Behavioral and mesocorticolimbic dopamine responses to non aggressive social interactions depend on previous social experiences and on the opponent's sex

In these experiments we evaluated the relationship between behavioral and brain dopamine (DA) responses to social interactions. Subjects were group housed male mice confronted with a non aggressive male or female conspecific following either repeated defeat (defeated) or repeated non aggressive experiences (social). Defeated mice showed more defensive/submissive reactions then mice of the social group regardless of the opponent sex. However, mice defeated by females showed reduced social exploration without significant differences in non social exploration whilst the opposite was true for mice defeated by male opponents. Non aggressive social interactions enhanced dopamine metabolism in the prefrontal cortex (pFC) of DEFEATED mice regardless of opponent sex. However, only mice defeated by females showed enhanced dopamine metabolism and release in the nucleus accumbens septi (NAS) and olfactory tubercle (OT) following interaction with the non aggressive opponent. Finally, correlation between central and behavioral responses evidenced that 3,4-dihydroxiphenilacetic acid levels in the pFC were positively correlated with defensive behaviors and negatively correlated with non social exploration in mice confronted with male opponents but not in those confronted with females. The latter, showed a significant positive correlation between 3-methoxytyramine (3-MT) levels in the OT and defensive responses and significant negative correlation between social investigation and 3-MT levels in the OT and in the NAS. These results indicate a strict relationship between mesocorticolimbic dopamine transmission and behavior responses to social cues. Moreover, they strongly support the view that mesocorticolimbic DA modulates social behavior by affecting perceptive processing.     

MAO-A and -B gene knock-out mice exhibit distinctly different behavior

MAO-A and -B are key isoenzymes that degrade biogenic and dietary amines. MAO-A preferentially oxidizes 5-HT and NE, whereas MAO-B preferentially oxidizes PEA. However, the substrate and inhibitor selectivity overlap depending on the concentration of the enzyme and substrate. A line of transgenic mice has been generated in which the gene that encodes MAO-A is disrupted. MAO-A KO mice have elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar to men with a deletion of MAO-A. We have also generated mice deficient in MAO-B by homologous recombination. Interestingly, MAO-B KO mice do not exhibit aggression and only levels of PEA are increased. MAO-B-deficient mice are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Thus, studies of MAO-A and -B KO mice have clearly shown that MAO-A and -B have distinct functions in neurotransmitter metabolism and behavior. MAO KO mice are valuable models for investigating the role of monoamines in aggression and neurodegenerative and stress-related disorders.     

Brain Monoamine Levels and El Mouse Convulsions

Abstract: El mice had higher levels of brain dopamine (DA) and serotonin (5-HT) and a lower level of brain norepinephrine (NE) compared with the other strains of inbred mice. In the interictal stage of "stimulated" El mouse, the brain DA, NE and 5-HT levels were significantly lower compared with the non-stimulated El mouse. The administration of 5-hydroxytryptophan with MK486 markedly depressed the incidence of seizures in the El mouse. Evidence of abnormal DA, NE and 5-HT metabolism was found at the development age when the seizures became frequent. These results show that 5-HT may be closely related to the El mouse seizure susceptibility.     

抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Brain monoamine levels and E1 mouse convulsions

E1 mice had higher levels of brain dopamine (DA) and serotonin (5-HT) and a lower level of brain norepinephrine (NE) compared with the other strains of inbred mice. In the interictal stage of "stimulated" E1 mouse, the brain DA, NE and 5-HT levels were significantly lower compared with the non-stimulated E1 mouse. The administration of 5-hydroxytryptophan with MK486 markedly depressed the incidence of seizures in the E1 mouse. Evidence of abnormal DA, NE and 5-HT metabolism was found at the development age when the seizures became frequent. These results show that 5-HT may be closely related to the E1 mouse seizure susceptibility.     

