Effects of the putative anxiolytic SM-3997 on central monoaminergic systems

The effects of SM-3997 on central monoaminergic systems were evaluated by ex vivo measurement of monoamines and their metabolite levels in rat brain after intraperitoneal treatment of drugs and by in vitro measurement of monoamine uptake into rat brain slices. The effects of SM-3997 were also compared with those of other new nonbenzodiazepine anxiolytic compounds. SM-3997, buspirone, gepirone and ipsapirone showed no effects on serotonin uptake and dopamine uptake, and a weak inhibition of norepinephrine uptake at the concentration of 100 microM. SM-3997 decreased the serotonin metabolite (5-hydroxyindole-3-acetic acid) level without changing the serotonin level in hippocampus and increased dopamine metabolite (3,4-dihydroxyphenylacetic acid, homovanillic acid) level with no effect on the dopamine level in striatum. SM-3997 also produced an increase in the norepinephrine metabolite (3-methoxy-4-hydroxyphenylglycol) level with a decrease in the norepinephrine levels in hippocampus. Similar effects on serotonin metabolites and norepinephrine metabolites were observed in several other regions. Although the serotonergic effect of SM-3997 was similar to that of buspirone, gepirone and ipsapirone, the dopaminergic effect of SM-3997 was much weaker than that of buspirone.     

The influence of central monoaminergic systems on the anticonvulsive action of propranolol

The influence of substances modulating the activity of central monaminergic systems on the anticonvulsant effect of propranolol was investigated with the maximal electroshock test in mice. The results demonstrated that especial the noradrenergic system plays an important role in modulating the efficacy of propranolol. Pharmacological stimulation of the noradrenergic system (e. g. with desipramine, pargyline, yohimbine) resulted in an enhanced anticonvulsant effect of propranolol. Compounds that suppress the noradrenergic transmission reduced this action. On the other hand manipulations of serotonergic (with 5,7-DHT, 5-HTP, PCPA) or dopaminergic (with 6-OHDA + desipramine, apomorphine) mechanisms seems to be without marked influence on the protective effect of propranolol in maximal electroshock.     

Effects of acetaminophen on monoaminergic systems in the rat central nervous system

Although acetaminophen is a well established analgesic, its mechanism of action is still unknown. We investigated whether this drug could affect central monoaminergic neurotransmission in rats. Significant increases in serotonin (5-HT) levels were found in the posterior cortex, hypothalamus, striatum, hippocampus and brain stem, but not spinal cord, 45 min after per os administration of 200-400 mg/kg of acetaminophen. However, this treatment altered neither the levels of 5-hydroxyindoleacetic acid nor the accumulation of 5-hydroxytryptophan after blockade of aromatic L-amino acid decarboxylase. On the other hand, a decrease in both the levels of the dopamine (DA) metabolite, dihydroxyphenylacetic acid, and the accumulation of dihydroxyphenylalanine were noted in the striatum of acetaminophen-treated rats. Finally, acetaminophen administration significantly increased noradrenaline (NA) levels in the posterior cortex. In vitro studies showed that acetaminophen (1 mM) enhanced K+-evoked overflow of [3H]5-HT, but not [3H]DA and [3H]NA, previously taken up in brain slices, and exerted no direct effect on monoamine oxidase A, tyrosine hydroxylase and catechol-O-methyl-transferase activities. These results indicate that acetaminophen affects central monoaminergic neurotransmission, thereby suggesting that monoamines (especially 5-HT) might participate in its analgesic action.     

Cocaine modulation of central monoaminergic neurotransmission

Extracellular microelectrode studies were conducted to test the effects of cocaine HCl on the activity of spontaneously firing single serotonergic dorsal raphe (DRN), noradrenergic locus coeruleus (LC) and dopaminergic ventral tegmental (VTA) and zona compacta (ZC) neurons, and cerebellar Purkinje neurons (PC) in urethane anesthetized rats in vivo. Cocaine (0.0625-4 mg/kg) predominantly inhibited all of the central monoaminergic neurons and predominantly activated cerebellar Purkinje neurons. Cocaine (1 mg/kg, IV) failed to potentiate the inhibitory effects of LC stimulation on PC neurons. The temporal effects of intravenous cocaine on arterial pressure (i.e., pressor response) were not directly correlated with the effects on neurons. Cocaine did not decrease the amplitude or slope of neuron action potentials, and the effects of cocaine on firing rate were not shared by similar doses of procaine. Reserpine pretreatment (10 mg/kg, IP) attenuated the effects of cocaine (1 mg/kg, IV) on DRN, LC, and PC neurons. Specific adrenoceptor antagonists antagonized the inhibitory effects of cocaine on LC (piperoxane, yohimbine) and VTA (haloperidol) neurons. These results suggest that the central effects of cocaine on presynaptic monoaminergic neurons may in part be mediated by augmented monoamine neurotransmission at autoreceptors and that the effects of cocaine on postsynaptic target cells (PC) may be more complex, requiring the analysis of both pre- and postsynaptic elements.     

