Molecular mechanisms involved in receptor editing at the Ig heavy chain locus

The Anorexia (anx) mutation causes reduced food intake in preweanling mice, resulting in death from starvation within 3-4 weeks. We have found serotonin (5HT) hyperinnervation in the anx brain; altered noradrenergic (NE) innervation may also mediate eating disorders. We examined the expression of synthetic or catabolic monoamine enzyme genes in brainstem nuclei: serotonin transporter (5HTT) and monoamine oxidase A (MAOA) in the raphe nuclei (RN), and MAOA, norepinephrine transporter (NET), and tyrosine hydroxylase (TH) in the locus ceruleus (LC). We compared 3-week old anx with control and 24-h food-deprived wildtype littermates using in situ hybridization to measure mRNA levels by quantitative autoradiography. The anx mutation was correlated with decreased MAOA mRNA in the LC (but not RN), decreased 5HTT mRNA in the RN, and a trend towards lower NET mRNA in the LC. Food deprivation decreased MAOA mRNA in the LC (but not RN), increased TH mRNA in the LC, and did not alter NET or 5HTT mRNA levels. Thus, the effect of the anx mutation on MAOA expression in the LC paralleled the effect of food-deprivation, but the anx mutation and food-deprivation had differential effects on the expression of TH, NET, and 5HTT genes. Decreased 5HTT expression in the anx RN is consistent with upregulation of serotonergic neurotransmission that may accompany 5HT hyperinnervation. Central NE levels or innervation may be altered in anx mice by decreased expression of NET and MAOA and a lack of TH upregulation induced by food deprivation as in wild-type mice.     

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.     

Thermoregulatory effects of monoamine potentiators and inhibitors in the rat

Exogenously administered monoamines may elicit variable thermoregulatory responses dependent on dosage, species, site of administration, ambient temperature, etc. In an attempt to reconcile several inconsistencies, we have undertaken a series of studies related to monoaminergic control of temperature regulation. Thus, intraventricular administration of serotonin (2.64-26.4 mug) and norepinephrine (3.3-32.8 mug) in rats evoked acute (15-60 min) dose-dependent hypothermic responses (delta Tre = 2 degrees C) that were gradually superseded by significant, more persistent hyperthermia (delta Tre = 1 degreee C). Administration of chlorimipramine or imipramine (total dose 40 mug), even in monoamine-depleted animals, caused long-lasting hyperthermic responses, presumably by the prevention of reuptake of serotonin and norepinephrine at nerve terminals involved in thermoregulation. Pretreatment with the serotonin inhibitor cyproheptadine (4o mug) attenuated the hyperthermia achieved by central administration of chlorimipramine alone. We conclude that both monoamines can act as thermogenic agents under the conditions of these experiments.     

Disruption of the dopamine Β-hydroxylase gene in mice suggests roles for norepinephrine in motor function, learning, and memory.

Mice unable to synthesize norepinephrine (NE) were created by targeted disruption of the dopamine ,β-hydroxylase (DBH) gene. DBH-deficient (DBH -/-) mice display normal home cage activity; however, they swim more slowly than their littermates, and some drown. The mutant mice also perform less well on a rapidly rotating rod, and –20% do not learn to walk when the rod begins to turn. Restoration of NE with dihydroxyphenylserine eliminated these motor deficits. DBH -/- mice exhibit normal learning and retention of a passive avoidance paradigm; however, they do not master an active-avoidance paradigm as readily as controls and exhibit more rapid extinction of the active-avoidance task. DBH -/- mice learn to find the hidden platform in the Morris water maze in spite of their slower swim speed and show normal preference for the correct quadrant in the transfer test immediately after training. However, this preference declines relative to controls during the next 2 days. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increases in vocalization and motor reflex thresholds generated by the intrathecal administration of serotonin or norepinephrine.

The capacity of serotonin and norepinephrine to elevate the thresholds of spinal motor reflexes (SMRs), vocalizations during shock (VDSs), and vocalization aftcrdischarges (VADs) when administered into the spinal subarachnoid space was evaluated. Both monoamines generated dose-dependent increases in the thresholds of all 3 responses. The minimum effective doses of serotonin and norepinephrine that elevated all 3 response thresholds were 40 μg and 1 μg, respectively. Monoamine-induced increases in response thresholds were reversed by the intrathecal administration of their corresponding receptor antagonists (phentolamine or methysergide). Threshold increases generated by serotonin were also partially reduced by phentolamine. These results indicate that dorsal horn neurons that underlie flexion reflex generation (SMR) and the rostral transmission of pain information (VDS and VAD) have similar thresholds of inhibition to spinopetal monoaminergic projections. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Animal models of psychopathology: The low-norepinephrine and low-serotonin rat.

