Concentration of monoamines in the brain of minks differing in their reaction to man

Content of dopamine in the striatum; of serotonin, 5-hydroxyindolacetic acid and noradrenaline in the hypothalamus, striatum and midbrain was studied in three groups of minks from population of an animal farm, differing by their reaction to humans (cowardly, calm, aggressive). The reaction to humans was estimated by a system of marks at the attempt to catch the mink with a mitten. Aggressive animals had a lowered level of serotonin in the hypothalamus and striatum, a lesser content of serotonin metabolite--5-hydroxyindolacetic acid in the striatum. Minks of different groups did not differ by noradrenaline content, but dopamine level in the striatum of cowardly minks was higher than in calm and aggressive animals. Conclusion is made that polymorphism of behaviour corresponds to polymorphism of the state of monoaminergic systems.     

The role of brain noradrenaline in regulating the endocrine function of the gonads in male brown rats selected for behavior

In two groups of gray rats--nonaggressive ones, selected by the lack of aggression towards investigator, and aggressive animals--studies have been made on the relationship between noradrenaline system of the brain and the activity of pituitary-testicular system. In tame rats, less evident dependence of the gonadal activity on activating effect of noradrenaline was noted. After injection of norepinephrine, dopamine, and serotonin in the same brain region. *****were less significant in tame rats as compared to those in aggressive ones. The disturbed relationship between noradrenaline system of the brain and hypothalamo-pituitary-testicular complex is presumably one of the causes of associate changes in the reproductive system during selection for the domestic type of behaviour.     

EFFECT OF γ-AMINOBUTYRIC ACID ON BRAIN SEROTONIN AND CATECHOLAMINES

—Intraperitoneal injections of GABA (5 mg/kg) to rats lowered the level of norepinephrine in brain, heart and spleen but not suprarenals and raised that of serotonin in brain. Changes of these monoamines were most pronounced in the hypothalamic region after 20min. A reduction of hypothalamic norepinephrine was also observed 15min following the intracarotid administration of 0·5 mg/kg of GABA. In these experiments there was a concomitant increase in the level of free GABA in the anterior portion of the ventral hypothalamus. Brain dopamine level and 5-hydroxytryptophan decarboxylase, dihydroxyphenylalanine decarboxylase and monoamine oxidase activities were not affected. The 20 per cent increase of endogenous GABA observed in the midbrain 30 min following the administration of amino-oxyacetic acid was accompanied by a sharp fall in norepinephrine level (39 per cent) and an increase in serotonin (20 per cent). In in vitro studies 10–300 μg/ml of GABA were shown to release norepinephrine from cortical and hypothalamic slices, and to inhibit serotonin release without affecting 5-hydroxytryptophan uptake and to have no effect on the release of dopamine from slices of the region of the corpus striatum nor on the activity of the enzymes mentioned. Subcellular studies showed that the particulate:supernatant ratio for norepinephrine was reduced from a control value of 2·04 to 1·75 and that of serotonin was raised from 2·8 to 3·5. Following pretreatment with iproniazid, GABA reduced the raised level of brain norepinephrine to a greater extent than reserpine but not as intensively as amphetamine. The results obtained suggest that these monoamines may be involved in the mechanisms underlying the action of GABA in brain and that the effect of GABA on brain monoamines may be of certain significance in synaptic events.     

Effects of monorecessive and double recessive mutations affecting coat color on the monoamine content of the brain of the American mink (<Emphasis Type="Italic">Mustela vison</Emphasis> Schreber, 1777)

The effects of mutations affecting the coat color on the dopamine, noradrenaline, and serotonin contents of the hypothalamus and brainstem of the American mink have been studied. The sample comprised standard (+/+) and mutant minks, including the monorecessive pastel (b/b), silver-blue (p/p), and white hedlund (h/h) and the combination double recessive sapphire (a/a p/p) and pearl (k/k p/p) ones. The dopamine content of the brainstem of the monorecessive pastel (b/b) and silver-blue (p/p) minks has been found to be higher than in standard (+/+) minks. Conversely, the homozigosity for two coat color loci in double recessive pearl minks (k/k p/p) significantly decreases the noradrenaline and serotonin contents of the hypothalamus. In addition, monorecessive and double recessive minks differ from each other in the serotonin contents of the midbrain and medulla.     

