Search

Parkinson's disease (PD) is a movement disorder, and its common characteristics include the loss of dopaminergic neurons and the accumulation of a special type of cytoplasmic inclusions called Lewy bodies in the substantia nigra pars compacta, which are more prevalent in the elderly. However, the pathophysiology of PD is still elusive. In this review, we summarized five common factors involved in PD, namely, (i) oxidative stress, (ii) mitochondrial dysfunction, (iii) inflammation, (iv) abnormal α-synuclein, and (v) endogenous neurotoxins, and proposed a hypothesis involving a damaging cycle. Oxidative stress-triggered aldehydes react with biogenic amines to produce endogenous neurotoxins. They cause mitochondrial dysfunction and the formation of inflammasomes, which induce the activation of neuroglial cells and the infiltration of T lymphocytes. The synergistic effect of these processes fosters chronic inflammation and α-synuclein aggregation and further exacerbates the impact of oxidative stress to establish a damaging cycle that eventually results in the degeneration of dopaminergic neurons. This damaging cycle provides an explanation of progressive neuronal death during the pathogenesis of PD and provides new potential targets beneficial for developing new drugs and approaches for clinical neuroprotection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Huntington's disease (HD) is a rare, autosomal neurodegenerative disease characterized by motor and cognitive impairments appearing in adults. The R6/1 mouse model of the disease recapitulates the adult onset of motor symptoms preceded by cognitive and affective deficits. The monoaminergic systems participate in the establishment of motor and cognitive loops and we postulated that their organization and interaction could be precociously altered. Using tissue measurement of dopamine (DA), serotonin (5-HT), noradrenaline, and some metabolites, we observed that DA and/or its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-HT or noradrenaline tissue content was reduced in an age-dependent manner (from two to six months) in the striatum, substantia nigra and globus pallidus of R6/1 mice. The metabolite of 5-HT was also lower in R6/1 mice, mainly in the substantia nigra and hippocampus. We then addressed early disorganization of monoaminergic systems in 18 brain regions encompassing several neurobiological networks in 35 day-old animals. DA tissue content was not altered in the striatum or substantia nigra but was decreased in the nucleus accumbens and increased in the globus pallidus. The correlations of monoaminergic index in-between the 18 selected brain regions revealed distinct organizations of monoamines in R6/1 mice, notably marked by a loss of the number of correlations of the DOPAC/DA ratio. The neurochemical analyses show that each monoaminergic system is distinctly altered in the R6/1 mouse model. The early abnormal organization of these systems likely points out altered maturation of neurobiological networks at early stages of HD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Methylphenidate-based designer drugs are new psychoactive substances (NPS) that are used outside medical settings and their pharmacology is largely unexplored. The aim of the present study was to characterize the pharmacology of methylphenidate-based substances in vitro., Methods: We determined the potencies of the methylphenidate-based NPS N-benzylethylphenidate, 3,4-dichloroethylphenidate, 3,4-dichloromethylphenidate, ethylnaphthidate, ethylphenidate, 4-fluoromethylphenidate, isopropylphenidate, 4-methylmethylphenidate, methylmorphenate, and propylphenidate and the potencies of the related compounds cocaine and modafinil with respect to norepinephrine, dopamine, and serotonin transporter inhibition in transporter-transfected human embryonic kidney 293 cells. We also investigated monoamine efflux and monoamine receptor and transporter binding affinities. Furthermore, we assessed the cell integrity under assay conditions., Results: All methylphenidate-based substances inhibited the norepinephrine and dopamine transporters 4 to >1000-fold more potently than the serotonin transporter. Similar to methylphenidate and cocaine, methylphenidate-based NPS did not elicit transporter-mediated efflux of monoamines. Besides binding to monoamine transporters, several test drugs had affinity for adrenergic, serotonergic, and rat trace amine-associated receptors but not for dopaminergic or mouse trace amine-associated receptors. No cytotoxicity was observed after drug treatment at assay concentrations., Conclusion: Methylphenidate-based substances had pharmacological profiles similar to methylphenidate and cocaine. The predominant actions on dopamine transporters vs. serotonin transporters may be relevant when considering abuse liability. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.', (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: 4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs., Methods: We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT 2A ) and 5-HT 2B receptors, activation of human trace amine-associated receptor 1 (TAAR 1 ), and inhibition of monoamine uptake transporters., Results: 2C-T drugs had high affinity for 5-HT 2A and 5-HT 2C receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1-53 nM and 44-370 nM, the drugs were potent 5-HT 2A receptor and 5-HT 2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT 2B receptor (EC 50  > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT 1A and adrenergic receptors. The compounds had high affinity for the rat TAAR 1 (5-68 nM) and interacted with the mouse but not human TAAR 1 . The 2C-T drugs did not potently interact with monoamine transporters (K i  > 4000 nM)., Conclusion: The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT 2 receptor interactions. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.', (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The symptoms of Parkinson's disease (PD) include motor behavioral abnormalities, which appear as a result of the extensive loss of the striatal biogenic amine, dopamine. Various endogenous molecules, including cholesterol, have been put forward as putative contributors in the pathogenesis of PD. Earlier reports have provided a strong link between the elevated level of plasma cholesterol (hypercholesterolemia) and onset of PD. However, the role of hypercholesterolemia on brain functions in terms of neurotransmitter metabolism and associated behavioral manifestations remain elusive. We tested in Swiss albino mice whether hypercholesterolemia induced by high-cholesterol diet would affect dopamine and serotonin metabolism in discrete brain regions that would precipitate in psychomotor behavioral manifestations. High-cholesterol diet for 12 weeks caused a significant increase in blood total cholesterol level, which validated the model as hypercholesterolemic. Tests for akinesia, catalepsy, swimming ability and gait pattern (increased stride length) have revealed that hypercholesterolemic mice develop motor behavioral abnormalities, which are similar to the behavioral phenotypes of PD. Moreover, hypercholesterolemia caused depressive-like behavior in mice, as indicated by the increased immobility time in the forced swim test. We found a significant depletion of dopamine in striatum and serotonin in cortex of hypercholesterolemic mice. The significant decrease in tyrosine hydroxylase immunoreactivity in striatum supports the observed depleted level dopamine in striatum, which is relevant to the pathophysiology of PD. In conclusion, hypercholesterolemia-induced depleted levels of cortical and striatal biogenic amines reported hereby are similar to the PD pathology, which might be associated with the observed psychomotor behavioral abnormalities., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The primary mechanism by which amphetamine exerts its neurobehavioral effects is through an enhancement of synaptic monoamine levels, which is mediated by interactions with monoamine transporters, storage, and metabolism. However, preclinical data are now emerging that support more widespread neurobiologic effects for amphetamine. This review describes preclinical evidence suggesting that direct interactions of amphetamine with monoamine systems, which results in increased synaptic monoamine availability, has