A variety of evidence implies that alterations in the midbrain neuronal systems that use the monamines norepinephrine and serotonin as transmitters are involved in emotional imbalances and psychopathology in humans. The effects of alterations in these circuits can be studied in animals administered selective monoamine neurotoxins. From 7 yrs of research on the effects of alterations in norepinephrine and serotonin on rat behavior, the author notes that rats with norepinephrine depletions are inactive, have hunger deficits, and model aspects of depression, while rats with serotonin depletions are hyperactive, are frightened in novel environments, and model aspects of anxiety. When kept in isolation cages following lesioning, these animals recover but develop paradoxical, overcompensatory behavioral syndromes. When allowed to recover in social rat-colony environments, these animals become progressively more similar to controls, but their presence in the social colony leads to gradually increasing social disruptions. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells

BACKGROUND: Ketamine has been characterized as having psychotomimetic and sympathomimetic effects. These symptoms have raised the possibility that ketamine affects monoaminergic neurotransmission. To elucidate the relation between ketamine and monoamine transporters, the authors constructed three cell lines that stably express the norepinephrine, dopamine, and serotonin transporters and investigated the effects of ketamine on these transporters. METHODS: Human embryonic kidney cells were transfected using the Chen-Okayama method with the human norepinephrine, rat dopamine, and rat serotonin transporter cDNA subcloned into the eukaryotic expression vector. Using cells stably expressing these transporters, the authors investigated the effects of ketamine on the uptake of these compounds and compared them with those of pentobarbital. RESULTS: Inhibition analysis showed that ketamine significantly inhibited the uptake of all three monoamine transporters in a dose-dependent manner. The Ki (inhibition constant) values of ketamine on the norepinephrine, dopamine, and serotonin transporters were 66.8 microM, 62.9 microM, and 162 microM, respectively. Pentobarbital, a typical general anesthetic agent with no psychotic symptoms, did not affect the uptake of monoamines, however. Further, neither the glycine transporter 1 nor the glutamate/aspartate transporter was affected by ketamine, indicating that ketamine preferentially inhibits monoamine transporters. CONCLUSIONS: Ketamine inhibited monoamine transporters expressed in human embryonic kidney cells in a dose-dependent manner. This result suggests that the ketamine-induced inhibition of monoamine transporters might contribute to its psychotomimetic and sympathomimetic effects through potentiating monoaminergic neurotransmission.     

Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice

The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT1A receptor-mutant mice. These animals lack functional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs.     

Links between temperamental dimensions and brain monoamines in the rat.

In 27 female Wistar rats, the authors obtained composite scores on harm avoidance and novelty seeking, as well as 57 measures of monoamines and metabolites from 10 different brain regions. A multivariate regression method was used to discover associations between individual differences in temperament and neurochemistry. Harm-avoidant subjects had low levels of striatal dopamine and high levels of cortical norepinephrine and amygdaloid 5-hydroxyindoleacetic acid. High novelty-seeking scores were linked to low levels of brainstem serotonin and dopamine and to low levels of 5-hydroxyindoleacetic acid in amygdala and accumbens. Moreover, rats scoring high on novelty seeking had higher-than-average levels of norepinephrine in the thalamus and amygdala and of serotonin in the amygdala. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of phenelzine in an experimental model for screening anxiolytic and anti-panic drugs: correlation with changes in monoamine-oxidase activity and monoamine levels

This study investigated the effects of acute and chronic (one daily i.p. injection for 14 days) treatments with the non-selective irreversible monoamine-oxidase (MAO) inhibitor phenelzine (10 and 30 mg/kg) on defensive behaviors of Swiss mice in the mouse defense test battery (MDTB) which has been designed for screening anxiolytic and anti-panic drugs. In the MDTB, subjects were confronted with a natural threat (a rat) and situations associated with this threat. MAO-A and MAO-B activities and levels of brain monoamines (serotonin (5-HT), dopamine (DA) and norepinephrine (NE)) and their deaminated metabolites were subsequently measured. Behavioral results showed that acute administration of phenelzine did not specifically modify defensive behaviors. By contrast, after chronic treatment, phenelzine produced a significant reduction in avoidance distance when the rat was approaching, an effect which is consistent with an anti-panic-like action. In addition, phenelzine displayed weak anxiolytic-like effects as it increased risk assessment responses when mice were constrained in one part of the apparatus facing the rat which remained at a constant distance. No other specific drug effect was observed. These behavioral changes were associated with a dramatic increase in 5-HT levels, in particular after chronic treatment, while levels of DA and NE increased only slightly. Importantly, no significant differences in DA and NE levels between acute and chronic regimens were observed. Levels of deaminated metabolites of monoamines were markedly decreased. Measurements of MAO activity revealed substantial reductions in both type A and B forms with a full inhibition of both forms being observed only after chronic treatment with phenelzine. These results suggest that the effects of phenelzine may be due mainly to its effects on the 5-HT system and presumably related to the full inhibition of MAO-A and/or MAO-B.     

Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system

The monoamines, serotonin, dopamine, norepinephrine, epinephrine and histamine, play a critical role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information in sensory, limbic, and motor systems. The primary mechanism for termination of monoaminergic neurotransmission is through reuptake of released neurotransmitter by Na+, CI-dependent plasma membrane transporters. A second family of transporters packages monoamines into synaptic and secretory vesicles by exchange of protons. Identification of those cells which express these two families of neurotransmitter transporters is an initial step in understanding what adaptive strategies cells expressing monoamine transporters use to establish the appropriate level of transport activity and thus attain the appropriate efficiency of monoamine storage and clearance. The most recent advances in this field have yielded several surprises about their function, cellular and subcellular localization, and regulation, suggesting that these molecules are not static and most likely are the most important determinants of extracellular levels of monoamines. Here, information on the localization of mRNAs for these transporters in rodent and human brain is summarized along with immunohistochemical information at the light and electron microscopic levels. Regulation of transporters at the mRNA level by manipulation in rodents and differences in transporter site densities by tomographic techniques as an index of regulation in human disease and addictive states are also reviewed. These studies have highlighted the presence of monoamine neurotransmitter transporters in neurons but not in glia in situ. The norepinephrine transporter is present in all cells which are both tyrosine hydroxylase (TH)- and dopamine beta-hydroxylase-positive but not in those cells which are TH- and phenyl-N-methyltransferase-positive, suggesting that epinephrine cells may have their own, unique transporter. In most dopaminergic cells, dopamine transporter mRNA completely overlaps with TH mRNA-positive neurons. However, there are areas in which there is a lack of one to one correspondence. The serotonin transporter (5-HTT) mRNA is found in all raphe nuclei and in the hypothalamic dorsomedial nucleus where the 5-HTT mRNA is dramatically reduced following immobilization stress. The vesicular monoamine transporter 2 (VMAT2) is present in all monoaminergic neurons including epinephrine- and histamine-synthesizing cells. Immunohistochemistry demonstrates that the plasma membrane transporters are present along axons, soma, and dendrites. Subcellular localization of DAT by electron microscopy suggests that these transporters are not at the synaptic density but are confined to perisynaptic areas, implying that dopamine diffuses away from the synapse and that contribution of diffusion to dopamine signalling may vary between brain regions. Interestingly, the presence of VMAT2 in vesicles underlying dendrites, axons, and soma suggests that monoamines may be released at these cellular domains. An understanding of the regulation of transporter function may have important therapeutic consequences for neuroendocrine function in stress and psychiatric disorders.     

A novel antimicrobial peptide from the loach, Misgurnus anguillicaudatus

We investigated the effects of thyrotropin releasing hormone (TRH) on changes in cortical concentrations of acetylcholine (ACh) and monoamines produced by concussion in mice. Concussion was induced by dropping a metal rod on the head, and the concentration of ACh, norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in the cerebral cortex were measured by HPLC. We also examined the arousal effects of 0.5 mg/kg of TRH and 0.015 mg/kg of L-pyro-2-aminoadipyl-histidyl-thiazolidine-4-carboxamide (MK-771), a TRH analogue, injected intraperitoneally 10 min before concussion, on neurotransmitter concentrations. Mice were sacrificed at 25 (representing the righting reflex time) and 210 s (representing spontaneous movement time). At 25 s after concussion, the concentration of ACh was significantly higher than in control mice, but pretreatment with TRH and MK-771 prevented the rise in ACh. In contrast, head injury significantly reduced NE concentration. TRH and MK-771 also prevented the fall in NE. Concussion did not change cortical concentrations of DA and 5-HT. Our results suggest that disturbances of consciousness produced by concussion may be due to increased ACh and diminished NE in the cerebral cortex. Our findings also suggest that the arousal effects of TRH on concussion-induced disturbances of consciousness are due to normalization of cortical cholinergic and noradrenergic neuronal systems.     

Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice

Serotonin systems have been implicated in the regulation of hippocampal function. Serotonin 5-HT2C receptors are widely expressed throughout the hippocampal formation, and these receptors have been proposed to modulate synaptic plasticity in the visual cortex. To assess the contribution of 5-HT2C receptors to the serotonergic regulation of hippocampal function, mice with a targeted 5-HT2C-receptor gene mutation were examined. An examination of long-term potentiation at each of four principal regions of the hippocampal formation revealed a selective impairment restricted to medial perforant path-dentate gyrus synapses of mutant mice. This deficit was accompanied by abnormal performance in behavioral assays associated with dentate gyrus function. 5-HT2C receptor mutants exhibited abnormal performance in the Morris water maze assay of spatial learning and reduced aversion to a novel environment. These deficits were selective and were not associated with a generalized learning deficit or with an impairment in the discrimination of spatial context. These results indicate that a genetic perturbation of serotonin receptor function can modulate dentate gyrus plasticity and that plasticity in this structure may contribute to neural mechanisms underlying hippocampus-dependent behaviors.     

In situ analysis of a variant surface glycoprotein expression-site promoter region in Trypanosoma brucei

Duchenne muscular dystrophy is frequently associated with a non-progressive cognitive deficit attributed to the absence of 427,000 mol. wt brain dystrophin, or to altered expression of other C-terminal products of this protein, Dp71 and/or Dp140. To further explore the role of these membrane cytoskeleton-associated proteins in brain function, we studied spatial learning and ex vivo synaptic plasticity in the mdx mouse, which lacks 427,000 mol. wt dystrophin, and in the mdx3cv mutant, which shows a dramatically reduced expression of all the dystrophin gene products known so far. We show that reference and working memories are largely unimpaired in the two mutant mice performing a spatial discrimination task in a radial maze. However, mdx3cv mice showed enhanced emotional reactivity and developed different strategies in learning the task, as compared to control mice. We also showed that both mutants display apparently normal levels of long-term potentiation and paired-pulse facilitation in the CA1 field of the hippocampus. On the other hand, an increased post-tetanic potentiation was shown by mdx, but not mdx3cv mice, which might be linked to calcium-regulatory defects. Otherwise, immunoblot analyses suggested an increased expression of a 400,000 mol. wt protein in brain extracts from both mdx and mdx3cv mice, but not in those from control mice. This protein might correspond to the dystrophin-homologue utrophin. The present results suggest that altered expression of dystrophin or C-terminal dystrophin proteins in brain did not markedly affect hippocampus-dependent spatial learning and CA1 hippocampal long-term potentiation in mdx and mdx3cv mice. The role of these membrane cytoskeleton-associated proteins in normal brain function and pathology remains to be elucidated. Furthermore, the possibility that redundant mechanisms could partially compensate for dystrophins' deficiency in the mdx and mdx3cv models should be further considered.     

P-impulsive sensation seeking and its behavioral, psychophysiological and biochemical correlates

Impulsive unsocialized sensation seeking (ImpUSS) is a major factor discovered in factor analyses of scales used in psychobiological research. It is strongly convergent with Eysenck's P dimension and conscientiousness in the 'big five'. The components of the dimension and the P scale, have been validated as correlates of various kinds of disinhibited behaviors, criminality, sexuality, and substance use and abuse. ImpUSS is related to a failure in passive avoidance learning, probably as a function of impulsivity and attention to reward stimuli. Psychophysiological markers for the trait include strong orienting and weak defensive reflexes and an augmenting, rather than reducing, of cortical reaction to intense stimuli. At the neurochemical level the trait is related to low levels of monoamine oxidase (MAO) and the neurotransmitters norepinephrine and serotonin, and theoretically high levels of dopaminergic activity. The trait components have high heritabilities for a personality trait.     

Role of focal adhesion proteins in signal transduction and oncogenesis

A monoamine pathophysiological hypothesis for paraphilias in males is based on the following data: (i) the monoamines norepinephrine, dopamine, and serotonin are involved in the appetitive dimension of male sexual behavior in laboratory animals; (ii) data gathered from studying the side effect profiles of antidepressant psychostimulant, and neuroleptic drugs in humans suggest that alteration of central monoamine neurotransmission can have substantial effects on human sexual functioning, including sexual appetite; (iii) monoamine neurotransmitters appear to modulate dimensions of human and animal psychopathology including impulsivity, anxiety, depression, compulsivity, and pro/antisocial behavior, dimensions disturbed in many paraphiliacs; (iv) pharmacological agents that ameliorate psychiatric disorders characterized by the aforementioned characteristics, especially central serotonin enhancing drugs, can ameliorate paraphilic sexual arousal and behavior.     