Effects of methamphetamine on central monoaminergic systems in normal and ascorbic acid-deficient guinea pigs

Repeated injections (s.c.) of methamphetamine (METH) were administered to normal and ascorbic acid-deficient (scorbutic) guinea pigs to assess a potential role for ascorbic acid in the METH-induced effects in central monoaminergic systems. The ascorbic acid-deficient condition differentially influenced the METH-induced responses of dopaminergic and serotonergic variables in the striatum: drug-induced changes in dopaminergic variables were identical in normal and scorbutic animals; METH-induced decreases in serotonergic variables [tryptophan hydroxylase activity, serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations], however, were prevented in scorbutic animals. The scorbutic condition did not alter significantly the distribution of METH in the brain, nor were striatal concentrations of dopamine (DA) or 5-HT affected. In vitro, ascorbic acid increased significantly DA-mediated [3H]5-HT release from striatal slices, thus suggesting a potential role for ascorbate in DA-mediated actions of METH on serotonergic systems. Although supplemental ascorbate failed to restore the METH-induced serotonergic effects in scorbutic guinea pigs, these data suggest that, in a normal animal, the effects of multiple injections of METH, on serotonergic systems, involve ascorbic acid.     

Electrophysiological effects of cocaine on central monoaminergic neurons

The electrical activity of three different single, identified, spontaneously firing central neurons was monitored by extracellular microelectrodes. Intravenous cocaine administration (0.25-2 mg/kg) elicited an activation of cerebellar Purkinje neurons (PN) and an inhibition of serotonergic dorsal raphe (DRN) and noradrenergic locus coeruleus (LC) neurons. These effects were not temporally correlated with the increase in mean arterial pressure elicited by the intravenous administration of cocaine. In addition, the administration of procaine, a structurally related local anesthetic, did not significantly affect any of the three central neurons studied. Our results suggest that cocaine has potent effects on the activity of DRN, LC and PN neurons, which are not directly related to its cardiovascular or local anesthetic actions.     

Acute effects of 6-hydroxydopa on central monoaminergic neurons

The effect of 6-hydroxydopa (6-OHDOPA) on mouse whole brain monoamines was studied. It was shown that i.v. administration of a 100 mg/kg dose of 6-OHDOPA reduced whole brain norepinephrine (NE) by 35% after 24 hr, while dopamine (DA) levels were unchanged. With a 150 mg/kg dose whole brain NE levels were reduced by 70% after 3 hr and 55% after 24 hr; whole brain DA content was reduced by 15–20% at both time periods. The effects of 6-OHDOPA (150 mg/kg, i.v.) on NE depletion in the brain could be prevented by d- and l-amphetamine, desipramine and chlorpromazine. MK-486, a peripherally acting dopa decarboxylase inhibitor, potentiated NE depletion by 6-OHDOPA in the brain. While 6-OHDOPA had no effect on monoamine oxidase and choline acetylase activity in the ‘cortex’, brainstem and cerebellum, catechol-O-methyl transferase activity was reduced in the brainstem after 14 days and acetylcholinesterase activity was reduced in the ‘cortex’ after 2 and 14 days. It is concluded that moderate doses of 6-OHDOPA have a marked effect on central noradrenergic neurons, while dopaminergic neurons remain intact.     

Kv7(KCNQ)钾离子通道对中枢单胺能神经传递的调控

KCNQ基因编码5种Kv7钾离子通道亚型(Kv7.1-Kv7.5),其中4种(Kv7.2-Kv7.5)表达于中枢神经系统内。神经元Kv7通道参与突触前后神经递质的调节,激活Kv7通道能够降低神经元兴奋性,减少单胺类神经递质释放,Kv7通道开放剂为单胺类神经元过度兴奋所致疾病(如精神分裂、焦虑、药物滥用等)提供了新的治疗方案,该文将针对Kv7通道在单胺类神经系统内的表达、功能及Kv7通道开放剂在治疗神经元过度兴奋所致疾病中的作用进行总结。     

Changes in central monoaminergic function during chronic treatment with clonidine in the spontaneously hypertensive rat

Clonidine was administered intravenously via osmotic minipumps at doses of 0.1 and 0.5 mg · kg^?1 · 24 h^?1. Both doses lowered blood pressure to the same degree by the third day of treatment. Only the higher dose significantly lowered heart rate. There was no tolerance to these cardiovascular effects which were maintained up to the seventh day of clonidine infusion. The only clonidine-induced change in central monoaminergic function was an increase in the adrenaline levels in the hindbrain. No other changes in central monoaminergic function in either cortex or hindbrain were detected at the level of the enzymes (tyrosine hydroxylase) of the neurotransmitters (noradrenaline, dopamine) or of the adrenoceptors ([³H]clonidine binding). Our results suggest that clonidine lowers blood pressure via inhibition of release of hindbrain adrenaline.     

