Eliyahu Dremencov

Background: There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Methods: Gestating Wistar rats were chronically treated with a selective deltaagonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by in vivo electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. Results: We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Conclusion: Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.

Exposure by women to stressors before pregnancy increases their risk of contracting prenatal depression, a condition which typically may require antidepressant treatment. And even though such perinatal antidepressant treatment is generally considered to be safe. For the mother, its effects on the development and functioning of the offspring`s brain remain unknown. In this study, we aimed to investigate the effects of pregestational chronic unpredictable stress (CUS) and perinatal bupropion on the anxiety behavior and firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT) neurons. Female rats underwent CUS for three weeks before mating. Bupropion was administered to them from gestation day ten until their offspring were weaned. Behavioral (elevated plus maze or EPM test) and neurophysiological (single-unit in vivo electrophysiology) assessments were performed on offspring who reached the age of 48-56 days. We found that maternal CUS and perinatal bupropion, as separate factors on their own, did not change offspring behavior. There was, however, an interaction between their effects on the number of entries to the open arms and time spent in the intersection: maternal CUS tended to decrease these values, and perinatal bupropion tended to diminish CUS effect. Maternal CUS increased the firing activity of 5-HT neurons in males, but not females. Perinatal bupropion did not alter the firing activity of 5-HT neurons but tended to potentiate the maternal CUS-induced increase in 5-HT neuronal firing activity. The CUS-induced increase in firing activity of 5-HT neurons might be a compensatory mechanism that diminishes the negative effects of maternal stress. Perinatal bupropion does not alter the offspring`s anxiety and firing activity of 5-HT, but it does intervene in the effects of maternal stress.

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol selfadministration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

Background Short-term treatment with non-peptide agonists of delta-opioid receptors, such as agonist SNC80, induced behavioral effects in rodents, which could be modulated via changes in central neurotransmission. The present experiments aimed at testing the hypothesis that chronic treatment with SNC80 induces anxiolytic effects associated with changes in hippocampal glutamate and brainstem monoamine pathways. Methods Adult male Wistar rats were used in experiments. Rats were treated with SNC80 (3 mg/kg/day) for fourteen days. Neuronal excitability was assessed using extracellular in vivo single-unit electrophysiology. The behavioral parameters were examined using the elevated plus maze and open field tests. Results Chronic SNC80 treatment increased the excitability of hippocampal glutamate and ventral tegmental area dopamine neurons and had no effect on the firing activity of dorsal raphe nucleus serotonin cells. Chronic SNC80 treatment induced anxiolytic effects, which were, however, confounded by increased locomotor activity clearly confirmed in an open field test. The ability to cope with stressful situations and habituation processes in a novel environment was not influenced by chronic treatment with SNC80. Conclusion Our study suggests that the psychoactive effects of SNC80 might be explained by its ability to stimulate hippocampal glutamate and mesolimbic dopamine transmission.

Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health commonly underrated. There is a pressing need for specific molecular biomarkers, with pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in both clinical and preclinical studies. In this review, we highlight the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for restoration of serum BDNF levels by antidepressant therapy, the strengthening association of perinatal depression with deficiency of BDNF advocates its potential as a surrogate endpoint for preclinical and clinical studies.

Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future antidepressant, antipsychotic, and anti-addiction drugs. Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic-and anti-addiction-like behavioral effects in rodents and primates. Acute RO5256390 suppressed, and RO5263397 stimulated serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopamine neurons of the ventral tegmental area (VTA) in brain slices, suggesting that the behavioral effects of TAAR1 ligands involve 5-HT and dopamine. For more comprehensive testing of this hypothesis, we examined acute and chronic effects of RO5256390 and RO5263397 on monoamine neurons in in vivo conditions. Excitability of 5-HT neurons of the DRN, noradrenaline neurons of the locus coeruleus (LC), and dopamine neurons of the VTA was assessed using single-unit electrophysiology in anesthetized rats. For acute experiments, RO5256390 and RO5263397 were administered intravenously; neuronal excitability after RO5256390 and RO5263397 administration was compared to the basal activity of the same neuron. For chronic experiments, RO5256390 was administered orally for fourteen days prior to electrophysiological assessments. The neuronal excitability in RO5256390-treated rats was compared to vehicle-treated controls. We found that acute RO5256390 inhibited 5-HT and dopamine neurons. This effect of RO5256390 was reversed by the subsequent and prevented by the earlier administration of RO5263397. Acute RO5256390 and RO5263397 did not alter the excitability of LC noradrenaline neurons in a statistically significant way. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.

The concentrations of circulating glucocorticoids are regulated by their synthesis and metabolism. Cytochrome P450 (CYP), primarily expressed in the liver, is one of the main metabolizers of glucocorticoids. Since glucocorticoids, as well as monoamines, are fundamental in stress, the link between hepatic glucocorticoid metabolism and central monoamine transmission might be important in pathophysiology of stress-related disorders. We had previously reported that CYP inhibition by proadifen (SKF525) led to the inhibition of central serotonin (5-HT) neurons. The aim of this study was to investigate the effect of SKF525 on the excitability of central catecholamine neurons. Adult male Wistar rats were administered SKF525 forty-eight, twenty-four, and one hour before electrophysiological assessments. Control animals were injected saline. Rats were anesthetized with chloral hydrate and glass electrodes were inserted into the locus coeruleus (LC) or ventral tegmental area (VTA). Noradrenaline neurons of the LC and dopamine of the VTA neurons were identified, and their firing activity was recorded. It was found that the SKF525 enhanced the excitability of noradrenaline and reduced the excitability of dopamine neurons. We suggest that corticosterone-induced inhibition of 5-HT neurons underlines, at least in part, the ability of SKF525 to stimulate noradrenaline neurons. The inhibitory effect of SKF525 on dopamine neurons might be in turn secondary to the stimulatory effect of this compound on noradrenaline neurons.

KEYWORDS Lipopolysaccharide (LPS); Prenatal immune activation; Serotonin (5-HT); Noradrenaline; Dopamine; Electrophysiology in vivo. Abstract Higher risk of depression and schizophrenia in descendants of mothers experienced acute infection during the pregnancy has been reported. Since monoamines are fundamental in mentioned psychopathologies, it is possible that maternal immune activation leads to impaired functioning of serotonin (5-HT), noradrenaline, and dopamine neurons in offspring. To test this hypothesis, we examined the effect of maternal immune activation by lipopolysaccharide (LPS) in rats on the excitability of monoamine-secreting neurons in the offspring. LPS was administered during days 15-19 of the gestation in the rising doses of 20-80 μg/kg; control dams received vehicle. During days 53-63 postpartum , rats were anesthetized and electrodes were inserted into the dorsal raphe nucleus, locus coeruleus, and ventral tegmental area for in vivo excitability assessment of 5-HT, noradrenaline, and dopamine neurons. Maternal immune activation suppressed the firing rate of 5-HT neurons in both sexes and stimulated the firing rate of dopamine neurons in males. Decrease in the firing rate of 5-HT neurons was accompanied with an increase, and Please cite this article as: K. Csatlosova, E. Bogi and B. Durisova et al., Maternal immune activation in rats attenuates the excitability of monoamine-secreting neurons in adult offspring in a sex-specific way, European Neuropsychopharmacology, https://doi. JID: NEUPSY [m6+; December 16, 2020;21:18 ] increase in the firing rate of dopamine neurons with a decrease, in the density of spontaneously active cells. Maternal immune activation also decreased the variability of interspike intervals in 5-HT and dopamine neurons. It is possible that the alteration of excitability of 5-HT and dopamine neurons by maternal immune activation is involved in the psychopathologies induced by infectious disease during the pregnancy. Stimulation of dopamine excitability in males might be a compensatory mechanism secondary to the maternal immune challenge-induced suppression of 5-HT neurons.