Bilateral augmentation of dopaminergic and serotonergic activity in the striatum and nucleus accumbens induced by conditioned circling

The involvement of dopaminergic (DA) and serotonergic (5-HT) systems in circling was assessed by determining the neurochemical correlates of circling induced and maintained by two different schedules of water reinforcement. The conditioned circling paradigm was employed in an attempt to replicate reports that levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were increased in the striatum and nucleus accumbens septi (NAS) contralateral to the direction of circling. Rats trained to circle using a continuous schedule of reinforcement did not exhibit any changes in concentrations of DA, DOPAC, or homovanillic acid (HVA). Bilateral increases in 5-HT concentrations were observed in the striatum. Use of an intermittent schedule of reinforcement (FR-2) produced higher rates of circling. In rats maintained on the FR-2 schedule, no changes in DA or its metabolites were observed in the striatum. The ratio of HVA to DA was, however, increased bilaterally, suggesting a bilateral augmentation of DA utilization. Concentrations of DA were lower in the NAS contralateral to direction of turning. While NAS levels of HVA were elevated bilaterally when compared to non-circling controls, HVA was lower in the NAS contralateral to the direction of circling. DA utilization, as estimated by HVA: DA ratios, was increased bilaterally in the NAS. None of the measures of DA activity within the olfactory tubercle (OT) were influenced by circling. Turnover of 5-HT, as estimated by the ratio of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA), was increased bilaterally in the striatum, NAS, and OT.(ABSTRACT TRUNCATED AT 250 WORDS)     

The biology of impulsivity and suicidality.

Abnormalities of 5-HT and noradrenergic functioning have been implicated in aggressive impulsivity, SIB, and suicidal behavior. The role of DA and GABA in human studies of these behaviors requires further investigation. Most studies suggest that impulsive aggression is related to lower levels of CNS 5-HT. Some studies demonstrate that increasing NE correlates to impulsive aggression, whereas other studies demonstrate an opposite relationship. The role of NE in impulsive aggressive behavior is still unclear. Self-injurious behavior is similar to impulsive aggression in that it seems to be mediated by the neurotransmitter systems previously mentioned. For example, the presence of lower levels of 5-HT and abnormalities in the DA system are related to SIB in patients with BPD and depression. SIB severity also seems to be influenced by neglect (e.g., severe isolation during rearing). As animal studies suggest, increasing the amount of isolation and an earlier onset of isolation increase the severity of SIB. Suicidal behaviors and the lethality of suicide attempts may also be linked to the abnormalities in neurotransmitter systems similar to those found in patients with impulsive aggression and SIB, namely, lowered 5-HT transmission and enhanced DA and NE functioning. Understanding the biological triggers of impulsive aggression or SIB may allow for the evaluation of suicidal attempts and completion from a different perspective and, in conjunction with genetic predictors, may eventually help with the early prediction and prevention of suicidal behaviors. Additional studies of live subjects and postmortem brains will assist in clarifying the neurobiology of suicidal behaviors that are common to many disorders and are clinically relevant to BPD.     

Accumbal dopamine and serotonin in anticipation of the next aggressive episode in rats

Autonomic and limbic neural activities are linked to aggressive behavior, and it is hypothesized that activities in the cardiovascular and monoaminergic systems play a role in preparing for an aggressive challenge. The objective was to learn about the emergence of monoamine activity in nucleus accumbens before an aggressive confrontation that was omitted at the regular time of occurrence, dissociating the motoric from the aminergic activity. Dopamine, serotonin, heart rate and behavioral activity were monitored before, during and after a single 10-min confrontation in resident male Long-Evans rats fitted with a microdialysis probe in the n. accumbens and with a telemetry sender (experiment 1). DA, but not 5-HT efflux, was confirmed to increase in n. accumbens during and after a single aggressive episode. In aggressive males that confronted an opponent daily for 10 days (experiment 2) heart rate rose 1 h before the regularly scheduled encounter relative to control rats, as measured on day 11 in the absence of any aggression. Concurrently, DA levels increased by 60-70% over baseline levels and 5-HT levels decreased by 30-35% compared to baseline levels. These changes were sustained over 1 h, and contrasted with no significant changes in DA, 5-HT, heart rate or behavioral activity in control rats. The rise in mesolimbic DA appears to be significant in anticipating the physiological and behavioral demands of an aggressive episode, and the fall in 5-HT in its termination, dissociated from the actual execution of the behavior.     