downstream effects on nonmonoaminergic systems, including glutamate, endogenous opioid, endocannabinoid, and acetylcholine systems. Furthermore, evidence suggests that amphetamine can modulate synaptic plasticity through modulation of glutamatergic systems, intracellular signaling cascades, and neurotrophic factor activity. Functional activity of these systems is implicated in the regulation of neurobehavioral processes that include cognition, mood, motivated behavior/hedonic processes/addiction, and arousal. As such, the ability of amphetamine to influence the function of systems that mediate these processes suggests amphetamine-based agents may have utility in the treatment of psychiatric disorders in which these systems and processes are dysfunctional. Amphetamine-based agents are currently approved by the US Food and Drug Administration only for the treatment of attention-deficit/hyperactivity disorder and narcolepsy. Preclinical and clinical research for amphetamine-based pharmacotherapy for other psychiatric disease states is examined. This should encourage further research on the preclinical pharmacology of amphetamine and its implications for the treatment of neuropsychiatric disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We have characterized the changes in tissue concentrations of amino acids and biogenic amines in the central nervous system (CNS) of mice with MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE), an animal model commonly used to study multiple sclerosis (MS). High performance liquid chromatography was used to analyse tissue samples from five regions of the CNS at the onset, peak and chronic phase of MOG(35-55) EAE. Our analysis includes the evaluation of several newly examined amino acids including d-serine, and the inter-relations between the intraspinal concentration changes of different amino acids and biogenic amines during EAE. Our results confirm many of the findings from similar studies using different variants of the EAE model as well as those examining changes in amino acid and biogenic amine levels in the cerebrospinal fluid (CSF) of MS patients. However, several notable differences were observed between mice with MOG(35-55)-induced EAE with findings from human studies and other EAE models. In addition, our analysis has identified strong correlations between different amino acids and biogenic amines that appear to change in two distinct groups during EAE. Group I analyte concentrations are increased at EAE onset and peak but then decrease in the chronic phase with a large degree of variability. Group II is composed of amino acids and biogenic amines that change in a progressive manner during EAE. The altered levels of these amino acids and biogenic amines in the disease may represent a critical pathway leading to neurodegenerative processes that are now recognized to occur in EAE and MS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Sojourners to high altitude experience poor-quality of sleep due to hypobaric hypoxia (HH). Brain neurotransmitters are the key regulators of sleep wakefulness. Scientific literature has limited information on the role of brain neurotransmitters involved in sleep disturbance in HH. The present study aimed to investigate the time dependent changes in neurotransmitter levels and enzymes involved in the biosynthesis of brain neurotransmitters in frontal cortex, brain stem, cerebellum, pons and medulla and the effect of these alterations on sleep architecture in HH. Thirty adult Sprague-Dawley rats, body weight of 230-250 g were exposed to simulated altitude ∼7620 m, 282 mm Hg, partial pressure of O(2) 59 mm Hg for 7 and 14 days continuously in an animal decompression chamber. After 7 and 14 days of HH, brain nor-epinephrine and dopamine levels were significantly increased in frontal cortex, brain stem, cerebellum and pons and medulla whereas serotonin level was significantly reduced in frontal cortex and pons and medulla after 14 days of HH. Tyrosine hydroxylase level in locus coeruleus (LC) was significantly increased whereas Choline Acetyl Transferase and Glutamic Acid Decarboxylase (GAD) levels were significantly reduced in laterodorsal-tegmentum and pedunculopontine-tegmentum after 7 days of HH. GAD was also reduced in LC after 7 days HH. Alteration in these neurotransmitters and enzyme levels was accompanied with reduction in quality and quantity of sleep. There was a significant increase in sleep latency, rapid eye movement (REM) latency, duration of active awake, quiet awake, quiet sleep and a significant decrease in duration of REM sleep and deep sleep on day 7 and 14 of HH. It was concluded that HH alters the expression of enzymes linked to sleep neurotransmitter synthesis pathway and subsequent loss of homeostasis at neurotransmitter level disrupts the sleep pattern in hypobaric hypoxia., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Behavioral and neurochemical effects of chronic administration of high doses of 2-phenylethylamine (PEA; 25-75 mg/kg, i.p. for up to 7 days) have been investigated in Balb/c mice. Depression and anxiety, as demonstrated respectively by increased floating time in forced swim test, and reduction in number of entries and the time spent in the open arms in an elevated plus maze were observed in these animals. General motor disabilities in terms of akinesia, catalepsy and decreased swimming ability were also observed in these animals. Acute and sub-acute administration of PEA caused significant, dose-dependent depletion of striatal dopamine, and its metabolites levels. PEA caused dose-dependent generation of hydroxyl radicals in vitro in Fenton's reaction in test tubes, in isolated mitochondrial fraction, and in vivo in the striatum of mice. A significant inhibition of NADH-ubiquinone oxidoreductase (complex-I; EC: 1.6.5.3) activity suggests the inhibition in oxidative phosphorylation in the mitochondria resulting in hydroxyl radical generation. Nissl staining and TH immnunohistochemistry in brain sections failed to show any morphological aberrations in dopaminergic neurons or nerve terminals. Long-term over-consumption of PEA containing food items could be a neurological risk factor having significant pathological relevance to disease conditions such as depression or motor dysfunction. However, per-oral administration of higher doses of PEA (75-125 mg/kg; 7 days) failed to cause such overt neurochemical effects in rats, which suggested safe consumption of food items rich in this trace amine by normal population., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The review describes the initial experiments suggesting a fast intra-axonal transport of transmitter related substances, in addition to the "classic" slow flow. Early experiments were mainly conducted in the peripheral adrenergic system, focusing on transport of amine storage granules, the extent of the vast sympathetic adrenergic system and the importance of axonal transport of amine granules for the adrenergic system. Further, it describes important advances obtained from studies of other neuron systems regarding local axonal protein synthesis, motor proteins and new insights regarding relation between faults in the transport machinery and some neuropathological conditions., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the "trace amines" (TA) beta-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of 2 publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers Borowsky et al. as TA1 and Bunzow et al. as TA receptor 1 (TAR1). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines, recombinant rodent and human TAR dose-dependently couple to the stimulation of adenosine 3',5'-monophosphate (cAMP) production. Structure-activity profiling based on this functional response has revealed that in addition to the TA, other biologically active compounds containing a 2-carbon aliphatic side chain linking an amino group to at least 1 benzene ring are potent and efficacious TA receptor agonists with amphetamine (AMPH), methamphetamine, 3-iodothyronamine, thyronamine, and dopamine (DA) among the most notable. Almost 100 years after the search for TAR began, numerous TA1/TAR1-related sequences, now called TA-associated receptors (TAAR), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TAR, a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCR. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