Background: Repeated exposure to predator scent stress (PSS) has been used as an animal model of complex post-traumatic stress disorder (CPTSD). The aim of the current study was to assess brain monoamines and their primary metabolites concentrations in male Wistar rats (16 control, 19 exposed to chronic PSS). Methods: Rats were exposed to PSS for ten days. Fourteen days later, the rats' anxiety index (AI) was assessed with an elevated plus maze test; based on differences in AI, the rats were segregated into low-(AI ≤ 0.8, n = 9) and high-(AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone levels were measured by radio-immunoassay. Brain monoamines and their metabolites were measured using high-performance liquid chromatography with electrochemical detector. Results: PSS exposure led to a significant increase in average rats' AI and a reduction in plasma corticosterone levels. Medullar catecholamines and hippocampal and neocortical norepinephrine levels were increased, and pontine norepinephrine and cerebellar dopamine decreased in PSS-exposed rats. Cerebellar norepinephrine levels were increased, and midbrain, hippocampal, and neocortical 5-HT and hypothalamic and hippocampal dopamine levels-decreased in high-, but not in low-anxiety rats. The decrease in hippocampal dopamine levels was accompanied by an increase of DOPAC levels, suggesting and abnormal metabolism of this transmitter. Conclusion: Reductions in 5-HT and dopamine in mid-and forebrain brain areas are associated with stress susceptibility in rodents and perhaps also with PTSD vulnerability in humans. Dopamine and 5-HT metabolism and its modulation by glucocorticoids appear to play a role in stress susceptibility and in CPTSD.

Post-traumatic stress disorder (PTSD) is a severe psychiatric illness which may develop in individuals exposed to trauma [1], including exposure to military combat, interpersonal violence, and childhood maltreatment. The disorder is characterized by an alternating pattern of re-experiencing symptoms, avoidance of traumatic stimuli, changes in mood and cognition, numbing of general responsiveness, and increased arousal (DSM 5).

Knowledge of the PTSD biology continues to expand whereby earlier observations of elevated catecholamines and decreased cortisol in urine of chronic PTSD of combat veterans [2] were criticized for reflecting only downstream or peripheral components of a very complex pathology [3]. Nonetheless, more recent and sophisticated studies have, by in large, supported these early observations and have provided important additional data relevant to the pathomechanism of PTSD [4]. For example, neuroimaging studies identified important neural circuits in the limbic system, including amygdala, hippocampus, and prefrontal cortex (PFC) which are involved in PTSD [5] [6] [7], but did not explain the initial neuroendocrine findings, especially of decreased urinary cortisol. The concept of allostatic load is a useful paradigm to connect PTSD-related neuroendocrine findings to altered neural circuits [8] [9], however, to date, the relationship between glucocorticoid and catecholamine metabolism in PTSD has not been studied, although monoamine oxidase (MAO)-A, the key enzyme of catecholamine metabolism is glucocorticoid-dependent [10]. Here we present a new hypothesis to explain the link between activation of glucocorticoid metabolism and depression of catecholamine metabolism among different allostatic states in PTSD.

The concepts of allostatic load and overload, i.e. a dramatic increase in the allostatic load that predisposes to disease, have been
extensively described in the literature. Here, we show that rats engaging in active offensive response (AOR) behavioral strategies
to chronic predator scent stress (PSS) display less anxiety behavior and lower plasma cortisol levels versus rats engaging in
passive defensive response (PDR) behavioral strategies to chronic PSS. In the same chronic PSS paradigm, AOR rats also have higher
lactate and lower glutamate levels in amygdala but not in control-region hippocampus versus PDR rats. The implications of these
findings for regulation of allostatic and stress responses, and post-traumatic stress disorder (PTSD) are discussed.