Effects of oral administration of chlordecone and mirex on brain biogenic amines in mice

Levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and the 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA) were determined in brains of mice after daily oral administration of 10, 25 or 50 mg/kg of chlordecone or mirex until mortality occurred. Significant decreases in whole brain and striatal DA levels were observed in chlordecone-treated mice exhibiting tremors. Mirex had no effect at the 3 doses tested. In mice treated with chlordecone or mirex, the 5-HT levels were elevated only in animals exhibiting severe tremors or diarrhea, respectively. NE levels were not altered by chlordecone or mirex. These results suggest that chlordecone-induced neurotoxicity may be due in part to a decrease in the inhibitory state of dopamine neurons.     

Effect of brain monoamine precursors on stress-induced behavioral and neurochemical changes in aged mice

Male CF-1 mice aged 22 months showed approximately the same level of motor activity and aggressive behavior as 3-month-old mice under control (no stress) conditions, or 45 min following cold swim stress. Increasing brain catecholamine activity by dietary l-tyrosine treatment had no effect on these two age groups either under control conditions or after stress. In contrast, 30-month-old mice showed lower motor activity under control conditions which was raised significantly by supplementation of the diet with l-tyrosine. However, marked reductions in activity and aggression following stress were observed in the 30-month-old animals and these deficits were not reversed by l-tyrosine treatment prior to stress. Reduction in motor activity was greatest in stressed, 30-month-old mice on l-tyrosine supplemented diets. Compared to 3-month-old mice, the 30-month-old animals had lower brain tyrosine following dietary l-tyrosine treatment, lower brain tryptophan, norepinephrine (NE), dopamine (DA) and DOPAC, but higher HVA, serotonin (5-HT) and 5-HIAA levels. Under both control (no stress) and stress conditions, l-tyrosine pretreatment decreased brain 5-HT in the young animals, but increased 5-HT in the old mice. After stress the 30-month-old animals evidenced only slight increases in levels of blood corticosterone. Brain tyrosine was reduced by stress in the young animals but increased by stress in the old animals. Stress-induced decreases in brain NE and increased in serotonin and 5-HIAA levels were observed in both age groups. These results are consistent with hypotheses concerning age-related alterations in brain monoamine functions and adrenocortical control mechanisms.     

Brain regional levels of neurotransmitter amines as neurochemical correlates of sex-specific ontogenesis in the rat.

Brain regional levels of three neurotransmitter amines - serotonin (5-HT), norepinephrine (NE), dopamine (DA) - were measured in young rats prior to weaning to determine the extent to which modifications in levels of amines might reflect alterations in the sex steroid hormonal environment during the first postnatal week in the life of the rat. Sex-related levels of DA, NE, and 5-HT were found in some brain regions of the 12-day-old rat. Male midbrain DA exceeded the corresponding female value while female hypothalamic NE levels were greater than those of the male. Levels of 5-HT in the corpus striatum and the midbrain of males were greater than those of the female. Castration of the male on day 1 or testosterone propionate (TP) administration to the newborn female resulted in modifications of levels of midbrain 5-HT which reflected feminization of the castrated males and masculinization of the TP-treated females. Castration on day 1, or diethylstilbestrol given on days 2, 4, and 6, resulted in apparent feminization of NE levels in the hypothalamus of 12-day-old male rats. Thus, it appears that regional levels of hypothalamic NE and midbrain 5-HT in the 12-day-old rat may reflect the course of brain organizational activity which becomes recognizable in the adult as sex-specific behavior.     

Neonatal isolation alters estrous cycle effects on ventral striatal extracellular monoamine levels