A role for the Ras signalling pathway in synaptic transmission and long-term memory

Members of the Ras subfamily of small guanine-nucleotide-binding proteins are essential for controlling normal and malignant cell proliferation as well as cell differentiation. The neuronal-specific guanine-nucleotide-exchange factor, Ras-GRF/CDC25Mm, induces Ras signalling in response to Ca2+ influx and activation of G-protein-coupled receptors in vitro, suggesting that it plays a role in neurotransmission and plasticity in vivo. Here we report that mice lacking Ras-GRF are impaired in the process of memory consolidation, as revealed by emotional conditioning tasks that require the function of the amygdala; learning and short-term memory are intact. Electrophysiological measurements in the basolateral amygdala reveal that long-term plasticity is abnormal in mutant mice. In contrast, Ras-GRF mutants do not reveal major deficits in spatial learning tasks such as the Morris water maze, a test that requires hippocampal function. Consistent with apparently normal hippocampal functions, Ras-GRF mutants show normal NMDA (N-methyl-D-aspartate) receptor-dependent long-term potentiation in this structure. These results implicate Ras-GRF signalling via the Ras/MAP kinase pathway in synaptic events leading to formation of long-term memories.     

Behavioral effects of estrogen receptor gene disruption in male mice

Gonadal steroid hormones regulate sexually dimorphic development of brain functions and behaviors. Their nuclear receptors offer the opportunity to relate molecular events in neurons to simple instinctive mammalian behaviors. We have determined the role of estrogen receptor (ER) activation by endogenous estrogen in the development of male-typical behaviors by the use of transgenic estrogen-receptor-deficient (ERKO) mice. Surprisingly, in spite of the fact that they are infertile, ERKO mice showed normal motivation to mount females but they achieved less intromissions and virtually no ejaculations. Aggressive behaviors were dramatically reduced and male-typical offensive attacks were rarely displayed by ERKO males. Moreover, ER gene disruption demasculinized open-field behaviors. In the brain, despite the evident loss of functional ER protein, the androgen-dependent system appears to be normally present in ERKO mice. Together, these findings indicate that ER gene expression during development plays a major role in the organization of male-typical aggressive and emotional behaviors in addition to simple sexual behaviors.     

Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine

The human dopamine D4 receptor (D4R) has received considerable attention because of its high affinity for the atypical antipsychotic clozapine and the unusually polymorphic nature of its gene. To clarify the in vivo role of the D4R, we produced and analyzed mutant mice (D4R-/-) lacking this protein. Although less active in open field tests, D4R-/- mice outperformed wild-type mice on the rotarod and displayed locomotor supersensitivity to ethanol, cocaine, and methamphetamine. Biochemical analyses revealed that dopamine synthesis and its conversion to DOPAC were elevated in the dorsal striatum from D4R-/- mice. Based on these findings, we propose that the D4R modulates normal, coordinated and drug-stimulated motor behaviors as well as the activity of nigrostriatal dopamine neurons.     

Monoamine- and histamine-synthesizing enzymes and neurotransmitters within neurons of adult human cardiac ganglia

BACKGROUND: Cardiac ganglia were originally thought to contain only cholinergic neurons relaying parasympathetic information from preganglionic brain stem neurons to the heart. Accumulating evidence, however, suggests that cardiac ganglia contain a heterogeneous population of neurons that synthesize or respond to several different neurotransmitters and neuropeptides. Reports regarding monoamine and histamine synthesis and neurotransmission within cardiac ganglia, however, present conflicting information or are limited in number. Furthermore, very few studies have examined the neurochemistry of adult human cardiac ganglia. The purpose of this study was, therefore, to determine whether monoamine- and histamine-synthesizing enzymes and neurotransmitters exist within neurons of adult human cardiac ganglia. METHODS AND RESULTS: Human heart tissue containing cardiac ganglia was obtained during autopsies of patients without cardiovascular pathology. Avidin-biotin complex immunohistochemistry was used to demonstrate tyrosine hydroxylase, L-dopa decarboxylase, dopamine beta-hydroxylase, phenylethanolamine-N-methyltransferase, tryptophan hydroxylase, and histidine decarboxylase immunoreactivity within neurons of cardiac ganglia. Dopamine, norepinephrine, serotonin, and histamine immunoreactivity was also found in ganglionic neurons. Omission or preadsorption of primary antibodies from the antisera and subsequent incubation with cardiac ganglia abolished specific staining in all cases examined. CONCLUSIONS: Our results suggest that neurons within cardiac ganglia contain enzymes involved in the synthesis of monoamines and histamine and that they contain dopamine, norepinephrine, serotonin, and histamine immunoreactivity. Our findings suggest a putative role for monoamine and histamine neurotransmission within adult human cardiac ganglia. Additional, functional evidence will be necessary to evaluate what the physiological role of monoamines and histamine may be in neural control of the adult human heart.