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The aim of this work was to evaluate whether oxytocin administered in male rats subcutaneously early in life in the absence or presence of food restriction during pregnancy has life-long effects on the α2-agonist binding sites in the nucleus of the solitarii tract (NTS), in the hypothalamus and the amygdala, as evaluated by quantitative receptor autoradiography. Maternal food restriction alone increased the affinity of the α2-agonist [3H]UK14.304 binding sites exclusively in the NTS. In offspring from ad libitum fed dams, oxytocin treatment significantly increased the density of α2-agonist binding sites in the NTS and in the hypothalamus. The Kd value of the α2-agonist binding sites in the hypothalamus of these rats, but not in the other regions studied, was also significantly increased. In offspring from food-restricted dams, oxytocin treatment produced a significant increase of the Bmax values in the hypothalamus and the amygdala and the Kd value of the α2-agonist binding sites in the NTS of these rats also was selectively and significantly increased. These results suggest that a postnatal, oxytocin-induced increase of regional α2-adrenoceptor function can be seen in adulthood by a persistent, regionally selective increase in the density of central α2-adrenoceptor agonist binding sites, in the absence of an affinity change in the NTS. Such a regional increase of α2-adrenoceptor signalling in adulthood may contribute to the anti-stress action of postnatal oxytocin. By contrast, after prenatal stress, the potential increase in α2-adrenoceptor signalling takes place via selective increases of density with no changes of affinity of the α2-agonist binding sites in the hypothalamus and the amygdala. [ABSTRACT FROM AUTHOR]

Abstract 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.

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.

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.

The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia.

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 1980s and 1990s, it was shown that neurotensin (NT) through selective antagonistic NTR-D2 like receptor interactions increased the diversity of DA signaling by reducing D2R-mediated dopamine signaling over D1R-mediated dopamine signaling. Furthermore, D2R protomer appeared to bias the specificity of the NTR orthosteric binding site toward neuromedin N vs. NT 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 signaling in A2A-D2R heteroreceptor complexes. A conformational state of the D2R was induced, which moved away from Gi/o signaling and instead favored β-arrestin2-mediated signaling. 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 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.

Oxytocin (OT) is a peptide involved in several physiological functions in the central nervous system including central cardiovascular regulation. To clarify the role of endogenous OT in cardiovascular control, one group of anesthetized rats received unilateral microinjections of the OT receptor antagonist [d(CH(2))(5),Tyr(Me)(2),Orn(8)]-vasotocin (OTA) in the nucleus tractus solitarii (NTS) and a second group was injected with specific OT antiserum (Anti-OT). Moreover, the modulation of the cardiovascular effect of L-glutamate (GLU) by OT was also evaluated by cardiovascular analysis using effective and threshold doses of GLU. Mean arterial pressure (MAP) and heart rate (HR) were measured from a femoral catheter. OTA significantly (p<0.01) decreased the vasopressor and tachycardiac long-lasting response elicited by an effective dose of OT. Microinjections of Anti-OT antibody did not modify the values of MAP and HR compared with the control group. With regard to the OT/GLU coinjections, a subthreshold dose of OT significantly (p<0.001) counteracted the vasodepressor and bradycardiac responses induced by GLU. The coinjection of subthreshold doses of OT and GLU did not produce a change in MAP or in HR. These findings seem to exclude an endogenous tonic action of OT on central regulation of MAP and HR, although they confirm the significant role of OT on central cardiovascular control within the NTS. In fact, the modulation of GLU responses by OT supports the importance of OT on the central cardiovascular adjustments likely acting on the baroreceptor reflex sensitivity.