Mice prenatally exposed to cocaine (25 mg/kg), physiological saline or non-treated during the last 6 days of pregnancy were evaluated as adults for the rewarding properties of 2 mg/kg of morphine, using the conditioned place preference (CPP) procedure. Likewise, isolated animals underwent a social interaction test with conspecifics after receiving the same morphine dose. Unlike control or animals pre-treated with saline, subjects prenatally treated with cocaine did not develop CPP with this dose of morphine. Only cocaine-exposed animals showed increased threat, avoidance and fleeing during the social encounter. No differences in motor effects of morphine were observed. Analysis of monoamines revealed effects of housing conditions, isolated animals having fewer DOPAC but higher levels of HVA than those grouped, but in both groups there was a decrease in DOPAC in cocaine- and saline-treated mice. Prenatal cocaine exposure decreases the response to the rewarding properties of drugs in mature offspring. They also implicate cocaine consumption during pregnancy could affect the response of offspring to take other drugs of abuse.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

The abuse of cocaine in pregnant women could affect emotional behaviors in their descendents. The aim of this work was to evaluate the effects of prenatal cocaine exposure on spontaneous and cocaine-induced motor and social behaviors in mice. Three kinds of prenatal treatment were used: non-treated animals; mice treated daily with physiological saline during the last week of pregnancy; and finally, those treated with cocaine (25 mg/kg) during the same period. Behavioral studies took place on adult males, which were housed in two different conditions: grouped (non-aggressive), or isolated (aggressive). Cocaine-pretreated animals exhibited slight differences in spontaneous motor activity, but alterations in their social relationship with conspecifics were presented, with decreases in isolated but increases in grouped mice. The cocaine challenge increased aggression specifically in grouped prenatally cocaine-treated mice, but increases in motor activity or avoidance and flee behavior were presented in those animals pretreated with either saline or cocaine. Isolated saline-or cocaine-treated animals exhibited greater concentrations of DA and DOPAC than those grouped. A decrease in 5-HIAA concentrations was presented in pretreated animals, irrespective of their housing conditions. In conclusion, cocaine administration during pregnancy induces long lasting effects on the offspring, for both behavioral abnormalities and cocaine response, which last to adult life.

A biological odor treatment system has several advantages compared to conventional physical and chemical treatment technologies: (1) it is highly efficient in the treatment of waste gases characterized by high flow rates and low concentrations of contaminants; (2) the biodegradable pollutants are completely destroyed; and (3) it has low cost [Devinny, J.S., Deshusses, M.A., Webster, T.S., 1999. Biofiltration for Air Pollution Control. Lewis Publisher, New York, USA; Kennes, C., Veiga, M.C., 2001. Bioreactors for waste gas treatment. Kluwer Academic Publishers, London]. Because microorganisms play the major role in the successful biological odor treatment system, the understanding of microbial degradation of the key odorants is very important. This article describes the occurrence and the characteristics of selected key odorous compounds such as sulphides, amines, and pyrazine compounds. The article reviews available information in the literature and our experimental results of microbial degradation of the selected compounds. This is the first article that presents the isolation and characterization of bacterial strains that can utilize dimethyl trisulfide (DMTS), triethylamine (TEA) or different pyrazines, as a sole carbon and energy source. The biological degradation pathways of some of these compounds are postulated. Moreover, the influence of the presence of other odorous compounds in the culture medium on the degradation of the target odorous compounds by the isolated bacteria is presented. The information presented in the paper can be used to develop new systems for biological odor treatment.

Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses. However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors. Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1). Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1). Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.

The term neuropeptides commonly refers to a relatively large number of biologically active molecules that have been localized to discrete cell populations of central and peripheral neurons. I review here the most important histological and functional findings on neuropeptide distribution in the central nervous system (CNS), in relation to their role in the exchange of information between the nerve cells. Under this perspective, peptide costorage (presence of two or more peptides within the same subcellular compartment) and coexistence (concurrent presence of peptides and other messenger molecules within single nerve cells) are discussed in detail. In particular, the subcellular site(s) of storage and sorting mechanisms within neurons are thoroughly examined in the view of the mode of release and action of neuropeptides as neuronal messengers. Moreover, the relationship of neuropeptides and other molecules implicated in neural transmission is discussed in functional terms, also referring to the interactions with novel unconventional transmitters and trophic factors. Finally, a brief account is given on the presence of neuropeptides in glial cells.

Testfilter experiments are reported for river Elbe water spiked with aromatic amines in order to determine biodegradation rates. For river Elbe water the mean degradation rate of DOC (C0 = 6.64 mg l-1) was 26.7 +/- 8.8% after 6.8 days. No significant effect on the DOC degradation rate was observed with the addition of aromatic amines. Large differences in the biodegradation behaviour of the aromatic amines were observed: aniline was eliminated within 3 h, whereas the degradation of 2-nitroaniline was only 40% after 14 h effective contact time. Degradation curves were mostly of a simple logarithmic type, demonstrating first-order kinetics. The degradation rate of 2,4,6-trichloraniline increased by a factor of 20 within 6 weeks due to the adaptation of the testfilter biofilm. A linear relationship between available pKa-values and the logarithm of the experimental degradation rates was found. Thus, the results of the testfilter experiments may be extended to the estimation of the biodegradability of non-tested aromatic amines.

Bufo melanostictus (common Indian toad) acquire different bioactive substances in their skin during their life-time in wide ecological habitat. Earlier investigation from this laboratory revealed that toad (B. melanostictus) skin extract (TSE) posses different bioactive compounds of different diversity (Das, M., Auddy, B. and Gomes, A., 1996. Pharmacological study of the toad skin extract on experimental animals. Indian J. Pharmacol. 28, 72-76). Among these sleep induction and sleep potentiation indicated the possibility of sleep inducing factor(s) in TSE. One such sleep inducing factor (SIF) was isolated and purified by neutral alumina column chromatography followed by HPLC. Spectroscopy (UV, IR, FAB-MASS) study indicated that the sleep inducing factor was a 880 Dalton conjugated aromatic compound with a hydroxyl and carbonyl functional group. Biological study showed that SIF produced no lethality in male albino mice upto the dose of 8 mg/kg, i.v. Cyproheptadine antagonised SIF induced contraction of isolated smooth muscle indicating histamine/serotonin receptor mediated action of SIF. EEG studies showed that SIF increased sleep and decreased awakening condition of freely moving rats. Biochemical studies showed that SIF produced significant alteration of brain biogenic amine levels, monoamine oxidase (MAO) and tryptophan hydroxylase (TH) activity. This may be the reason of SIF induced sleep, although the SIF induced sleep mechanism needs further detail investigation.

This study compared the pharmacological activity of venom from male and female white-tailed spiders (L. cylindrata). In guinea-pig ileum, male L. cylindrata venom (1-10 microg/ml) caused dose-dependent contractions. The response to venom (5 microg/ml) was significantly inhibited by mepyramine (0.5 microM). Venom (5-50 microg/ml) from female L. cylindrata had no contractile activity in this tissue. However, female L. cylindrata venom (50 microg/ml) inhibited electrically-evoked twitches of guinea-pig ileum. This inhibitory effect was attenuated by 8-phenyltheophylline (10 microM) or by prior exposure of venom to adenosine deaminase. In the rat vas deferens, male (5 microg/ml) and female (50 microg/ml) L. cylindrata venom inhibited electrically-evoked twitches. 8-Phenyltheophylline (20 microM) significantly attenuated the response to female L. cylindrata venom, while the histamine H(2)- and H(3)-receptor antagonists ranitidine (10 microM) and thioperamide (0.2 microM) significantly attenuated the response to male L. cylindrata venom. Male L. cylindrata venom (5-20 microg/ml) caused dose-dependent contractions in the epididymal segment of the rat vas deferens. The response to male L. cylindrata venom (10 microg/ml) was significantly inhibited by prazosin (0.3 microM) but was unaffected by depleting monoamine stores with reserpine. Male L. cylindrata venom (5-15 microg/ml) caused dose-dependent increases in rate and force of rat atria which were significantly inhibited by propranolol (5 microM) but not by reserpine. Female L. cylindrata venom (50 microg/ml) had no effect in atria. In the anaesthetised (pentobarbitone, 100 mg/kg, i.p.) rat, male L. cylindrata venom (10-300 microg/kg, i.v.) caused dose-dependent depressor responses while venom (up to 1 mg/kg, i.v.) from female L. cylindrata had no effect on arterial pressure. A histamine content of 5 and 0.01% (dry weight) was detected in venom from male and female L. cylindrata, respectively. Venom from male L. cylindrata was found to contain 56 pg noradrenaline/microg whereas venom from the female contained negligible noradrenaline. The results of this study show the presence of histamine and noradrenaline in venom from male L. cylindrata. Although devoid of significant quantities of these amines, female L. cylindrata venom has activity at adenosine receptors.