Depression is a severe disorder of the central nervous system (CNS), characterized by multiple emotional, cognitive, and neuroendocrine malfunctions. The lack of the objective diagnostic means for depression and limited efficacy of the existing antidepressants make depression the second major reason for disability and the costliest medical condition in Europe. There is a strong evidence that depression is an organic disease of the CNS rather than simple mood perturbation. However, the exact biomarkers directly linked with depression, such as Lewy Bodies in Parkinson disease, not yet discovered. It can be hypothesizing that the organic brain abnormalities directly linked with depression can be detected on the level of subcellular neuronal structures, such as dendritic spines. Four lines of evidence support the hypothesis that dendritic spines are involved in pathophysiology of depression. Firstly, dendritic spines are the basic information processing units of the brain, and depression can be seen a disorder characterized by impaired information processing. Secondly, dendritic spines are heavily expressed in the limbic areas of the brain, which are responsible for the brain functions impaired in depression. Thirdly, dendritic spines are regulated by monoamines, which are primary target of all known antidepressant drugs. Finally, there are initial reports that antidepressant drugs amend density and morphology of dendritic spines in animal models.

Depression is a brain disorder characterized by severe emotional, cognitive, neuroendocrine, and somatic dysfunctions. Although the last generation of antidepressant drugs demonstrate improved clinical efficacy and safety, the onset of their clinical effect is still significantly delayed from the beginning of the treatment course, and significant number of patients show lack of adequate response to these drugs and/or relapse of the disease even after initially successful treatment. Therefore, there is a need to develop new antidepressant drugs and/or adjuncts to existing ones. Recent studies suggest that the beneficial effect of antidepressant drugs is mediated, at least in part, via the stimulation of adult hippocampal neurogenesis and subsequent increase in hippocampal plasticity. The stimulatory effect of antidepressant drugs on hippocampal neurogenesis involves G-protein coupled receptors (GPCR) and voltage-dependent calcium channels (VDCC). It is therefore possible that the future antidepressant drugs will directly target specific GPCR and VDCC. Potential advantages and limitations of these treatment strategies are discussed in the article.

Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by SSRIs through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of serotonin (5-HT) and DA. In order to test this augmentation strategy, male Wistar rats were treated (s.c.) with an acute dose of the SSRI citalopram (Cit, 5 mg/kg), the 5-HT2C antagonist SB 242084 (SB, 2 mg/kg), or Cit + SB, and the effects on 5-HT and DA release in the nucleus accumbens (NAcc) was assessed by microdialysis. In a separate experiment, animals were treated with vehicle, Cit (20 mg/kg/d), SB (2 mg/kg/d) or Cit + SB for a period of 2 days (s.c.), and the impact on the release of 5-HT and DA in the ventral tegmental area (VTA) and NAcc was studied.. On the day of microdialysis, 5-HT2C receptor sensitivity was assessed with an SB challenge. Acutely administered Cit + SB increased 5-HT release in the NAcc more than Cit alone. SB alone increased DA release in the NAcc (not in the VTA), but when administered together with Cit, this effect was abolished. A 2-day treatment with Cit or Cit + SB increased 5-HT release in both VTA and NAcc. Combining Cit with SB augmented the effect of Cit in the VTA. DA release in VTA and NAcc was only significantly increased after 2-days of treatment with Cit + SB. In conclusion, Cit + SB had synergistic effects on 5-HT and DA release after 2-days of treatment, probably related to a decreased tonic inhibition of DA release via 5-HT2C receptors. Regional differences occur and future studies should elucidate if this augmentation strategy is beneficial on the behavioural level.

Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examined the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, especially in depression with 5-HT deficiency.