Immunohistochemical detection of tyrosine hydroxylase and concentrations of monoamines in the substantia nigra and hypothalamus of hereditary microphthalmic rats.

We compared tyrosine hydroxylase immunoreactivity in the substantia nigra and hypothalamus of hereditary microphthalmic rats with that of normal rats. A considerable number of neuronal cell bodies expressing tyrosine hydroxylase were present in the substantia nigra of the microphthalmic mutant as well as normal rats. Neuronal cells positive for tyrosine hydroxylase in the hypothalamus were fewer than in the substantia nigra in both rats. The concentrations of monoamines (dopamine, noradrenaline, adrenaline, and serotonin) in the substantia nigra and hypothalamus in the microphthalmic mutant were approximately the same as those of normal rats, although the diurnal fluctuation of a few monoamines was observed in normal rats. These results suggest that the metabolic aspects of catecholamine in the substantia nigra and hypothalamus of the microphthalmic mutant rat do not markedly differ from those of normal rats.     

Effect of Long-Lasting Diabetes Mellitus on Rat and Human Brain Monoamines

Experimental alloxan- or streptozotocin-produced diabetes in rats was accompanied by an increase in the levels of norepinephrine, dopamine, and serotonin, whereas the contents of metabolites, i.e., 5-hydroxyindoleacetic acid and homovanillic acid, in the whole brain gradually decreased with the duration of diabetes. Among the striatum, thalamus, and hypothalamus of alloxan diabetic rats, monoamine alterations were observed only in the hypothalamus; after 1 week an increase of norepinephrine content and after 13 weeks an increase of norepinephrine and dopamine contents were found. Tissues of 11 brain regions of 10 diabetic and 12 control patients post mortem were investigated for monoamine concentrations. Patients were all male, of similar age and interval between death and autopsy. Diabetic patients had an increase in the content of serotonin in the medial and lateral hypothalamus. The content of dopamine increased in the medial hypothalamus, putamen, and medial and lateral pallidus. In diabetic patients, the content of norepinephrine increased in the lateral pallidus and decreased in the nucleus accumbens and claustrum. Thus, it seems that diabetes mellitus in rats, as well as in humans is associated with regionally specific changes in brain monoamines.     

1, 2, 3, 4-Tetrahydro-2-Methyl-4, 6, 7-Isoquinolinetriol Depletes Catecholamines in Rat Brain

1, 2, 3, 4-Tetrahydro-2-methyl-4, 6, 7-isoquinolinetriol (TMIQ) was synthesised and tested for activity as a dopamine-depleting agent in rat brain. After intracerebroventricular infusion, TMIQ caused reductions in dopamine concentrations in substantia nigra, striatum, hypothalamus, and dorsal raphe, and reduction in noradrenaline concentrations in locus coeruleus. TMIQ also reduced 5-hydroxytryptamine concentrations in dorsal raphe and substantia nigra, although with a lower potency. Comparisons between TMIQ and MPTP showed that they were approximately equipotent in depleting dopamine in the substantia nigra, hypothalamus, and dorsal raphe. Pretreatment of animals with a combination of monoamine oxidase A and B inhibitors completely prevented the TMIQ-induced reductions in dopamine concentrations in substantia nigra and hypothalamus. Direct unilateral intrastriatal injections of TMIQ produced marked ipsilateral reductions in striatal dopamine, correlating with a behavioural response consisting of turning towards the side of injection. The results suggest that TMIQ should be evaluated further as a possible MPTP-like compound, which may derive from endogenous β-hydroxylated catecholamines.     