The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.2, 13.7 and 34.8 respectively. PD 158771 showed high affinity for cloned human 5-HT(1A) (K(i) = 2.6 nM) and rat hippocampal 5-HT(1A) receptors (K(i) = 3.5 nM). Weaker affinities were observed at alpha 1-adrenergic (K(i) = 43 nM), histamine H(1) (IC(50) = 30 nM), 5-HT(2A) (K(i) = 24.5 nM) and sigma (sigma) -1 binding sites (K(i) = 24.5 nM). In measures of in vitro functional activity, PD 158771 stimulated [(3)H]thymidine uptake in CHO p-5 cells transfected with hD(3) receptors with a maximal effect of 23% relative to quinpirole. In hD(2)L, the corresponding value was 60% with an EC(50) of 29 nM, again indicating partial DA agonist action of PD 158771. In vivo, PD 158771 produced a dose-related decrease in DA synthesis in the striatum and mesolimbic regions of rat brain treated with gamma-butyrolactone (GBL), indicating a DA autoreceptor agonist action. In animals not treated with GBL, PD 158771 produced a dose-related decrease in DA synthesis and extracellular DA. A decrease in 5-HT synthesis in several brain areas was observed consistent with an agonist response. Further support for DA autoreceptor agonist action is that PD 158771 produced a partial inhibition of the firing of substantia nigra zona compacta DA neurons, an effect reversed by haloperidol. In conclusion, PD 158771 exhibited affinities for DA and 5-HT receptors, appears to possess DA and 5-HT agonist actions; and it could provide improved antipsychotic profile with minimal side effects.

In an attempt to elucidate the contribution of the extent of nitrogen protonation on the in vivo binding of methamphetamine in the brain, the enantiomers of [N-methyl-11C]beta, beta-difluoroamphetamine (4) were prepared for use in positron emission tomography (PET) studies. Thus, the enantiomers of beta, beta-difluoroamphetamine were prepared from trans-beta-methylstyrene, via bromination, conversion into the azirine, fluorination and resolution as the tartrate salts. (R)- and (S)-beta, beta-difluoroamphetamine (3) were then each labelled with carbon-11 (tt/2 = 20.4 min) by N-methylation of the corresponding homochiral beta, beta-difluoroamphetamine with [11C]methyl iodide. The labelled products were each synthesised, purified and formulated in 35 min, starting from [11C]carbon dioxide in 15-16% decay-corrected radiochemical yield, with a radiochemical purity of > 99% and specific radioactivity of 50-150 GBq mumol-1 at end of synthesis.

1. The levels of the main norepinephrine, serotonin, and dopamine metabolite excretion in the urine, MHPG, 5HIAA and HVA respectively, were measured in 84 patients with major depressive disorder, 34 delusional (psychotic) and 50 nondelusional (DSM-III-R criteria). 2. Associations with the 17 items of the HDRS were evaluated using the multiple regression analysis model. In the delusional group, MHPG excretion was positively related to the scores in the items of depressed mood (p = 0.04), middle insomnia (p = 0.008) and genital symptoms (p = 0.001). 5HIAA excretion was negatively associated with late insomnia (p = 0.02), work and interests (p = 0.001) and genital symptoms (p = 0.007). HVA was positively related to agitation (p = 0.043). In the nondelusional group the only association found was between agitation and HVA excretion (p = 0.03).

1. The levels of the urinary main metabolites of norepinephrine 3-methoxy-4-hydroxyphenylglycol (MHPG), of dopamine homovanillic acid (HVA) and of serotonin 5-hydroxyindoleacetic acid (5-HIAA) were measured in 84 patients with major depressive disorder, 34 delusional and 50 nondelusional. Melancholia subtype was also defined (N = 62). 2. MHPG was significantly higher in the delusional depressed group (p = 0.023). Female patients with delusional major depression also had significantly higher HVA excretion than female patients with non delusional major depression (p = 0.036). 5-HIAA excretion was similar in the two patient subgroups. 3. No significant differences in the three monoamine metabolites were found between the melancholic and nonmelancholic depressed patients.

Phencyclidine (PCP), a psychotomimetic drug with anticonvulsant and neuroprotective properties interacts with several central nervous system (CNS) macromolecules. These include cholinergic receptors, potassium channels, biogenic amine reuptake systems, the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor, and sigma binding sites. The good correlation between the affinity of arylcycloalkylamines for high affinity PCP binding sites and their ED50 values for inhibition of [3H]dopamine uptake supports the notion that a PCP binding site associated with the transporter for the biogenic amines should be detectable in ligand binding studies. This article reviews data primarily from the author's laboratory, which shows that the PCP analog, [3H]1-[1-(2-thienyl)cyclohexyl]piperidine, binds to a second site, not associated with the NMDA receptor/ionophore complex, called PCP site 2. The ligand-selectivity of this binding site and the evidence that it is associated with the biogenic amine transporters are reviewed.

The synapse has dominated the conceptual model of neurotransmission; other mechanisms, such as neuromodulation, have been considered to support and complement synaptic transmission. In this commentary, the conceptual framework considers synaptic transmission as one of several mechanisms of neurotransmission. One of these is nonsynaptic diffusion neurotransmission (NDN), which includes both the diffusion of neurotransmitters and other neuroactive substances through the extracellular fluid to reach extrasynaptic receptors, and the diffusion of substances such as nitric oxide through both the extracellular fluid and cellular membranes to act within the cell. The possible roles of NDN in mass, sustained functions such as mood, sleep and brain "tone", as well as in various other functions, such as in long term potentiation, at the retinal, lateral geniculate nucleus and visual cortex levels of the visual system, in recovery from brain damage and in neuropharmacology, are explored.

