Whole Brain Levels Of Dopamine Research Articles

Characterization of early communicative behavior in mouse models of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)-relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1.

Interaction between handling induced stress and anxiolytic effects of ethanol in zebrafish: A behavioral and neurochemical analysis

Stress is often considered an important factor in the development of alcohol addiction. In rodents, various types of stressors have been shown to potentiate the effects of alcohol on behavioral responses, and to increase consumption of this substance. However, few have investigated the interaction between stress and alcohol in zebrafish. In the current study we present a repeated handling stress paradigm we developed for zebrafish, and examine whether stress alters alcohol induced behavioral and neurochemical responses. Our results show that repeated handling of zebrafish conducted for 2 consecutive days is sufficient to increase anxiety-like behavioral responses quantified 24h post-stressor. Repeatedly handled zebrafish also exhibited a reduction in the levels of serotonin’s metabolite, 5-hydroxyindole acetic acid (quantified by high precision liquid chromatography) compared to unhandled controls. A 60-min acute exposure to 1% ethanol was found to significantly increase locomotor activity and decrease anxiety-like behavioral responses in stressed zebrafish but not in controls. Furthermore, unhandled control zebrafish exhibited a significant increase in whole-brain dopamine levels following exposure to ethanol but the increase was not observed in repeatedly handled fish. Our findings suggest that ethanol induced locomotor activity and anxiolysis is potentiated by handling stress and may be partially mediated by changes in dopaminergic and serotonergic activity. Overall, we demonstrate the validity of our repeated handling stressor paradigm for zebrafish, which can be used to investigate the interaction between stress and ethanol.

MK-801 increases locomotor activity in a context-dependent manner in zebrafish

Zebrafish have become a popular animal model for behavioral neuroscience with an increasing number of studies examining the effects of pharmacological compounds targeting the brain. Exposure to MK-801, a non-competitive N-methyl-d-aspartate receptor antagonist has been shown to increase locomotor activity in zebrafish. However, others have failed to replicate this finding as several contradicting studies report no changes in locomotor activity following exposure to similar doses. In the current study we reconcile these behavioral reports by demonstrating that zebrafish do not exhibit changes in locomotor activity during exposure to non-sedative doses of MK-801. Interestingly, zebrafish do exhibit significant increases in locomotion if pre-treated with MK-801 followed by subsequent testing in a novel environment, which suggests the effects of MK-801 are context-dependent. In addition, we examine the potential role of the dopaminergic system in mediating MK-801’s locomotor stimulant effect by quantifying the levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the brains of zebrafish following a 30min exposure to 10μM of MK-801 (the dose found to induce the largest increase in locomotor activity). Our findings indicate that the MK-801-induced increase in locomotor activity is not accompanied by changes in whole-brain levels of dopamine or DOPAC. Overall, our results suggest that MK-801's context-dependent locomotor stimulant effect may be independent of whole-brain dopaminergic activation.

Antidepressant-like effects in various mice strains in the forced swimming test

Strain differences in mice have been reported in response to drugs in the mouse forced swimming test (FST), even if few antidepressants were examined. The aim of the present study was to investigate the influence of genetic factors, using five antidepressants (imipramine, desipramine, citalopram, paroxetine and bupropion) in the mouse FST, in outbred strains (Swiss, NMRI) and inbred strains (DBA/2, C57BL/6J Rj). Moreover, whole brain levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) in vehicle treated animals, which were or were not subjected to the FST, were measured by HPLC analysis in an attempt to explain behavioural differences. For each antidepressant, a dose range (1-16 mg/kg) was tested in the locomotor apparatus and only non-psychostimulant doses were then tested in the FST in order to detect antidepressant-like activity. No baseline differences among Swiss, NMRI, DBA/2 and C57BL/6J Rj strains were observed in our experiments, allowing the comparison of different antidepressants in each strain. Imipramine (16 mg/kg), desipramine, citalopram (4-16 mg/kg) and paroxetine (8 and 16 mg/kg) treatment decreased the immobility time in the Swiss strain and the size of the effect reached more than 20% for each of these antidepressants. C57BL/6J Rj was the only strain sensitive to bupropion (2 and 4 mg/kg). In the NMRI strain, only paroxetine treatment decreased the immobility time (16 mg/kg). Our study showed that drug sensitivity is genotype dependent. FST results have shown that Swiss mice are the most sensitive strain to detect 5-HT and/or NA treatment. The use of DBA/2 inbred mice may be limited, as an absence of antidepressant-like response was observed in the FST. The lack of sensitivity to antidepressant treatment in DBA/2 strains could be due to high DA, NA and 5-HT whole brain concentrations.

