According to the literature, the cerebrospinal fluid (CSF) in the cerebral ventricles contains numerous neuron-derived physiologically active substances that can function as neurohormones and contribute to volume neurotransmission in the periventricular region of the brain. This study was aimed at carrying out a comparative analysis of CSF and the blood levels of monoamines in rats during ontogenesis as an indicator of age-related characteristics of monoamine transport to body fluids and their function as neurohormones in volume neurotransmission in the periventricular region of the brain. We have shown that CSF in the perinatal period and adulthood contains the most functionally significant monoamines: dopamine, noradrenaline, and serotonin. A comparison of the monoamine levels in the CSF and blood of animals of different age groups revealed that CSF contains monoamines of predominantly neuronal (cerebral) origin and almost no monoamines derived from the general circulation. We also established that monoamines are found in the CSF at physiologically active levels that allow them to act as neurohormones in both reversible volume neurotransmission in the adult brain and irreversible regulation of brain development in the perinatal period.

Since the 1980s, the concept of dopamine-rich brain centers as clusters of only dopaminergic neurons has been fundamentally revised. It has been shown that, in addition to dopaminergic neurons, most of these centers contain neurons expressing one of the enzymes of dopamine synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). We have obtained convincing evidence that in rats, the hypothalamic periventricular nucleus (PeVN) is one of the largest dopamine-rich centers, containing dopaminergic and monoenzymatic neurons. Indeed, using double immunostaining for TH and AADC, the PeVN was shown to contain almost three thousand dopaminergic and monoenzymatic neurons. According to high-performance liquid chromatography, PeVN contains L-DOPA and dopamine, which, apparently, are synthesized in monoenzymatic TH neurons and bienzymatic neurons, respectively. According to confocal microscopy, neurons (cell bodies, fibers), which were immunopositive only to TH, only to AADC, or both, are in close topographic relationships with each other and with the 3rd ventricle. These data suggest the mutual regulation of the neurons, as well as the delivery of dopamine and L-DOPA to the third ventricle, which is confirmed by their detection in the cerebrospinal fluid. Thus, evidence has been obtained that PeVN is one of the largest dopamine-rich centers of the brain, containing dopaminergic and monoenzymatic neurons.

Since the discovery of striatal neurons expressing dopamine-synthesizing enzymes, researchers have attempted to identify their phenotype and functional significance. In this study, it was shown that in transgenic mice expressing green fluorescent protein (GFP) under the tyrosine hydroxylase (TH) gene promoter, (i) there are striatal neurons expressing only TH, only aromatic L-amino acid decarboxylase (AADC), or both enzymes of dopamine synthesis; (ii) striatal neurons expressing dopamine-synthesizing enzymes are not dopaminergic since they lack a dopamine transporter; (iii) monoenzymatic neurons expressing individual complementary dopamine-synthesizing enzymes produce this neurotransmitter in cooperation; (iv) striatal nerve fibers containing only TH, only AADC, or both enzymes project into the lateral ventricles, providing delivery pathways for L-3,4-dihydroxyphenylalanine and dopamine to the cerebrospinal fluid; and (v) striatal GFP neurons express receptor genes for various signaling molecules, i.e., classical neurotransmitters, neuropeptides, and steroids, indicating fine regulation of these neurons. Based on our data, it is assumed that the synthesis of dopamine by striatal neurons is a compensatory response to the death of nigral dopaminergic neurons in Parkinson’s disease, which opens broad prospects for the development of a fundamentally novel antiparkinsonian therapy.

We have recently shown that the periventricular nucleus (PeVN) of adult rats is a “mixed dopaminergic (DAergic) center” containing three thousand neurons: DAergic neurons and those expressing one of the dopamine (DA)-synthesizing enzymes. This study aims to evaluate the development of the PeVN as a mixed DAergic center in rats in the perinatal period, critical for brain morphogenesis. During this period, the PeVN contains DAergic neurons and monoenzymatic neurons expressing individual enzymes of DA synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). In the perinatal period, the total number of such neurons triples, mainly due to monoenzymatic neurons; the content of L-DOPA, the end product of monoenzymatic TH neurons, doubles; and the content of DA, the end product of monoenzymatic AADC neurons and DAergic neurons, increases sixfold. Confocal microscopy has shown that, in the PeVN, all types of neurons and their processes are in close relationships, which suggests their mutual regulation by L-DOPA and DA. In addition, monoenzymatic and DAergic fibers are close to the third cerebral ventricle, located in the subependymal zone, between ependymal cells and in the supraependymal zone. These observations suggest that these fibers deliver L-DOPA and DA to the cerebrospinal fluid, participating in the neuroendocrine regulation of the brain.

Parkinson’s disease (PD) is diagnosed by the onset of motor symptoms and treated long after its onset. Therefore, the development of the early diagnosis of PD is a priority for neurology. Advanced methodologies for this include (1) searching for patients at risk of developing prodromal PD based on premotor symptoms; (2) searching for changes in the body fluids in these patients as diagnostic biomarkers; (3) verifying the diagnosis of prodromal PD and diagnostic-value biomarkers using positron emission tomography (PET); (4) anticipating the development of motor symptoms. According to our data, the majority of patients (n = 14) at risk of developing PD selected in our previous study show pronounced interhemispheric asymmetry in the incorporation of 18F-DOPA into dopamine synthesis in the striatum. This was assessed for the caudate nucleus and putamen separately using the specific binding coefficient, asymmetry index, and putamen/caudate nucleus ratio. Interhemispheric asymmetry in the incorporation of 18F-DOPA into the striatum provides strong evidence for its dopaminergic denervation and the diagnostic value of previously identified blood biomarkers. Of the 17 patients at risk of developing prodromal PD studied using PET, 3 patients developed motor symptoms within a year. Thus, our study shows the promise of using the described methodology for the development of early diagnosis of PD.