1. Brofaromine or placebo were administered to female bulimia nervosa patients over a period of eight weeks. Plasma and urinary trace amines, their acidic metabolites and the acidic metabolites of the catecholamines and serotonin were assessed prior to treatment and at four and eight weeks after commencement of treatment. 2. The levels of both plasma and urinary homovanillic and vanilmandelic acids declined significantly during the first four weeks of treatment with brofaromine and then partially recovered to pre-drug levels by the eighth week. 5-Hydroxyindoleacetic acid levels were not affected by drug treatment at the times assessments were made. Urinary tryptamine increased significantly during the first four weeks of brofaromine treatment then partially recovered towards pre-drug levels by the eighth week. No effect from placebo treatment was observed.

1. Central 5-HT is thought to be involved in neuronal inhibition and as such as a modulating influence in restraining the organism from responding to (e.g., especially adverse) stimuli. 2. Evidence for a role of central 5-HT in suicide arises from reduced concentrations of brain 5-HT or 5-HIAA in brain stem, reduced binding of [3-H]-IMI in brain tissue of frontal cortex/hypothalamus, and increased binding of radioligands to 5-HT-2 receptors in the frontal cortex. 3. Evidence for a role of central 5-HT in parasuicide arises from reduced concentrations of lumbar CSF 5-HIAA, reduced PRL responses to d,l-fenfluramine challenge, and increased CORT responses to 5-HTP challenge. 4. Since reduced central 5-HT activity appears to be consistently associated with impulsive aggression, it is possible that suicidal and parasuicidal acts in individuals with evidence of reduced central 5-HT activity are a manifestation of reduced impulse control. 5. Agents which enhance central 5-HT function and/or diminish the activity of neuronal systems involved in arousal (e.g. norepinephrine or dopamine) should be efficacious in reducing parasuicidal behavior.

1. Psychotropic drugs ameliorate psychotic symptoms only after repeated administration. 2. To assess the neurochemical effects of chronic haloperidol and lithium administration, microdialysis was performed simultaneously in the prefrontal cortex, the nucleus accumbens, and the striatum after haloperidol, and separately in the lateral hypothalamus and the hippocampus after lithium. 3. Chronic administration of haloperidol decreased dopamine turnover in the prefrontal cortex and the striatum. It did not affect the nucleus accumbens detectably. 4. No tolerance to haloperidol developed in any of the three regions. 5. Lithium enhanced the response of the serotonergic system to amphetamine in the lateral hypothalamus but not in the hippocampus. 6. The antipsychotic effect of haloperidol might be related to dopamine turnover decrease in the prefrontal cortex. 7. The antidepressant effect of lithium might be related to enhancement of serotonin responsiveness in the hypothalamus.

1. The mechanism of action of trimipramine, a clinically efficacious tricyclic antidepressant, is not well understood. In order to investigate whether it might affect the activities of different enzymes involved in biogenic amine metabolism we have undertaken a comparative study of it along with amitriptyline. 2. Neither trimipramine nor amitriptyline, at concentrations up to 1 mM, exhibited any significant effect on phenylalanine hydroxylase, tyrosine hydroxylase, L-aromatic amino acid decarboxylase, dopamine-beta-hydroxylase, phenylethanolamine-N-methyltransferase, catechol-O-methyltransferase, phenylsulfotransferase or tyrosine aminotransferase. 3. Monoamine oxidase, however, was inhibited by both drugs with the greatest effect being on MAO-B. The inhibition was reversible, non-competitive and relatively weak.

For a long time antidepressants have been considered to act via enhancement of central monoaminergic activity (due to reuptake or MAO inhibition). An alternative hypothesis holds that their action is based on down-regulation of monoaminergic activity (due to decrease in density or sensitivity of certain receptor populations). In this paper the likelihood of both hypotheses is discussed and the conclusion reached that the first one is the most plausible. The following arguments are discussed: (1) the 5-HT precursor 5-HTP, which is transformed to 5-HT in the brain, has antidepressant properties; (2) there are indications that the same holds true for tyrosine, a catecholamine precursor transformed in the brain to DA and NA; and (3) evidence was found that the effects of 5-HTP in depression are potentiated by tyrosine. Since activation rather than suppression of monoaminergic activity seems to be linked to antidepressant activity, it seems likely that the signs of decreased monoamine metabolism that have been demonstrated in certain types of depression are the expression of a primary metabolic deficit rather than a phenomenon secondary to receptor hypersensitivity. Further clinical studies of 5-HT/CA precursor combinations in depression are justified.

In rats, with bilateral lesions of the paraventricular nuclei induced by 6-hydroxydopamine, restraint stress failed to elevate levels of corticosterone in plasma, although the resting levels in lesioned animals were similar to those of control rats. Prazosin inhibited the plasma-corticosterone response to restraint in intact rats, at doses which did not by themselves influence resting hormone levels. These results suggest a positive role for noradrenaline, acting through alpha-adrenoceptors, on the stress-induced output of corticotrophin.

