Microdialysis was used to assess extracellular dopamine in striatum, nucleus accumbens, and medial frontal cortex of unanesthetized rats both under resting conditions and in response to intermittent tail-shock stress. The dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid also were measured. The resting extracellular concentration of dopamine was estimated to be approximately 10 nM in striatum, 11 nM in nucleus accumbens, and 3 nM in medial frontal cortex. In contrast, the resting extracellular levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were in the low micromolar range. Intermittent tail-shock stress increased extracellular dopamine relative to baseline by 25% in striatum, 39% in nucleus accumbens, and 95% in medial frontal cortex. 3,4-Dihydroxyphenylacetic acid and homovanillic acid also were generally increased by stress, although there was a great deal of variability in these responses. These data provide direct in vivo evidence for the global activation of dopaminergic systems by stress and support the concept that there exist regional variations in the regulation of dopamine release.

Differential Effect of Stress on In Vivo Dopamine Release in Striatum, Nucleus Accumbens, and Medial Frontal Cortex

Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been suspected based on observations from clinical, neuropsychological and neuroimaging studies. Since the PFC receives a dense dopaminergic innervation, abnormalities of the mesocortical dopamine system have been proposed to contribute to the pathophysiology of schizophrenia. In this review, aspects of the anatomy, physiology and pharmacology of the mesencephalic-frontal cortical dopamine system as they may relate to schizophrenia are described, and evidence for altered dopaminergic neurotransmission in the frontal cortex of schizophrenic patients is presented.

Dopamine, the prefrontal cortex and schizophrenia:

Extracellular single-cell recording and microiontophoretic techniques were used to characterize the effects of cocaine on the activity of mesoaccumbens A10 dopamine (DA) neurons in the rat ventral tegmental area (VTA), which have been implicated in the rewarding effects of this and other drugs of abuse. Because cocaine inhibits the reuptake of DA, norepinephrine (NE), and serotonin (5-HT), and exerts local anesthetic actions, the possible involvement of each of these various mechanisms in the effects of cocaine on A10 DA neurons was investigated. Intravenous administration of cocaine caused a significant, dose- dependent, partial inhibition (50–70%) of the firing of antidromically identified mesoaccumbens DA neurons. Similar partial inhibition of A10 neurons was observed following intravenous administration of nomifensine, GBR-12909, and norcocaine, all of which inhibit DA reuptake. Neither the selective 5-HT uptake inhibitor fluoxetine nor the selective NE uptake inhibitor desmethylimipramine (DMI) inhibited the firing of A10 DA neurons. The local anesthetic agent procaine, which lacks DA uptake blocking efficacy, caused a slight, transient increase in firing rate. These results suggest that the effects of cocaine on A10 DA neurons are due to inhibition of DA reuptake, a conclusion that has been supported by several other findings. Pretreatment with reserpine to deplete vesicular stores of DA significantly reduced the ability of intravenous cocaine to suppress A10 DA neuronal activity. Microiontophoretic administration of cocaine caused only a weak (15–20%) inhibition of the activity of A10 DA neurons, but significantly increased and prolonged the inhibition produced by iontophoretic DA. This effect was not observed with iontophoretically administered procaine iontophoresis of cocaine also significantly potentiated the inhibition of A10 DA activity caused by electrical stimulation of the nucleus accumbens (NAc). Both unilateral ibotenic acid lesions of the NAc and hemitransections of the brain rostral to the VTA significantly reduced the inhibitory effects of intravenous cocaine on A10 DA neurons, suggesting that both somatodendritic impulse-regulating DA autoreceptors and inhibitory NAc- VTA feedback processes are involved in the effects of intravenous cocaine on A10 DA neurons. Therefore, it is hypothesized that the relatively weak inhibitory effects of cocaine on A10 DA neurons may represent a poor compensatory response to enhanced DA neurotransmission within the NAc, and may help to explain the extremely potent rewarding effects of this important drug of abuse.

https://www.jneurosci.org/content/jneuro/8/1/100.full.pdf

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area.

Intracerebral dialysis was used with a specifically designed HPLC with electrochemical detection assay to monitor extracellular levels of endogenous 3,4-dihydroxyphenylethylamine (dopamine, DA) and its major metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in brain regions of the halothane-anesthetized rat. Significant amounts of DA, DOPAC, and HVA were detected in control perfusates collected from striatum and n. accumbens whereas the medial prefrontal cortex showed lower monoamine levels. The ratio of DA in perfusate to DA in whole tissue suggests that in f. cortex, compared to n. accumbens and striatum, there is a greater amount of DA in the extracellular space relative to the intraneuronal DA content. The DOPAC/HVA ratio in control perfusates varied between regions in accordance with whole tissue measurements. This ratio was highest in n. accumbens and lowest in f. cortex. The monoamine oxidase inhibitor pargyline (100 mg/kg i.p.) caused an exponential decline in DOPAC, but not of HVA, in regional perfusates, an effect that was associated with an increase in DA. The data indicated a higher turnover of extracellular DOPAC in n. accumbens than in striatum and the lowest DOPAC turnover in f. cortex. The rate of decline in extracellular DA metabolite levels was slow compared to whole tissue measurements. In the perfusates there was no statistical correlation between basal amounts of DA in the perfusates and DOPAC and HVA levels or DOPAC turnover for any of the areas, indicating that measurement of DA metabolism in the brain under basal conditions does not provide a good index of DA release. In summary, this study shows clear regional differences in basal DA release and metabolite levels, metabolite patterns, and DOPAC turnover rates in rat brain in vivo.