Serotonin receptors in the brain of animals selected for their domesticated type of behavior

Participation was studied of central serotonin receptors of the first and second types in behaviour change of animals selected by the character of defensive reaction to man. Serotonin receptors were determined by radioligand method by binding of the brain preparations 3H-serotonin and 3H-spiperone. An increase of C2 receptors number was found in the frontal brain cortex of the tame brown rats in comparison with the aggressive ones. Differences were not found in specific C1-receptor binding in the frontal brain cortex of tame and aggressive brown rats, silver foxes and American minks in various relatively early selection stages. It is supposed that disappearance of aggressive reaction to man at domestication is connected with an increase of C2 receptors number.     

Adolescent exposure to anabolic/androgenic steroids and the neurobiology of offensive aggression: A hypothalamic neural model based on findings in pubertal Syrian hamsters

Considerable public attention has been focused on the issue of youth violence, particularly that associated with drug use. It is documented that anabolic steroid use by teenagers is associated with a higher incidence of aggressive behavior and serious violence, yet little is known about how these drugs produce the aggressive phenotype. Here we discuss work from our laboratory on the relationship between the development and activity of select neurotransmitter systems in the anterior hypothalamus and anabolic steroid-induced offensive aggression using pubertal male Syrian hamsters (Mesocricetus auratus) as an adolescent animal model, with the express goal of synthesizing these data into an cogent neural model of the developmental adaptations that may underlie anabolic steroid-induced aggressive behavior. Notably, alterations in each of the neural systems identified as important components of the anabolic steroid-induced aggressive response occurred in a sub-division of the anterior hypothalamic brain region we identified as the hamster equivalent of the latero-anterior hypothalamus, indicating that this sub-region of the hypothalamus is an important site of convergence for anabolic steroid-induced neural adaptations that precipitate offensive aggression. Based on these findings we present in this review a neural model to explain the neurochemical regulation of anabolic steroid-induced offensive aggression showing the hypothetical interaction between the arginine vasopressin, serotonin, dopamine, γ-aminobutyric acid, and glutamate neural systems in the anterior hypothalamic brain region.     

Visualizing Dopamine and Serotonin Transporters in the Human Brain with the Potent Cocaine Analogue [125I]RTI-55: In Vitro Binding and Autoradiographic Characterization

Abstract: The cocaine analogue RTI-55 was evaluated as a probe for in vitro labeling and localization of dopamine and serotonin transporters after death in the human brain. Kinetic, saturation, and competition binding experiments indicated complex interactions of the radioligand with the identification of multiple recognition sites. In membrane binding assays, the association of [¹²⁵I]RTI-55 at 25°C to putamen membranes was monophasic. In contrast, dissociation of [¹²⁵I]RTI-55 occurred in two phases with t_1/2 values of 9.4 and 36.5 min, respectively. Saturation analysis of [¹²⁵I]RTI-55 binding demonstrated two binding sites in the human putamen with K_D values of 0.10 ± 0.02 and 1.81 ± 0.46 nM. The binding of [¹²⁵I]RTI-55 was displaced by a wide range of cocaine analogues and monoamine uptake inhibitors. The rank order of potency demonstrated in competition assays with human putamen membranes indicates that the radioligand labels cocaine recognition sites on the dopamine transporter (mazindol > GBR 12909 > GBR 12935 > paroxetine > nisoxetine > desipramine ≥ fluoxetine > citalopram). In the human occipital cortex, [¹²⁵I]RTI-55 recognized multiple binding sites with K_D values of 0.02 ± 0.01 and 4.18 ± 0.46 nM. The rank order of potency for inhibition of [¹²⁵I]RTI-55 binding to cerebral cortex membranes (paroxetine > citalopram > GBR 12909 ≥ mazindol ≥ nisoxetine > benztropine) suggests that [¹²⁵I]RTI-55 labels the serotonin transporter in the human occipital cortex. Autoradiographic mapping of [¹²⁵I]RTI-55 revealed very high densities of cocaine recognition sites over areas known to be rich in dopaminergic innervation, including the caudate, putamen, and nucleus accumbens. Moderately elevated densities of [¹²⁵I]RTI-55 binding sites were also seen throughout the thalamus, hypothalamus, and substantia nigra. [¹²⁵I]RTI-55 binding sites were prevalent throughout the cerebral cortex and amygdala. In autoradiographic studies, the addition of the selective serotonin transport blocker citalopram completely prevented [¹²⁵I]RTI-55 labeling in the thalamus, hypothalamus, and throughout most of the cerebral cortex. In the presence of citalopram, [¹²⁵I]RTI-55 binding site densities remained elevated over the striatum and substantia nigra, with selective residual labeling also seen in the external segment of the globus pallidus and the lateral nucleus of the amygdala. These results demonstrate that in the human brain, [¹²⁵I]RTI-55 labels multiple recognition sites on dopamine and serotonin transporters.     