We demonstrated that neonatal isolation (ISO) enhances cocaine self-administration in male and female adult rats and alters ventral striatal extracellular levels of serotonin (5-HT) and dopamine (DA) basally or in response to psychostimulants in infant rats. Now, we examine basal 5-HT, DA, and norepinephrine (NE) levels in nucleus accumbens (NAc) using in vivo microdialysis in adult male and female rats with or without ISO experience. NAc shows estrous cycle-dependent effects as do behavioral responses to cocaine. Because our prior work showed ISO eliminated estrous-cycle effects on behavior, we now test separate groups of females in proestrus, estrus, or diestrus stages. Litters were assigned to the ISO (1-h isolation; postnatal days 2-9) or non-handled (NH) condition. During adulthood (postnatal day 70-90), microdialysis probes were implanted and aimed at NAc core. Ten samples were collected over 150-min and measures of 5-HT, DA, and NE were analyzed via HPLC. ISO did not affect 5-HT levels in males. However, ISO modified estrous stage effects on 5-HT. The pattern of 5-HT levels in NH females (higher in diestrus and proestrus vs. estrus) was reversed in ISO females. DA levels were unaffected by ISO, similar to our findings at other ages, and did not differ by gender or estrous stage. None of these factors affected NE levels. Because 5-HT modulates DA and levels of both transmitters are increased by cocaine, this neurochemical effect of ISO may contribute to the ability of ISO to alter the behavioral responses to cocaine as we showed previously.     

Effects of neonatal rat Borna disease virus (BDV) infection on the postnatal development of the brain monoaminergic systems

Effects of neonatal Borna disease virus infection (BDV) on the postnatal development of brain monoaminergic systems in rats were studied. Tissue content of norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenol acetic acid (DOPAC), and serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed by means of HPLC-EC in frontal cortex, cerebellum, hippocampus, hypothalamus and striatum of neonatally BDV-infected and sham-inoculated male Lewis rats of 8, 14, 21, 60 and 90 days of age. Both NE and 5-HT concentrations were significantly affected by neonatal BDV infection. The cortical and cerebellar levels of NE and 5-HT were significantly greater in BDV-infected rats than control animals at postnatal days (PND) 60 and 90. Tissue content of NE in hippocampus was unaffected. In hippocampus, neonatally BDV-infected rats had lower 5-HT levels at PND 8 and significantly elevated levels at PND 21 and onwards. Neither striatal levels of 5-HT nor hypothalamic levels of 5-HT and NE were affected by neonatal BDV infection, suggesting that the monoamine systems in the prenatally maturing brain regions are less sensitive to effects of neonatal viral infection. 5-HIAA/5-HT ratio was not altered in BDV-infected rats indicating no changes in the 5-HT turnover in the brain regions damaged by the virus. Neither DA nor DOPAC/DA ratio was affected by neonatal BDV infection in any of the brain regions examined. The present data demonstrate significant and specific alterations in monoaminergic systems in neonatally BDV-infected rats. This pattern of changes is consistent with the previously reported behavioral abnormalities resulting from neonatal BDV infection.     

Dopaminergic and serotonergic correlates of stimulation-induced circling

Rotation induced by electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus was associated with increases in dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum ipsilateral to the site of stimulation (i.e. contralateral to direction of turning). The concentrations of DA, DOPAC and HVA within the nucleus accumbens (NAS) were not altered. In the olfactory tubercle (OT), concentrations of DA and both metabolites were, in general, elevated ipsilateral to the electrode. However, relative to non-stimulated controls, HVA concentrations were increased bilaterally in rats exhibiting circling. Stimulation-induced circling also resulted in a bilateral enhancement of striatal serotonin (5-HT) metabolism as indicated by elevated 5-hydroxyindoleacetic acid: 5-HT ratios. No changes in 5-HT metabolism were observed in the NAS. The utilization of 5-HT was elevated in the OT ipsilateral to the electrode in rats that exhibited stimulation-induced rotation. While most subjects that exhibited contraversive rotation in response to the stimulation demonstrated enhanced DA activity, the neurochemical changes were not observed in all subjects. As such, it is concluded that while stimulation of the mesotelencephalic DA system can be associated with stimulation-induced rotation it is not necessary for its elicitation.     

Cellular mechanisms of acute estrogen negative feedback on LH secretion: norepinephrine, dopamine and 5-hydroxytryptamine metabolism in discrete regions of the rat brain