In a low-sodium, choline+ (Ch+) medium, rat heart slices, that were labelled in vivo with [3H]norepinephrine, exhibited a delayed Ca2+-dependent release of radioactivity, these radioactive compounds consisted of both amines and deaminated metabolites. The Ca2+-dependent release of radioactivity was largely blocked by cocaine suggesting that the release may represent an outward transport of [3H]amines. Reserpine, which is known to inhibit binding of norepinephrine to synaptic vesicles, stimulated the release of deaminated metabolites and some amines from the slices. Cocaine increased the release of [3H]amines in monoamine oxidase inhibited, reserpinized slices in the control medium. When Ch+-Ca2+ and reserpine stimulation were combined, the effects of Ch+-Ca2+ predominated. These effects were blocked by cocaine, which then permitted the response to reserpine to become established. The conclusion derived from the above experiments is that norepinephrine coming from synaptic vesicles brought in close proximity to the plasma membrane by a Ca2+-dependent system can be transported outwardly to the extraneuronal space by a cocaine-sensitive mechanism.

The effects of daily treatment with GM-1 ganglioside (30 mg/kg i.p.) or saline (1 ml/kg i.p.) in rats with discrete unilateral electrolytic lesions of the dorsal substantia nigra were investigated. Treatment with GM-1 ganglioside, beginning 3 days prior to surgery and continuing for 33 days post-operatively, caused reductions in the total ipsilateral turns and peak turning rates induced by apomorphine (0.75 mg/kg s.c.) between 7 and 31 days post-operatively, without altering the time course of the effect of apomorphine. No effects of GM-1 on lesion-induced changes in synaptosomal uptake of [3H]dopamine, dopamine, serotonin in the striatum or corresponding levels of metabolites were found. Treatment with GM-1 ganglioside had no effect on the rostrocaudal extent of the electrolytic lesion, but caused morphological changes at the site of the lesion, including a reduction in the density of glial cells. Treatment with GM-1 ganglioside resulted in a relative preservation of cell bodies, staining immunocytochemically for tyrosine hydroxylase, in the substantia nigra pars compacta (expressed as a percentage of the intact side), when compared with saline-treated rats. The results showed that GM-1 ganglioside promoted a partial functional recovery from apomorphine-induced circling, which may be due in part to a reduction in the extent of damage at the lesion site.

The 14C-selective irreversible "suicide" MAO A (clorgyline, Lilly 51641; M & B 9303) and MAO B inhibitors (deprenyl, AGN 1135 and pargyline) bind to the enzyme active site stoichiometrically mol/mol of enzyme. In the case of the acetylenic inhibitors (clorgyline, deprenyl and pargyline) this binding occurs at the N (5) of the FAD isoalloxazine moiety, the enzyme co-factor. Since the inhibitor binding sites of both enzyme forms are identical, it would appear that enzyme inhibitor selectivity must be related to the presence of different recognition sites near their active sites. Studies of structure-MAO inhibitory relationship have shown that the MAO B recognition site is smaller than the enzyme A site. Considering that MAO A for most part is intraneuronal and its substrates noradrenaline (NA) and serotonin (5-HT) have been implicated in the pathogenesis of depressive illness, it would appear that selective A inhibitors would be more effective as antidepressants. Data presented shows that MAO A inhibitors rather that the B inhibitors potentiate pharmacological and behavioural actions mediated by NA and 5-HT. Furthermore, if down-regulation of beta-adrenergic receptors is involved in the mechanism of action of antidepressants it is interesting that chronic treatment with a selective MAO A (clorgyline) but not MAO B (deprenyl) inhibitor resulted in the reduction of [3H]dihydroalprenolol binding and cyclic AMP response to NA in the rat cortex. Recently similar changes were found in peripheral adrenergic systems. These data support the theory that neuronal MAO A inhibition results in elevation of cytoplasmic and synaptic NA and 5-HT, which mediates pre- and post-synaptic receptor changes.

The present study of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane(Z) hydrochloride, was undertaken to determine its biochemical profile. The properties of midalcipran, in inhibiting the uptake of monoamines were tested and compared with that of imipramine. In vitro, midalcipran was found to inhibit the uptake of radiolabelled serotonin and noradrenaline (IC50 = 203 and 100 nM, respectively), but not that of dopamine, into brain slices. Hyperthermia induced by the centrally-acting displacers of monoamines, H77/77 and H75/12, were almost equipotently antagonized by midalcipran, confirming the inhibition of the uptake of serotonin and noradrenaline by midalcipran in vivo (ID50 = 11 and 4.8 mg/kg, respectively). Midalcipran showed no inhibition of the activity of monoamine oxidase in vitro or in vivo. The interaction between midalcipran and neurotransmitter receptors and binding sites in the CNS was studied in the rat in comparison with imipramine and desipramine. In contrast to these two antidepressant drugs, midalcipran showed no affinity for alpha- or beta-adrenoceptors, muscarinic, histaminergic H1, dopaminergic D2 or serotonergic 5-HT2 receptors, suggesting a general absence of anticholinergic, sedative and other side-effects. Midalcipran was equipotent with imipramine at inhibiting the binding of [3H]imipramine. Chronic administration of midalcipran to rats did not alter the number of beta-adrenergic receptors in the cortex, in contrast to imipramine and desipramine which decreased the binding of beta-adrenoceptors. Thus midalcipran appears to act exclusively presynaptically, inhibiting the uptake of serotonin and noradrenaline. This activity, coupled to the total absence of interaction at postsynaptic sites, suggests that midalcipran may be a useful and novel antidepressant drug.

In patients with Alzheimer-type dementia, in addition to the well-known losses of cholinergic neurones, there is evidence of degeneration of the noradrenergic and serotonergic innervation of the cerebral cortex. While noradrenergic and cholinergic receptors are preserved there is a loss of serotonin S1 and S2 receptors, particularly in the temporal lobe. The loss of serotonin S2 receptors may occur at an early stage of the disease and, in temporal and frontal cortex, is correlated with the loss of somatostatin immunoreactivity. In patients dying in hospital with depression, and in individuals committing suicide, there are no consistent changes in monoamine metabolites. Noradrenergic, serotonergic, and other neurotransmitter receptors were found to be unchanged, although there was a moderate decrease in imipramine binding in a small group (n = 6) of subjects with a history of depression, who had committed suicide.