Further insights into the molecular mechanisms of action of the serotonergic neurotoxin 5,7-dihydroxytryptamine.

Autoxidation and various enzyme-mediated oxidations of the serotonergic neurotoxin 5,7-dihydroxytryptamine (1) give 5-hydroxytryptamine-4,7-dione (2) and 6,6'-bi(5-hydroxytryptamine-4,7-dione) (3) as the major products. When administered into the ventricular system of mice 2 and 3 are general toxins. The LD50 values for 2 (29.6 +/- 0.04 micrograms) and 3 (25.4 +/- 0.30 micrograms) are lower than that for 1 (51.8 +/- 0.28 micrograms). In the presence of cellular reductants (glutathione, cysteine, ascorbate) and molecular oxygen, or when incubated with rat brain homogenate, 2 and 3 redox cycle and form superoxide radical anion, O2.-, as a byproduct. The lethal effects of 2 and 3 when introduced into the brain may in part be due to such redox cycling reactions which deplete oxygen levels and, as a result of Haber-Weiss chemistry deriving from O2.-, form the cytotoxic hydroxyl radical (HO.). Intraventricular administration of 2 and 3 to mice causes only relatively minor and transient (ca. 1 h to 1 day) changes in whole brain levels of dopamine, 5-hydroxytryptamine (from both 2 and 3), acetylcholine, and choline (from 2 only). These changes differ from the profound and long-lasting serotonergic deficit evoked by 1. On the basis of these results a hypothesis has been formulated which proposes that the selective neurotoxicity of 1 derives from its rapid uptake into serotonergic neurons where it is oxidatively converted to 2 and 3. Redox cycling reactions of 2 and 3 then result in the depletion of intraneuronal oxygen and concomitant formation of O2.-. Dismutation of O2.- gives H2O2 which, as a result of transition metal ion-catalyzed Haber-Weiss chemistry, yields HO.. Thus, neuronal damage and death might result from the combined effects of hypoxia and HO. formation.

Prenatal Effects of Acute Harmaline Exposure on Fetal Brain Biogenic Amine Metabolism

Harmaline, a known type A monoamine oxidase (MAO) inhibitor in adult brain of various species was found to elevate whole brain levels of dopamine and serotonin (5-HT) in rat fetuses of mothers injected 2-4 h before Caesarean delivery. Similar stimulatory effects were observed for the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG), however, no significant effect was obtained for norepinephrine. The dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA) were decreased with the same treatment. These results imply that harmaline or one of its metabolites may cross the placental barrier to affect the fetal brain system not merely as a type A MAO inhibitor (i.e., relatively 5-HT-specific), but possibly also as a stimulatory agent for aldehyde reductase or catechol-O-methyltransferase (COMT) or alternately as an agent inhibiting the conjugation, efflux, or turnover of biogenic amine metabolites such as MHPG.

The development of brain biogenic amines, cyclic nucleotides and hyperactivity in 6-OHDA-treated rat pups

Developmental changes in the behavior and brain biochemistry of rat pups were investigated in rats administered intracisternal injections of 6-hydroxydopamine (6-OHDA) or its vehicle at 5 days of age. Although pups of both groups were equivalent in their activity at 15 days of age, 6-OHDA-induced hyperactivity emerged at 20 and 30 days of age in a between-group design in which rats were only tested at one age. Body weightmeasurements revealed that 6-OHDA-treated rats were underweight at 15, 25 and 30 days of age. Furthermore, at 20 days of age, total activity was inversely related to body weights in the 6-OHDA-treated pups. Whole-brain levels of dopamine (DA) were decreased at very age by the 6-OHDA treatment, whereas norepinephrine (NE) levels were virtually unaffected by 6-OHDA at these same ages. Total activity was inversely correlated with whole-brain DA levels at 20 and 30 days of age when 6-OHDA-treated pups were hyperactive. Measures of cerebellar and “rest-of-brain” adenosine 3′,5′-monophosphate (cyclic AMP) and guanosine 3′,5′-monophosphate (cyclic GMP) were not uniformly altered by either the 6-OHDA treatment or by maturation. Results are discussed both in terms of brain biochemistry modulation of hyperactivity and the contribution of decreased body weights induced by 6-OHDA to the production of hyperactivity.