Role of monoaminergic systems in morphine-induced respiratory depression

The respiratory response to morphine sulfate was assessed in rats pretreated with different modifiers of noradrenergic and serotonergic activity and, additionally, the respiratory depression was related to the brain levels of the two amines, serotonin (5-HT) and norepinephrine (NE). At respiratory depressant doses, morphine induced an increase in 5-HT and a decrease in NE levels in the medullapons area. The time sequence of respiratory depression correlated with a decline in NE and a rise in 5-HT levels. Pretreatments which increased 5-HT levels potentiated the respiratory depression and agents which increased NE levels antagonized the depression. A system of antagonistic modulation by the two amines of morphine-induced respiratory depression is proposed, whereby 5-HT functions as a depressant mediator and NE as an excitatory mediator. Naloxone appears to reverse the respiratory depression by altering the serotonergic component of the action of morphine.     

Influences of chronic stress on central nervous systems]

Chronic mild or moderate stress elicits an adaptive change in central nervous systems that function to maintain homeostasis. The principal components of stress response are the extrahypothalamic corticotropin-releasing hormone (CRH) and the locus coeruleus (LC)-norepinephrine (NE) systems. CRH is known to produce various stress-, anxiety- and arousal-associated behaviors in animals. Moreover, CRH causes an increase in the firing rate and activity of tyrosine hydroxylase in the LC, and NE release in LC projection areas. It is thought that chronic inescapable and unpredictable stress can result in a sustained dysregulation of both CRH neuronal activity and LC-NE systems. One may hypothesize that the NE-CRH interaction occurs in the terminal projection of forebrain NE systems, the hypothalamic paraventricular nucleus (PVN), the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) where NE stimulates CRH release. Such CRH-NE-CRH feed-forward systems elicit progressive augmentation of stress responsivity with repeated exposure. The beta-adrenergic receptor down-regulation is induced by acute and chronic exposure to moderate and predictable stress, implying an adaptation to stress. However, chronic unpredictable (variable) stress (CVS), a model for depression, up-regulated the beta-AR. In our laboratory, we found that concurrent treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram caused beta-R down-regulation in the frontal cortex of rats treated with CVS for 14 days. As previously reported by the authors, an increase in 5-HT availability plays a role in preserving beta-R down-regulation by NE potentiating agents. In depressed patients, hyperactivation of the CRH-NE systems caused by the CRH-NE feed-forward system is thought to be involved in generating anxiety, sympathetic activation and hyperarousal. Moreover, a decrease in the 5-HT turnover in depressed patients has been reported. Accordingly, it is proposed that an increase in 5-HT availability by SSRI might contribute to normalize beta-R down-regulation as an adaptive regulatory mechanism against excessive CRH-NE neurotransmission under a "stressful" situation.     

Role of monoaminergic neurotransmitter systems in MDP-induced adjuvant effect.

The changes in delayed hypersensitivity in guinea pigs stimulated by muramyl dipeptide (MDP) after administration of agonists or antagonists of neurotransmitter systems were studied. Muramyl dipeptide was given in Freund's incomplete adjuvant three weeks before administration of drugs and antigen. Pretreatment with methiotepine, haloperidol and clonidine increased, while lisuride, apomorphine and yohimbine decreased the reaction of delayed hypersensitivity. These results suggest that serotonergic, dopaminergic as well as presynaptic alpha-receptors might have an inhibitory effect on cell-mediated immunity.     

Molecular mechanisms for the development and aging of the primate central nervous system]

The central nervous system (CNS) of primates, including humans, is more complex than the CNS of other mammals. In particular, the cerebral cortex expands during evolution and this has resulted in the emergence of higher cognitive abilities in primates. Recent neurochemical and neuroanatomical methods have clarified the presence of various neuroactive substances including neuropeptides, neurotrophic factors and growth associated proteins in the developing mammalian cerebral cortex. Among these signal molecules, we have focused on somatostatin (SRIF), neurotrophins (BDNF, NT-4/5 and NT-3) and their receptors (Trk), growth associated proteins such as GAP-43 and SCG-10 during the development and aging of primate CNS. We found that although full-length TrkB, a high affinity receptor for BDNF and NT4/5, was detected from the embryonic stage to adulthood, the level of truncated TrkB which lacks tyrosine kinase domain, only increased after birth. This development of truncated TrkB correlated well with down-regulation in the gene expression of GAP-43 and SCG-10. The reductions of GAP-43 and SCG-10 may result in the elimination of callosal axons in the monkey cerebral cortex after birth. The highest levels of BDNF protein in the various cerebral cortices occurred between postnatal 1 and 6 when the number of synapses is highest. In contrast, there was no transient increase in the levels of NT4/5 or NT3 after birth. These findings suggest that BDNF is one of the candidates for the synaptic development of the primate cerebral cortex. During aging processes, we observed decreases in the levels of SRIF and BDNF mRNAs in the cerebral cortex. Since BDNF is an upstream gene expression molecule of SRIF, the decline of SRIF mRNA during aging may be due to the decrease in the gene expression of BDNF. Similar reductions of gene expressions of SRIF and BDNF in the brains of the patients with Alzheimer's disease, suggest that aged monkeys are good model animals for these neuro-degenerative diseases.     