After Golgi-Cajal mapped neural circuits, the discovery and mapping of the central monoamine neurons opened up for a new understanding of interneuronal communication by indicating that another form of communication exists. For instance, it was found that dopamine may be released as a prolactin inhibitory factor from the median eminence, indicating an alternative mode of dopamine communication in the brain. Subsequently, the analysis of the locus coeruleus noradrenaline neurons demonstrated a novel type of lower brainstem neuron that monosynaptically and globally innervated the entire CNS. Furthermore, the ascending raphe serotonin neuron systems were found to globally innervate the forebrain with few synapses, and where deficits in serotonergic function appeared to play a major role in depression. We propose that serotonin reuptake inhibitors may produce antidepressant effects through increasing serotonergic neurotrophism in serotonin nerve cells and their targets by transactivation of receptor tyrosine kinases (RTK), involving direct or indirect receptor/RTK interactions. Early chemical neuroanatomical work on the monoamine neurons, involving primitive nervous systems and analysis of peptide neurons, indicated the existence of alternative modes of communication apart from synaptic transmission. In 1986, Agnati and Fuxe introduced the theory of two main types of intercellular communication in the brain: wiring and volume transmission (WT and VT). Synchronization of phasic activity in the monoamine cell clusters through electrotonic coupling and synaptic transmission (WT) enables optimal VT of monoamines in the target regions. Experimental work suggests an integration of WT and VT signals via receptor-receptor interactions, and a new theory of receptor-connexin interactions in electrical and mixed synapses is introduced. Consequently, a new model of brain function must be built, in which communication includes both WT and VT and receptor-receptor interactions in the integration of signals. This will lead to the unified execution of information handling and trophism for optimal brain function and survival.

Previously we reported that basal neuropeptide Y (NPY)-like immunoreactivity-(LI) in hippocampus of the "depressed" Flinders Sensitive Line (FSL) rats was lower compared to the control Flinders Resistant Line (FRL) and that electroconvulsive stimuli (ECS) raise NPY-LI in discrete brain regions. Here we studied NPY mRNA expression, NPY Y(1) receptor (Y(1)) mRNA expression and binding sites, and behavior under basal conditions (Sham) and after repeated ECS. Baseline NPY and Y(1) mRNAs in the CA1-2 regions and dentate gyrus were lower while the Y(1) binding was higher in the FSL. ECS had larger effects on both NPY and behavior in the FSL rats. ECS increased NPY mRNA in the CA1-2, dentate gyrus and hypothalamus in FSL, but only in the dentate gyrus in FRL. ECS also increased Y(1) mRNA in the CA1-2, dentate gyrus and the parietal cortex in both strains, while in the hypothalamus the increase was observed only in the FSL rats. Consistently with Y(1) mRNA increase, Y(1) binding was downregulated in the corresponding regions. ECS decreased FSL immobility in the Porsolt swim test. These findings suggest that NPY is involved in depressive disorder and that antidepressant effects of ECS may in part be mediated through NPY.

Oxytocin induces long-term changes in, for example, blood pressure, spontaneous motor activity and corticosterone levels in rats. Previous studies in male rats have suggested a role for alpha(2)-adrenoceptors within the central nervous system in these effects. The aim of the present study was to investigate if oxytocin treatment in female rats would influence alpha(2)-adrenoceptors within the hypothalamus, the amygdala and the nucleus of the solitary tract (NTS). For this purpose, female ovariectomized (OVX) rats were treated with oxytocin (1 mg/kg s.c.) or saline once a day for 10 days. Rats were decapitated 5 days after the last injection, and brains and plasma were collected. Quantitative receptor autoradiography for characterization of high affinity alpha(2)-adrenoceptor agonist binding and radioimmunoassay for corticosterone were performed. Oxytocin increased the B(max) values of the alpha(2)-adrenoceptor agonist [3H]UK14.304 binding sites significantly in all the analyzed areas (P<0.05). K(d) values were unchanged. Plasma levels of corticosterone were significantly decreased in the oxytocin-treated rats (P<0.05). These findings are in further support of an interaction between oxytocin receptors and alpha(2)-adrenoceptors and show that oxytocin treatment may increase alpha(2)-adrenoceptor recognition probably leading to an increase in alpha(2)-adrenoceptor signaling in several parts of the brain.

Galanin given i.c.v. increased the K(D) values of 5-HT1A receptors in the DR by 100% 10 min after administration. This effect had disappeared 2 h and 5 h after galanin administration. In contrast, i.c.v. galanin caused a 40% increase in the Bmax values at 2 h without affecting the Bmax values 10 min and 5 h after i.c.v. galanin. The mRNA levels of 5-HT1A receptors and of galanin in the DR were significantly decreased by 33% and 56% respectively 2h but not 5h after i.c.v. galanin. These results suggest that in vivo galanin can modulate somatodendritic 5-HT1A receptors in the DR in a time-dependent manner via galanin-5-HT1A receptor interactions. The findings implicate a potential role of galanin in affective disorders.