Rats on diestrous day 1 were ovariectomized (OVX) and killed 10 days later. LH was measured by RIA and the metabolism of NE, DA and 5-HT were assayed concurrently in the suprachiasmatic (SCN), medial preoptic (MPO), dorsomedial (DMN), rostral (ANr) and caudal (ANc) arcuate nuclei as well as the median eminence (ME) utilizing HPLC with electrochemical detection. Serum LH increased 10-12 fold 10 days following OVX compared to diestrous controls. The injection of estradiol benzoate (Eb, 20 micrograms in corn oil/rat, SC) did not affect LH concentrations at 30 minutes but decreased serum LH both 60 and 180 min following its administration. OVX caused an increased NE metabolism (estimated by the concentration of the NE metabolite, 3-methoxy-4-hydroxyphenylethylene glycol) in the SCN, MPO, ME, and DMN and a decreased NE metabolism in the ANc compared to diestrous control values. All of these changes were reversed or attenuated 180 minutes following Eb treatment. Observed changes in the DA and 5-HT neuronal systems were more restricted and less dramatic with the largest effects on DA metabolism occurring in the DMN and ME and the clearest changes in 5-HT metabolism occurring in the MPO, ANr, and ANc. The results demonstrate that the inhibition of LH secretion following the injection of Eb to OVX rats is accompanied by changes in metabolism in NE neurons in preoptic (SCN and MPO) and medial (ME, DMN, and ANc) hypothalamic areas, as well as in DA neurons in the DMN and ME, and in 5-HT neurons in the MPO, ANr, and ANc.     

Effects of dopamine and norepinephrine on neuronal activity of the olfactory tubercle

The effects of iontophoretic administration of norepinephrine (NE) and dopamine (DA) on olfactory tubercle (OT) neurons that respond to lateral hypothalamus (LH) or locus coeruleus (LC) electrical stimulation were studied. NE and DA decreased the frequency of OT neurons which were increased or decreased by the LH stimulation. An increased firing of OT neurons following NE or DA administration was less frequently observed. NE administration decreased the firing of OT neurons that responded to LC stimulation. These results suggest that the LC fibers which reach the OT use NE as a neurotransmitter. DA administration also suppressed the unitary discharge of OT neurons responding to LC stimulation. The increase in frequency of OT neurons observed following LH stimulation cannot be attributed to DA. The possibility that other suspected neural transmitters are involved in this effect is discussed.     

Effects of blinding and pinealectomy on regional brain monoamine concentrations

The effects of blinding with or without pineal ablation on brain monoamine levels were studied in male rats. Brain dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) were measured by radioenzymatic assays. Four weeks following pinealectomy, E levels were significantly enhanced in the frontal cortex. Chronic blinding decreased striatal DA levels and increased striatal 5-HT levels in both sham-operated and pinealectomized (Px) animals. In a second experiment Px animals were sacrificed 1 or 7 d after pinealectomy in order to examine the short-term effects of pinealectomy. There were no differences between controls and Px animals in their cortical levels of DA, NE, and E and their hippocampal and hypothalamic 5-HT levels. However, the E concentrations measured 1 d after surgery were significantly greater than after 7 d. The implications of these findings with regard to the reported role of the pineal and melatonin in brain homeostasis and endocrine regulation are discussed.     

Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain

Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.     

Concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism compared to Parkinson's disease patients

Summary The concentration of catecholamines and indoleamines in the cerebrospinal fluid of patients with vascular parkinsonism (VP) was compared to that in patients with Parkinson's disease (PD) and controls. Compared to the controls, the concentration of tyrosine was significantly higher, and the concentration of L-dopa and 3-O-methyldopa (3-OMD) was significantly lower in both VP and PD patients. The balance between the 3-OMD/L-dopa and dopamine (DA)/L-dopa ratios was changed in favor of 3-OMD/L-dopa in both VP patients and PD patients suggesting the preservation of a compensatory mechanism. All these changes were less marked in VP patients than in PD patients. A remarkable finding was that in contrast to PD patients the concentration of DA and norepinephrine (NE) was significantly higher in VP patients than in the controls. The decrease in the concentration of 5-hydroxytryptamine (5-HT) was significantly greater in VP patients than in PD patients. In PD patients, the concentration of DA, NE, and 5-HT showed significant correlation with the severity of motor symptoms. In VP patients, the concentration of 5-HT alone showed significant correlation with the severity of motor symptoms and cognitive dysfunction. These findings suggest that VP patients may have similar disturbances in the DA synthesis pathway as PD patients, but differ from PD patients in that the concentrations of DA and NE are elevated and the decrease in the 5-HT concentration is greater in VP patients.