Brain monoamines are involved in mediating the action of neurohypophyseal peptide hormones on ethanol tolerance

Two doses (0.3 and 3 ng peptide/animal) of oxytocin (OXT) and lysine-8-vasopressin (LVP) were earlier found to inhibit the development of tolerance to the hypothermic effect of ethanol in mice upon icv. administration. In the present paper the possible central monoaminergic correlates of the behavioral data were investigated. In tolerant animals the steady-state level of noradrenaline (NA) was increased in the hypothalamus, as was that of dopamine (DA) in the medulla oblongata; the serotonin (5-HT) and DA levels were decreased in the striatum as compared to those in the non-tolerant control. In the peptide-pretreated animals the NA level was increased in the hypothalamus, the DA level in the striatum, and the 5-HT level in the hippocampus and striatum. Opposite changes were observed in the steady-state levels of the monoamines in the hippocampus and striatum as compared to those in the tolerant controls. The data suggest that the central monoamines may be involved in mediating the actions of neurohypophyseal peptides on ethanol tolerance.     

Low Selenium Diet Affects Monoamine Turnover Differentially in Substantia Nigra and Striatum

Abstract: Turnover of dopamine, noradrenaline. serotonin, and their metabolites has been measured in striatum and substantia nigra of adult female rats that were fed control or selenium-deficient diets for 15 days. In addition, the glutathione peroxidase activity has been studied. The most striking result was the increase of dopamine turnover (63%) and 3- methoxytyramine turnover (55%) in substantia nigra between control and experimental animals. On the other hand, no changes were found in the turnover rate of dopamine and its metabolites in the striatum. Likewise, no changes were found in noradrenaline turnover in substantia nigra. In the striatum, there was a significant increase of serotonin turnover versus no change for 5-hydroxy-3-indoleacetic acid. However, in the substantia nigra, serotonin turnover did not show significant changes, whereas 5-hydroxy-3-indoleacetic acid turnover decreased. At the same time, glutathione peroxidase activity significantly decreased in both structures after selenium-deficient diets. These results suggest that a selenium-deficient diet for a short period of time decreases brain protection. principally in the substantia nigra, against oxidative damage.     

Inhibitory role of serotonin in manifestations of predatory aggression in the mink and silver fox

The predatory aggression of minks and silver-black foxes were estimated by their attacks on the rats placed in their cage. Intraperitoneal injection of 5-hydroxytryptophan (serotonin precursor) in a dose of 100 mg/kg to foxes and 50 mg/kg to minks, caused a significant blocking of predatory aggression. Estimation of serotonin level in the brain following administration of corresponding doses of 5-HTP inhibiting the predatory aggression, revealed a considerable increase of serotonin content. It may be assumed that serotonin inhibitory mechanisms of predatory aggression are homologous in different species of animals.     