This monograph is a collection of selected articles on the subject of mood disorders such as depression and schizophrenia. It is divided into 3 sections: 1) Research methods in psychopharmacology - which highlights some established experimental techniques to study mood disorders in human and relevant animal models, 2) Pathophysiology of mood disorders – which explains the physiological and pharmacological mechanisms responsible for mood disorders and 3) New strategies for the treatment of mood disorders – a concluding section that provides recent examples on the beneficial effects of pharmacological and non-pharmacological interventions in the relief of mood disorders. The e-book serves as a primer for graduate students and researchers interested in the physiology and treatment of affective psychological disorders. Free sample is available for downloading; order the whole book at: http://benthamscience.com/ebooks/9781608054671/index.htm

Introduction: The current study aimed to identify and characterize the spontaneous firing activity of the neurons of rat arcuate nucleus (ARN) of the hypothalamus in vivo. The ARN contains two types of neurons: pro-opiomelanocortin (POMC) neurons which release β-endorphin and neuropeptide-Y (NPY) secreting neurons [1]. These neurons play an important role in pain modulation, reward, motivation, and appetite regulation. Therefore, in vivo electrophysiological characterization of the firing activity of ARN neurons might contribute to better understanding of their function under physiological and pathophysiological conditions.

Methods: Adult male and female Sprague-Dawley rats (200–250 g) were used in experiments. Rats were anesthetized with urethane (1.25 g/kg, i.p.) and mounted in stereotaxic apparatus (David Kopf, Tujunga, CA, USA). One-mm scull holes were drilled above the ARN (3.9 mm posterior and 0.6 mm lateral from the bregma). The glass electrodes filled with 2M NaCl (impedance 4–6 MΩ) were lowered throughout the lateral ARN three times in each animal (3.8, 3.9, and 4.0 mm posterior and 0.6 mm lateral from the bregma) to the depth from 9.5 to 10.0 mm ventral from the brain surface [2]. Spontaneously active neurons were recorded using HEKA-10 amplifier.

Results: Spontaneously active neurons were detected in the lateral ARN of both male and female rats. The firing pattern of the spontaneously active ARN neurons included both single action potentials and short bursts of two or three action potentials. The average duration of an action potential was ∼5 msec, with ∼1.5 msec depolarization, ∼1 msec repolarization, and ∼3 msec refractory period. The average number of spontaneously active neurons per electrode tack was slightly higher in males (2.65±0.33) than in females (1.85±0.25); however, this difference was not statistically significant. The average firing rate of spontaneous active ARN neurons was 3.14±0.50 in males (59 neurons from 7 rats) and 3.02±0.95 in females (23 neurons from 6 rats). According to preliminary results, in male rats, 75% of neurons were stimulated by intravenous administration of 1 mg/kg of leptin and 25% neurons did not respond to the leptin administration. In female rats, 50% of neurons were activated, and 25% of neurons were inhibited by leptin and 25% of neurons did not respond to the leptin administration. In summary, a significant main effect of time (Fdf17,143 = 2.45, p < 0.01) and significant interaction between gender and time (Fdf17,143 = 1.75, p < 0.05) in the response of spontaneous active ARN neurons to leptin administration was observed (two-way ANOVA for repeated measures).

Conclusion: Based on previous study [1], it can be suggested that ARN neurons which were stimulated by leptin are POMC cells. The cells which were inhibited by leptin are likely to be NPY neurons. It is possible that male Sprague-Dawley rats have higher density of spontaneously active POMC and smaller density of spontaneous active NPY neurons.

References

[1] Elias, C.F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R.S., Bjorbaek, C., Flier, J.S., Saper, C.B., Elmquist, J.K., 1999. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–86.

[2] Paxinos, G., Watson, C., 2013. The Rat Brain in Stereotaxic Coordinates, Seventh Edition. Academic Press, Cambridge, UK.

Disclosure statement: This work was supported by Slovak Academy of Sciences Scholarship and by VEGA grant 2/0024/15. Leptin was provided by the National Hormone & Peptide Program (NHPP) of the University of California in Los Angeles, CA, USA.