Gas chromatographic/mass spectrometric evidence for the identification of 6,7-dihydroxy-1, 2,3,4-tetrahydroisoquinoline as a normal constituent of rat brain: Its quantification and comparison to rat whole brain levels of dopamine

Gas chromatographic/mass spectrometric data are presented which demonstrate the presence of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (DHTIQ) as a normal constituent of rat brain. The level of DHTIQ was calculated to be 10.0 ± 3.0 mg/g wet weight (±S.D., N = 9) of brain tissue while the level of dopamine (DA) was measured as 1.22 ± 0.2+2 μg/g (N = 14). The ratio of DHTIQ:DA was thus observed to be approximately 1:100. The possible formation of DHTIQ in alcoholism and schizophrenia is discussed.

The effect of cyclo (Leu-Gly) on chemical denervation supersensitivity of dopamine receptors induced by intracerebroventricular injection of 6-hydroxydopamine in mice

Chemical denervation supersensitivity of postsynaptic dopamine receptors was induced in mice by intracerebroventricular injection of 6-hydroxydopamine. Fourteen days after the 6-hydroxydopamine injection, mice exhibited greater spontaneous locomotor activity and hypothermic response when challenged intraperitoneally with apomorphine. Whole brain levels of dopamine were reduced by 80%. Daily subcutaneous administration of cyclo (Leu-Gly) (50 μg/mouse/day) for 14 days inhibited the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine as evidenced by the blockade of an apomorphine induced locomotor and hypothermic effect. Cyclo (Leu-Gly) did not alter the depletion of brain dopamine induced by 6-hydroxydopamine. These data suggest that cyclo (Leu-Gly) can block the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine without protecting the neurons from dopamine depletion.

Differential tolerance to dietary amino acid-induced changes in aggressive behavior and locomotor activity in mice.

Male albino mice were maintained on a semisynthetic 12% casein protein diet for 2 weeks, then switched to diets modified by the addition of a 4% L-amino acid supplement (L-tyrosine, L-phenylalanine, and L-tryptophan) or 4% casein (control). Territorial=induced aggressive behavior increased following 1 week on the amino acid supplements, especially after tyrosine, but an apparent tolerance developed to these effects after 5 weeks on the amino acid supplements. Locomotor activity also increased following 1 week on the supplements, most notably after phenylalanine alone or in combination with tyrosine, and these effects tended to persist after 5 weeks on the supplements. Endogenous whole brain levels of dopamine, norepinephrine, serotonin, 5-hydroxyindoleacetic acid, tyrosine, phenylalanine, and tryptophan showed no tolerance to increased concentrations of brain catecholamines and indoleamines over the 5-week period, and no clear relation between the concentrations of these monoamines and the behavioral changes.

The prolonged exposure of Japanese quail to carbaryl and its effects on neurochemical and blood chemical parameters.

Whole-brain dopamine levels were significantly elevated in male Japanese quail fed 600 and 1200 ppm carbaryl in the diet for 14 weeks. Whole-brain AChE activity, whole-brain and heart norepinephrine levels, adrenal norepinephrine and epinephrine levels and plasma glucose levels were not altered by carbaryl. No effects were noted in the females.