Luliberin of the synaptosomal fraction of the mediobasal hypothalamus in male rats and a change in its level as affected by monoamines

Investigation of the effects of injecting monoamines (noradrenaline, dopamine and serotonin) into the third ventricle of the brain on the LH-RH content in the synaptosomal fraction of the mediobasal hypothalamus in intact and castrated male rats has demonstrated that all the three monoamines are involved in the regulation of synthesis and secretion of LH-RH and that their effects on LH-RH-producing neurons are steroid-dependent.     

Biochemistry of Somatodendritic Dopamine Release in Substantia Nigra: An In Vivo Comparison with Striatal Dopamine Release

Abstract: The somatodendritic release of dopamine in substantia nigra previously has been suggested to be nonvesicular in nature and thus to differ from the classical, exocytotic release of dopamine described for the dopaminergic nerve terminal in striatum. We have compared the effects of reserpine, a compound that disrupts vesicular sequestration of monoamines, on the storage and release of dopamine in substantia nigra and striatum of rats. Reserpine administration (5 mg/kg, i.p.) significantly decreased the tissue level of dopamine in substantia nigra pars reticulata, substantia nigra pars compacta, and striatum. In these brain areas, reserpine-induced reductions in tissue dopamine level occurred within 2 h and persisted at 24 h postdrug. In vivo measurements using microdialysis revealed that reserpine administration rapidly decreased the extracellular dopamine concentration to nondetectable levels in substantia nigra as well as in striatum. In both structures, it was observed that reserpine treatment significantly attenuated the release of dopamine evoked by a high dose of amphetamine (10 mg/kg, i.p.) given 2 h later. In contrast, dopamine efflux in response to a low dose of amphetamine (2 mg/kg, i.p.) was not altered by reserpine pretreatment either in substantia nigra or in striatum. The present data suggest the existence, both at the somatodendritic and at the nerve terminal level, of a vesicular pool of dopamine that is the primary site of transmitter storage and that can be displaced by high but not low doses of amphetamine. The physiological release of dopamine in substantia nigra and in striatum is dependent on the integrity of this vesicular store.     

The regional distribution of dopamine and serotonin uptake and transmitter concentrations in the human brain

The regional distribution of the dopamine and serotonin uptake sites in human brain have been assessed and compared with the distribution of the transmitters and their metabolites measured in the same brains and also with a limited regional distribution of the uptake sites in rat and sheep brain. The affinity of the uptake sites for both transmitters was determined and found to be c. 0.2 μ M in all 3 species. Most dopamine uptake in all species was in caudate and putamen samples. Many regions of the human brain showed no dopamine uptake and little dopamine uptake was seen in sheep cortex or nigral preparations. Dopamine and metabolite concentrations were highest in the caudate, putamen and substantia nigra. Most serotonin uptake was seen in the hypothalamus in all 3 species; less was observed in the striatal regions; the cortical and nigral preparations of sheep brain showed little serotonin uptake though cortical preparations of rat brain had high levels of uptake. In the human brain, other regions did not show serotonin uptake. Highest concentrations of serotonin were found in the substantia nigra and medulla, intermediate concentrations in the putamen, globus pallidus, hypothalamus, olfactory tubercle and thalamus; very low concentrations of serotonin were found in other regions. The use of the human uptake site for pharmacological studies and as a marker for monoaminergic afferents in human health and disease is discussed.     

CHEMICAL SPECIFICITY OF DOPAMINE TRANSPORT IN THE NIGRO-NEOSTRIATAL PROJECTION

Axoplasmic transport of dopamine in the nigro-neostriatal system has previously been shown by the specific accumulation of labelled dopamine in the striatum following injections of labelled DOPA or dopamine into the substantia nigra. To test the specificity, 17 different labelled materials (pipecolic acid, inulin, taurine, GABA, glycine, histidine, histamine, serotonin, 5-HTP, D-amphetamine, 3-methoxytyramine, dopamine, tyramine, norepinephrine, octopamine and high and low specificity activity DOPA) were injected into the substantia nigra and the distribution of radioactivity in the brain studied after 6 and 24 h. Only the catecholamines and octopamine gave evidence of specific accumulation in the ipsilateral striatum although some of the other compounds caused diffuse labelling of the striatum along with other brain areas.     