An in vivo study of dopamine release and metabolism in rat brain regions using intracerebral dialysis.

Despite its serious limitations, measuring the concentrations of homovanillic acid (HVA) in body fluids is perhaps the most direct method currently available to assess the changing activity of central dopamine (DA) neurons in living humans. The concentrations of HVA in body fluids are determined not only by the activity of central DA neurons but also by a number of unrelated factors such as the other sources of HVA and the elimination of HVA from the body. This article reviews many factors that help to determine the concentrations of HVA in body fluids and therefore must be considered in studies employing HVA as a possible index of central DA neuronal activity. The need for further methodological work is indicated to improve the use of body fluid HVA measurements in clinical research.

Homovanillic Acid Measurement in Clinical Research: A Review of Methodology

The synthesis rate of dopamine and noradrenaline in different parts of the rat brain was estimated by measuring the accumulation of DOPA following decarboxylase inhibition. Although the synthesis of dopamine was enhanced in all regions by haloperidol and gammabutyrolactone, it was increased to almost 400% of the control in the corpus striatum but to only somewhat more than 200% in the olfactory tubercle and some other limbic regions. The dopamine autoreceptor agonist B-HT 920 was more potent and effective in lowering the synthesis of dopamine in the limbic regions than in the corpus striatum. These differences between the extrastriatal and striatal brain areas in the pharmacological responses might be explained by a 50% higher normal synthesis rate constant of the dopamine in the limbic system than in the corpus striatum. The lower dopamine synthesis rate in the latter region may be due to a negative neuronal feedback from the corpus striatum to the substantia nigra. Functional studies support this proposal. Indeed, B-HT 920 was less effective than haloperidol in changing the direction of head turning of rats with a diencephalic hemisection at doses equieffective in reducing the motor activity. The findings indicate that B-HT 920 is relatively more potent than haloperidol in inhibiting the dopamine neurotransmission in the limbic system than in the corpus striatum.

Synthesis rate of dopamine: difference between corpus striatum and limbic system as a possible explanation of variations in reactions to drugs.

A spectrofluorimetric method for determination ofγ-aminobutyric acid (GABA) in tissues is described. The GABA was extracted with perchloric acid, purified on a strong cation exchange column and converted to a fluorophor witho-phthalaldehyde andβ-mercaptoethanol at a high pH. Data on recovery, reproducibility, specificity and sensitivity are reported. The concentration of GABA in different parts of the normal rat brain is presented.

A fluorimetric method for determination of GABA in tissues following cation exchange chromatography and condensation witho-phthalaldehyde

The contents of dopamine, noradrenaline and their deaminated metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethylene glycol (DOPEG) were determined in rats in two noradrenaline cell body regions, ie, the superior cervical ganglion and the locus coeruleus, and in one dopamine cell body region, the substantia nigra In the two noradrenaline cell body regions, the tyrosine hydroxylase inhibitor alpha-methyltyrosine rapidly lowered the contents of noradrenaline and DOPEG and it lowered the contents of dopamine and DOPAC even more rapidly The dopamine-beta-hydroxylase inhibitor FLA-63 swiftly elevated the content of dopamine and it lowered the content of noradrenaline in the two noradrenaline regions, but it was ineffective in the substantia nigra The monoamine oxidase inhibitor pargyline rapidly reduced the deaminated catechols and increased somewhat the contents of the two amines in the superior cervical ganglion and in the locus coeruleus The alpha-methyltyrosine-induced disappearance of dopamine in the two noradrenaline cell body regions was markedly inhibited by FLA-63 and pargyline in combination, but not by only one of the two drugs The results indicate that most of the dopamine in the superior cervical ganglion and in the locus coeruleus occurs in the cell body region of noradrenaline neurons, whereas only a minor part of the dopamine in the superior cervical ganglion is present in SIF cells Axonal transport did not contribute to the disappearance of dopamine in the superior cervical ganglion A high dose of reserpine reduced the contents of dopamine and noradrenaline in the superior cervical ganglion and in the locus coeruleus, indicating that most of the amines is present in storage granules(ABSTRACT TRUNCATED AT 250 WORDS)

Very rapid turnover of dopamine in noradrenaline cell body regions.

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Synthesis rate of dopamine: difference between corpus striatum and limbic system as a possible explanation of variations in reactions to drugs.

A fluorimetric method for determination of GABA in tissues following cation exchange chromatography and condensation witho-phthalaldehyde

Very rapid turnover of dopamine in noradrenaline cell body regions.