 5-HT release has a deleterious effect on axial locomotor activity through 5-HT1A receptors. This is consistent with studies in limb networks of turtle and mouse, suggesting that this part of the complex 5-HT modulation of spinal locomotor circuits is common to limb and axial networks in limbed vertebrates.NEW & NOTEWORTHY Little is known about the modulation exerted by endogenous serotonin on axial locomotor circuits in tetrapods. Using axial ventral root recordings in salamanders, we found that a serotonin reuptake blocker destabilized fictive locomotor activity through 5-HT1A receptors. Our anatomical results suggest that serotonin is released on motoneurons and glutamatergic interneurons possibly involved in rhythmogenesis. Our study suggests that common serotoninergic mechanisms modulate axial motor circuits in amphibians and limb motor circuits in reptiles and mammals.

1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain

Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.

Modafinil reduces choice impulsivity while increasing motor activity in preadolescent rats treated prenatally with alcohol

Rats exposed prenatally to alcohol show a reduction in the spontaneous activity of dopaminergic neurons of the ventral tegmental area (VTA), as well as greater impulsive behavior and motor activity, behavioral alterations that have been related to dopaminergic dysfunction. Modafinil (MOD) is a dopamine (DA) reuptake blocker prescribed to treat sleep disorders; however, in recent years it has been used for the treatment of ADHD with positive results. Also, studies in humans and rodents show beneficial effects on learning and attention; however, studies evaluating MOD effects on impulsivity are few and show contradictory results. The purpose of this work was to evaluate the effect of a daily dose of MOD (60 mg/kg i.g.) on cognitive (or choice) impulsivity and motor activity in male preadolescent rats exposed prenatally to alcohol or sucrose (isocaloric control). MOD reduced the impulsive responses in a delay discounting task (DDT) at the same time that increased the motor activity, in both healthy and prenatal alcohol treated rats; however, MOD reduced the response latency in DDT only in prenatal alcohol treated rats. This differential effect of DA activation on impulsivity and motor activity show that the MOD dose that improves the impulse control, does not necessarily decrease motor activity, and suggests a possible differential neural mechanism underlying the expression of these behaviors. On the other hand, the changes in the response latency, only in prenatal alcohol treated groups, suggest that decision-making in animals with a dopaminergic dysfunction is more susceptible to be affected by MOD action.