Phenotypic differences in behavior, physiology and neurochemistry between rats selected for tameness and for defensive aggression towards humans

To better understand the biology of tameness, i.e. tolerance of human presence and handling, we analyzed two lines of wild-derived rats (Rattus norvegicus) artificially selected for tameness and defensive aggression towards humans. In response to a gloved human hand, tame rats tolerated handling, whereas aggressive rats attacked. Cross-fostering showed that these behavioral differences are not caused by postnatal maternal effects. Tame rats were more active and explorative and exhibited fewer anxiety-related behaviors. They also had smaller adrenal glands, larger spleens and lower levels of serum corticosterone. Blood glucose levels were lower in tame rats, whereas the concentrations of nine amino acids were higher. In the brain, tame rats had lower serotonin and higher taurine levels than aggressive rats. Our findings reinforce the notion that tameness is correlated with differences in stress response and will facilitate future efforts to uncover the genetic basis for animal tameness.     

Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: Role of glutamic acid

We studied the effect of local administration of nicotine on the release of monoamines in striatum, substantia nigra, cerebellum, hippocampus, cortex (frontal, cingulate), and pontine nucleus and on the release of glutamic acid in striatum of rats in vivo, using microdialysis for nicotine administration and for measuring extracellular amine and glutamic acid levels. Following nicotine administration the extracellular concentration of dopamine, increased in all regions except cerebellum; serotonin increased in cingulate and frontal cortex; and norepinephrine increased in substantia nigra, cingulate cortex, and pontine nucleus. Cotinine, the major nicotine metabolite, had no effect at similar concentrations. The cholinergic antagonists mecamylamine and atropine, the dopaminergic antagonists haloperidol and sulpiride, and the excitatory amino acid antagonist kynurenic acid all inhibited the nicotine-induced increase of extracellular dopamine in the striatum. The fact that kynurenic acid almost completely prevented the effects of nicotine, and nicotine at this concentration produced a 6-fold increase of glutamic acid release, suggests that the effect of nicotine is mainly mediated via glutamic acid release.     

Effect of Theanine,r-Glutamylethylamide,on Brain Monoamines and Striatal Dopamine Release in Conscious Rats

Theanine, r-glutamylethylamide, is one of the major components of amino acids in Japanese green tea. Effect of theanine on brain amino acids and monoamines, and the striatal release of dopamine (DA) was investigated. Determination of amino acids in the brain after the intragastric administration of theanine showed that theanine was incorporated into brain through blood-brain barrier via leucine-preferring transport system. The concentrations of norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5HIAA) in the brain regions were unaffected by the theanine administration except in striatum. Theanine administration caused significant increases in serotonin and/or DA concentrations in the brain, especially in striatum, hypothalamus and hippocampus. Direct administration of theanine into brain striatum by microinjection caused a significant increase of DA release in a dose-dependent manner. Microdialysis of brain with calcium-free Ringer buffer attenuated the theanine-induced DA release. Pretreatment with the Ringer buffer containing an antagonist of non-NMDA (N-methyl-D-aspartate) glutamate receptor, MK-801, for 1 hr did not change the significant increase of DA release induced by theanine. However, in the case of pretreatment with AP-5, (±)-2-amino-5-phosphonopentanoic acid; antagonist of NMDA glutamate receptor, the theanine-induced DA release from striatum was significantly inhibited. These results suggest that theanine might affect the metabolism and/or the release of some neurotransmitters in the brain, such as DA.