Sixteen male Wistar strain rats were trained to have their skin conductance activity recorded through the soles of their hind limbs, and the effects of the intraventricular administration of 6-OHDA (200 micrograms) on this activity were studied. The intact rats showed skin conductance response and its habituation to repeated auditory stimuli (500 Hz, 90 dB, 1 sec). The 6-OHDA-treated rats exhibited either obliteration of the response or impairment of the habituation. The nonresponding state tended to be accompanied by a low rate of spontaneous skin conductance fluctuation, but the nonhabituating state was not accompanied by changes of the rate. The vehicle-treated rats showed no change in these activities. These electrodermal characteristics were discussed along with the CA hypothesis of schizophrenia.

The finding of a diminished TSH response to exogenously administered TRH in a significant proportion of depressed patients has now been established as one of the most reproducible findings in biological psychiatry. More than 50 reports, in which more than 1000 patients have been studied, reveal that the TSH response is blunted in approximately 25% of patients with major depression. TSH blunting is clearly not specific for depression, because it also has been observed in mania, alcoholism, and borderline personality disorder. It is doubtful that TSH blunting represents a non-specific response to mental stress: it was found only rarely in schizophrenic patients, and the TSH response to in vivo flooding therapy in phobic patients was normal. In both depression and alcoholism, TSH blunting has been reported to be sometimes a state marker and sometimes a trait marker, i.e. the fault was found to persist into remission in more than half the patients. In both conditions, TSH blunting was unrelated to the patients' age, body weight, height, body surface, thyroid status, and serum cortisol concentrations. It also is unlikely that TSH blunting was due to increased dopaminergic inhibition of thyrotroph cells: serum prolactin concentrations in TSH blunters were found to be normal, and pretreatment with haloperidol had no effect on either basal TSH levels or TSH blunting. In depression, TSH blunting was not associated with previous drug intake, dexamethasone suppression test abnormalities, or variables of biogenic amine metabolism, nor did it usefully segregate between primary and secondary depression or between unipolar and bipolar subgroups. Preliminary evidence suggests that TSH blunting in depression may be related to duration of illness, history of violent suicide attempts, and a reduced 24 h TSH secretion. In alcoholism, TSH blunting was unrelated to family or personal history of depression and duration of abstinence. With reference to clinical utility, TSH blunting may aid in assessing the response to antidepressant treatment, predicting outcome to such treatment, assessing the risk for violent suicide attempts, and describing relationships between different psychiatric populations (e.g. depression and alcoholism).

Following its chronic administration, the racemic mianserin analogue of Org. 3770 attenuated the hypermotility of bilaterally olfactory-bulbectomized rats in the "open-field" apparatus, over the dose range of 0.5-2 mg/kg; only the largest dose of the drug was found to reduce the motility of the sham-operated animals. The activity of this compound would appear to reside in its S(+)isomer; the R(-)isomer being inactive. Bulbectomy was associated with a slight decrease in the concentration of noradrenaline and its major metabolite MHPG in the amygdaloid cortex and mid-brain. Following chronic administration of Org. 3770, the concentration of noradrenaline and MHPG returned to control levels. When the enantiomers were tested, it was found that the behaviourally-inactive R(-)isomer was most effective in normalizing the deficit in this neurotransmitter. Thus, no correlation could be found between the behavioural activity of the enantiomers of Org. 3770 and changes in the metabolism of noradrenaline in the amygdaloid cortex and mid-brain.

Cerebral amino acid concentrations in mice were determined following in vivo treatment with cycloheximide and anisomycin. Synaptosomes from untreated mice were then exposed to concentrations of amino acids designed to simulate the conditions existing extraneuronally following in vivo drug treatment. The synthesis of [3H]norepinephrine, [3H]dopamine and [3H]5-hydroxytryptamine from their labelled amino acid precursors was determined, as well as the accumulation of the precursors by the synaptosomes. Although the synthesis of both [3H]dopamine and [3H]norepinephrine was decreased below expected values predicted from samples in which only tyrosine was altered to represent the concentrations following drug treatment, it was not decreased significantly below control levels. Synthesis of [3H]5-hydroxytryptamine was increased in the presence of amino acid mixtures simulating drug treatment. The results suggest that alteration of amino acid levels is not involved in the inhibition of brain monoamine synthesis caused by these protein synthesis inhibitors.

Many antidepressant drugs inhibit the neuronal uptake of norepinephrine, serotonin, epinephrine and/or dopamine. Some newer antidepressant drugs are highly selective in their ability to inhibit the uptake of one or more of these monoamines. This uptake inhibition, which would be expected to increase the synaptic concentrations of the neurotransmitter initially, has traditionally been thought to be the mechanism of antidepressive action of these drugs. Some drugs, which are not uptake inhibitors, may block presynaptic alpha 2 receptors to enhance norepinephrine release, leading by a different mechanism to increased synaptic concentrations of norepinephrine. Adaptive changes in neurotransmitter receptors occur after chronic treatment of laboratory animals with these drugs, and these changes may be important components of the overall mechanism of antidepressant efficacy. Presently, evidence that these adaptive changes occur in humans is limited, and the significance of the changes to the treatment of depression is unknown. Some antidepressant drugs also have high affinity for neurotransmitter receptors, and direct antagonism of these receptors is the basis for some of their side effects, e.g., anticholinergic side effects that are prevalent with the tricyclic drugs.