Effect of α-methyl- p-tyrosine on the incidence of spontaneous convulsions observed following barbital withdrawal

Male Sprague-Dawley rats were made dependent on barbital by the administration of this drug in the drinking water following an established dosage regimen. Following abrupt barbital withdrawal, the incidence of convulsions was determined in barbital-dependent rats. Groups of these animals were treated with saline, 30, 60, 125 or 250 mg/kg α-methyl-para-tyrosine (αMPT) at the time of barbital withdrawal and a second time 16 hr later. A statistically significant (P < 0.01) dosage-related decrease in the incidence of withdrawal-related convulsions was observed in all of the αMPT-treated groups. Only the highest accumulative dosage of αMPT (500 mg/kg) produced any evidence of hypothermia. Pretreatment with the same dosages of αMPT did not affect pentylenetetrazol-induced convulsions indicating that αMPT in these concentrations possesses no general anticonvulsant properties. All of the dosages of αMPT utilized were capable of significantly decreasing whole brain levels of dopamine and noradrenaline, at least for a few hours. The results show that αMPT decreases the incidence of convulsions associated with barbital withdrawal and suggest that catecholamines may have a role in the manifestation of the barbiturate abstinence syndrome.

Biphasic nature of the effects of Δ9-tetrahydrocannabinol on body temperature and brain amines of the rat

The effect of i.v. injected Δ 9-tetrahydrocannabinol ( Δ 9-THC) on behaviour, body temperature and levels of brain monoamines, measured spectrophotofluorimetrically, of the rat were determined. Doses of Δ 9-THC in the range of 0.05–5.0 mg/kg produced biphasic changes in behaviour, body temperature and levels of 5-hydroxy-indoleacetic acid (5-HIAA). The whole brain levels of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were not altered by Δ 9-THC. The subjective behavioural biphasic responses did not appear to be dose related, whereas the biphasic changes in body temperature and brain levels of 5-HIAA were dose-related. Low dose of Δ 9-THC (0.05 and 0.1 mg/kg) caused hyperthermia, while doses of 1.0, 2.0 and 5.0 mg/kg induced hypothermia. On the other hand, 0.05 mg/kg Δ 9-THC significantly reduced, whereas doses of 1.0, 2.0 and 5.0 mg/kg significantly increased the 5-HIAA level in a dose-related manner. It is concluded that an inverse relationship exist between Δ 9-THC-induced changes in body temperature and alterations in brain 5-HIAA levels.

Testosterone manipulations: Effects on ranacide aggression and brain monoamines in the adult female rat

The effect of testosterone propionate on ranacide (frog-killing) behavior and brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) levels was determined in 40 female Wistar rats. Adult rats were screened for frog killing behavior on the basis of a single 30 min testing session. Aggressors were defined as animals which attacked or killed during this session while nonaggressors failed to do so. Using either aggressors or nonaggressors, testosterone and sesame oil equally aggressive behavior as measured in a second 30 min testing session. Biochemical analyses indicated that testosterone treated animals had significantly higher brain NE and NE/5-HT levels. Aggressors, testosterone or sesame treated had higher NE/5-HT ratios. Whole-brain levels of DA and 5-HT and the DA/5-HT ratios were unaffected. It is concluded that the elicitation of ranacide in the adult female rat is not androgen dependent nor is this behavior functionally related to the observed differences in brain noradrenergic/serotonergic levels. This study provides additional evidence that ranacide is a type of predatory aggression and yet presents data which may be at variance with the classic monoaminergic theory of aggressive behaviors.

Acute effects of 6-hydroxydopa and its interaction with dopa on brain amine levels

The intravenous administration of 400 mg/kg of DL-6-hydroxydopa (6-OH-DOPA) to mice markedly depleted whole brain norepinephrine (NE). Whole brain levels of dopamine (DA) were not affected whereas 5-hydroxytryptamine (5-HT) levels were slightly elevated. These findings show that even after a high dose of 6-OH-DOPA only brain NE appears to be markedly affected. This action might be mediated indirectly, through the endogenous formation of 6-hydroxydopamïne. DL-DOPA (DOPA), 400 mg/kg given intraperitoneally, failed to alter the whole brain level of NE, but depleted brain 5-HT while elevating brain DA. The increase in DA and reduction in 5-HT caused by DOPA were greatly potentiated by prior treatment with 6-OH-DOPA. Although the mechanism of this interaction is unknown, the enhanced effectiveness of DOPA following 6-OH-DOPA administration provides in vivo evidence that DOPA-induced depletion of 5-HT may be mediated by endogenously formed DA.