Spinal beta-endorphin analgesia involves an interaction with local monoaminergic systems

beta-Endorphin administered intrathecally (i.t.) in rats produced a dose-dependent elevation in tail-flick latency. Naltrexone administered i.t. as a pretreatment reversed the spinal antinociceptive action of beta-endorphin, suggesting that the opioid interacts directly with spinal opiate receptors. Spinal administration of the alpha 1-adrenoceptor antagonist WB-4101 failed to alter the analgesic effects of the opioid, whereas the alpha 2-adrenoceptor antagonist yohimbine completely blocked beta-endorphin-induced elevations in tail-flick latency. Thus, there is an apparent specificity for the alpha 2-adrenoceptor to mediate the spinal action of beta-endorphin. The 5-HT1 and 5-HT3 receptor antagonists (spiroxatrine and ICS 205-930, respectively) also reversed the analgesic effects of the opioid, while the 5-HT2 receptor antagonist ritanserin only partially blocked beta-endorphin-induced elevations in tail-flick latency. The present results suggest that beta-endorphin produces analgesia at the spinal level via an opiate receptor-mediated interaction with spinal monoaminergic nerve terminals.     

Effects of the antidepressant compound nefazodone on central monoaminergic neuronal discharge in rats

The effects of i.v. administration of the antidepressant compound nefazodone were assessed on the firing rates of spontaneously active noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the dorsal raphe (DR), and dopaminergic neurons in the substantia nigra (SN) of chloral hydrate anesthetized male albino adult rats, utilizing extracellular single-unit recording methods. Nefazodone, tested in doses of 0.1–10.0 mg/kg, had variable effects on LC neurons, but the predominant effect was a mild excitation of firing (ED₂₅ = 1.953 mg/kg). This may in part be caused by the 5-HT₂ antagonist properties of the compound, since ritanserin also produced a mild excitation of LC neurons. By comparison, desipramine very reliably inhibited LC neurons (ED₅₀ = 0.333 mg/kg, i.v.). For DR neurons, i.v. nefazodone (0.1–3.2 mg/kg) produced variable effects, with inhibition being the most common (63% of cases tested). The ED₂₅ for inhibition was 1.230 mg/kg, and in no case was inhibition of 50% or greater observed. By comparison, clomipramine very reliably inhibited DR neurons (ED₅₀ = 0.501 mg/kg, i.v.). For SN neurons, the effects of i.v. nefazodone were also variable, with no consistent effects observed. These results indicate that acute nefazodone produces relatively weak effects on monoaminergic neuronal impulse flow in anesthetized rats, and suggest that major modifications of monoaminergic neuronal impulse flow probably do not play an important role in any neuroadaptive changes that may contribute to the clinical antidepressant actions of nefazodone.     

Alterations in central monoaminergic neurotransmission induced by polycyclic aromatic hydrocarbons in rats.

Benzo[alpha]pyrene (B[a]P) is a product derived from incomplete combustion of organic material and is considered responsible for chemically-induced cancer in humans. In the present study, the levels of noradrenaline (NA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the brains of female Wistar rats 6, 12, 24 and 96 h after a single dose of B[alpha]P (50 mg kg(-1) b.w., i.p.), and also after repeated administration of B[alpha]P (50 mg kg(-1) b.w., i.p., 2 x wk, 1 mo). The brain regions studied were the striatum, hypothalamus, midbrain and cortex. Catecholamines were measured using high performance liquid chromatography (HPLC) and electrochemical detection. Significant changes were observed in the striatum where NA, DA, DOPAC were decreased after 24 h and HVA was decreased after 6 h. In contrast, no major alterations occurred in 5-HT and 5- HIAA. In the hypothalamus, a significant decrease in NA was observed after 96 h. In the midbrain, the most important change observed was the decrease in NA after 24 h. A trend toward an increase in 5-HIAA was observed in the cortex after 6 h. The results demonstrate that B[alpha]P induces alterations in the dopaminergic and serotoninergic systems throughout the brain. These alterations may lead to behavioural and hormonal disturbances.