Mapping of neurokinin-like immunoreactivity in the human brainstem

BACKGROUND: Using an indirect immunoperoxidase technique, we have studied the distribution of immunoreactive fibers and cell bodies containing neurokinin in the adult human brainstem with no prior history of neurological or psychiatric disease. RESULTS: Clusters of immunoreactive cell bodies and high densities of neurokinin-immunoreactive fibers were located in the periaqueductal gray, the dorsal motor nucleus of the vagus and in the reticular formation of the medulla, pons and mesencephalon. Moreover, immunoreactive cell bodies were found in the inferior colliculus, the raphe obscurus, the nucleus prepositus hypoglossi, and in the midline of the anterior medulla oblongata. In general, immunoreactive fibers containing neurokinin were observed throughout the whole brainstem. In addition to the nuclei mentioned above, the highest densities of such immunoreactive fibers were located in the spinal trigeminal nucleus, the lateral reticular nucleus, the nucleus of the solitary tract, the superior colliculus, the substantia nigra, the nucleus ambiguus, the gracile nucleus, the cuneate nucleus, the motor hypoglossal nucleus, the medial and superior vestibular nuclei, the nucleus prepositus hypoglossi and the interpeduncular nucleus. CONCLUSION: The widespread distribution of immunoreactive structures containing neurokinin in the human brainstem indicates that neurokinin might be involved in several physiological mechanisms, acting as a neurotransmitter and/or neuromodulator

Extrasynaptic Neurotransmission in the Modulation of Brain Function. Focus on the Striatal Neuronal–Glial Networks

Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular networks

Treadmill Exercise Buffers Behavioral Alterations Related to Ethanol Binge-Drinking in Adolescent Mice

The binge-drinking pattern of EtOH consumption, which is frequently observed in adolescents, is known to induce several neurobehavioral alterations, but protection strategies against these impairments remain scarcely explored. We aimed to study the protective role of treadmill physical exercise on the deficits caused after repeated cycles of binge-like EtOH exposure in the cognition, motivation, exploration, and emotion of C57BL/6J mice from adolescence to adulthood. Animals were divided into four groups: control group, exercised group, EtOH group, and exercised + EtOH group (20% in tap water). The exercise was performed for 20 min, 5 days/week at 20 cm/s. Then, animals were submitted to several behavioral tasks. Compared to binge-drinking mice, the exercised + EtOH group exhibited diminished anxiolytic-related behaviors in the elevated plus-maze, enhanced exploratory activity in the open field, reduced preference for alcohol odor when another rewarding stimulus was present (social stimulus) and lower latency to start self-cleaning behaviors in the sucrose splash test. In contrast, other measurements such as habituation learning and working memory were not improved by exercise. Besides, exercise was not able to reduce alcohol consumption across the weeks. In conclusion, physical activity during adolescence and early adulthood could buffer certain neurobehavioral alterations associated with binge-drinking, despite not reducing the quantity of consumed alcohol.This research was funded by the Spanish Ministry of Economy and Competitiveness (MINECO, Agencia Estatal de Investigación) cofounded by the European Research Development Fund (AEI/FEDER, UE-(PSI2017-82604-R), Consejeria de Salud y Familia Junta de Andalucía (PI-0083-2019), University of Malaga (Plan Propio 2017—‘Ayudas para proyectos dirigidos por jóvenes investigadores’ (PPIT.UMA.B1.2017/38). The author P.S-P holds a postdoctoral contract Juan de la Cierva-Incorporación (IJC2018-035935-I) from Ministry of Science.Ye

Diversity and Bias through Receptor–Receptor Interactions in GPCR Heteroreceptor Complexes. Focus on Examples from Dopamine D2 Receptor Heteromerization

Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Examples of dopamine D2R heteromerization are given to show how such allosteric mechanisms significantly change the receptor protomer repertoire leading to diversity and biased recognition and signaling. In 1980ies and 1990ies it was shown that neurotensin through selective antagonistic NTR-D2likeR interactions increased the diversity of DA signalling by reducing D2R mediated dopamine signalling over D1R mediated dopamine signalling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site towards neuromedin N vs neurotensin in the heteroreceptor complex. Complex CCK2R-D1R-D2R interactions in possible heteroreceptor complexes were also demonstrated further increasing receptor diversity. In D2R-5-HT2AR heteroreceptor complexes the hallucinogenic 5-HT2AR agonists LSD and DOI were recently found to exert a biased agonist action on the orthosteric site of the 5-HT2AR protomer leading to the development of an active conformational state different from the one produced by 5-HT. Furthermore, as recently demonstrated allosteric A2A-D2R receptor-receptor interaction brought about not only a reduced affinity of the D2R agonist binding site but also a biased modulation of the D2R protomer signalling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced which moved away from Gi/o signaling and instead favoured b-arrestin2 mediated signalling. These examples on allosteric receptor-receptor interactions obtained over several decades serve to illustrate the significant increase in diversity and biased recognition and signaling that develop through such mechanisms

Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal glial networks

Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular network

Receptor-Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment

Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A-FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A-5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1-15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1-GalR2-5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression

Understanding the balance and integration of volume and synaptic transmission. Relevance for psychiatry

The major difference of synaptic transmission vs volume transmission (VT) is about the channels which are private in synaptic transmission (axons and terminals) but diffuse in VT represented by the channel plexus of the extracellular space and the CSF. There exist different forms of VT: extrasynatic, long distance, CSF and roamer type VT, the last one mediated via microvesicles (extracellular vesicles). Interleukin-1b (IL-1b) may produce inflammation and sickness behavior via long distance and CSF VT. The balance and integration of VT and synaptic transmission through receptor–receptor interactions in heteroreceptor complexes appears crucial for CNS communication and of high relevance for psychiatric diseases like schizophrenia, depression, cocaine addiction and anxiety. The allosteric receptor–receptor mechanism causes a marked rise of the repertoire of GPCR recognition, pharmacology, trafficking and signaling of the participating receptor protomers. We have introduced the moonlighting concept into the GPCR heteromer field, since GPCR protomers can change their function through the allosteric receptor–receptor interactions. This is achieved through changes in recognition, G protein selectivity, and signaling via other proteins involving, e.g., a switch from G proteins to b-arrestin through conformationa

Understanding the balance and integration of volume and synaptic transmission. Relevance for psychiatry

The major difference of synaptic transmission vs volume transmission (VT) is about the channels which are private in synaptic transmission (axons and terminals) but diffuse in VT represented by the channel plexus of the extracellular space and the CSF. There exist different forms of VT: extrasynatic, long distance, CSF and roamer type VT, the last one mediated via microvesicles (extracellular vesicles). Interleukin-1b (IL-1b) may produce inflammation and sickness behavior via long distance and CSF VT. The balance and integration of VT and synaptic transmission through receptor\u2013receptor interactions in heteroreceptor complexes appears crucial for CNS communication and of high relevance for psychiatric diseases like schizophrenia, depression, cocaine addiction and anxiety. The allosteric receptor\u2013receptor mechanism causes a marked rise of the repertoire of GPCR recognition, pharmacology, trafficking and signaling of the participating receptor protomers. We have introduced the moonlighting concept into the GPCR heteromer field, since GPCR protomers can change their function through the allosteric receptor\u2013receptor interactions. This is achieved through changes in recognition, G protein selectivity, and signaling via other proteins involving, e.g., a switch from G proteins to b-arrestin through conformational changes in single or several strands of amino acids. It is of substantial interest to understand the role of altered receptor\u2013receptor interactions as a mechanism for how neuroinflammatory processes can contribute to mental dysfunctions. It is hypothesized that chemokine and cytokine receptors may directly form heteroreceptor complexes with neuronal receptors known to be dysfunctional in schizophrenia and targets for antipsychotic drugs. Based on the current bioinformatic analysis performed we can postulate that chemokine receptor CXCR4 may directly interact with GABAB2 and NR2A subunits of the NMDAR, chemokine receptor CCR2 with NMDAR, GABAB1 subunit and GABAAR and cytokine receptor IL1R2 with GABAB1 subunit and NMDAR, all known to be involved in schizophrenia. Through the allosteric receptor\u2013receptor interactions in such pathological heteroreceptor complexes the neuronal NMDA, GABAA and ABAB protomers may change their function (moonlighting) in neuronal networks of the brain. This process in neuroinflammation can contribute to positive, negative and/or cognitive symptoms of schizophrenia in line with the mild encephalitis hypothesis of schizophrenia. Neuroinflammation in schizophrenia may also disturb the integrative process of synaptic and volume transmission signals in glutamate synapses by altering kynurenines in the mammalian brain