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The concept of allosteric receptor–receptor interactions in G protein-coupled receptor homo- and heteroreceptor complexes in which they physically interact provides a new dimension to molecular integration in the brain. The receptor–receptor interactions dynamically change recognition, pharmacology, signaling, and trafficking of the participating receptors. Among the receptor complexes, disruption of the A2A receptor–dopamine D2 receptor (A2AR-D2R) complex by an A2AR agonist has been shown to fully block the inhibition of cocaine self-administration. Cocaine induced pathological A2AR-D2R-Sigma1R complexes may form a long-term memory with a strong and permanent D2R brake, leading to cocaine addiction. These heteroreceptor complexes can potentially be targeted for future pharmacotherapy of cocaine addiction by using heterobivalent compounds or A2AR-D2R receptor interface-interfering peptides that disrupt the A2AR-D2R-Sigma1R complexes. Highlights Cocaine can induce pathological A2AR-D2R-Sigma1R complexes in nucleus accumbens. These A2AR-D2R-Sigma1R complexes can put a brake on D2R signaling. These pathological A2AR-D2R-Sigma1R complexes are proposed to produce cocaine addiction. Future pharmacotherapy should target accumbal pathological A2AR-D2R-Sigma1R complexes by using interface-interfering peptides and heterobivalent compounds. [ABSTRACT FROM AUTHOR]

Galanin is a 29 amino acid neuropeptide widely distributed in neurons within the central nervous system. Galanin exerts its biological activities through three different G protein-receptors and participates in a number of functions, including mood regulation. Not only Galanin but also Galanin N-terminal fragments like Galanin(1–15) are active at the central level. In this work, we review the latest findings in studies on Galanin and Galanin(1–15) in depression-related behaviours. Our focus is on animal models for depression, and we pay some attention to research data obtained in human studies. Since Serotonin (5-HT), especially through 5-HT1A, and Galanin receptors interact at both pre-and postsynaptic level, the development of drugs targeting potential GAL 1 -GAL 2 -5-HT1A heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons may represent new treatment strategies in depression. [ABSTRACT FROM AUTHOR]

The D2R is a hub receptor interacting with a large number of other GPCRs. A2AR activation of the antagonistic A2AR–D2R interaction not only leads to inhibition of the Gi/o signaling but also to an increase in β-arrestin2 signaling over the D2R protomer. Hallucinogenic 5-HT2AR agonists can produce a biased agonist state at the 5-HT2AR protomer of D2R–5-HT2AR heteroreceptor complexes with increased D2R recognition and Gi/o mediated signaling. Allosteric receptor–receptor interactions in D2-NTR1 heteroreceptor complexes inhibit D2R function and can switch G protein coupling. These large numbers of D2R heterocomplexes and their allosteric receptor–receptor interactions produce a marked increase in diversity and bias of the participating D2R protomers opening a promised land for drug development in schizophrenia, addiction and Parkinson's disease. [ABSTRACT FROM AUTHOR]

Ethylene glycol ethers (EGEs) are compounds widely used in many branches of industry. Their toxicological profile in the peripheral tissues is relatively well described, but little is known about their action on the central nervous system (CNS). In this study, we evaluated the effect of 2-ethoxyethanol (EE), 2-butoxyethanol (BE), 2-phenoxyethanol (PHE) and their metabolites on necrotic (estimated by cell viability and lactate dehydrogenase release) and apoptotic (caspase-3 activity and mitochondrial membrane potential) processes and reactive oxygen species' (ROS) production in human neuroblastoma (SH-SY5Y) cells. We have shown that, similar to the peripheral tissues, EGE metabolites in most of the performed assays revealed greater potential to damage than the parent compounds in the CNS cells. Subsequently, we investigated the participation of some selected protein kinases in the degenerative activity of PHE and its main metabolite, phenoxyacetic acid (PHA). It has been found that a GSK3β inhibitor weakened the damaging effects of PHE and PHA in each of the performed assays. Furthermore, the kinases, p38-MAPK, JNK-MAPK and PKC, had a significant role in the cytotoxic and proapoptotic effects of PHA. These results indicate that the neurotoxic effect of EGEs may stem from their impact on many intracellular signal transduction pathways. [ABSTRACT FROM AUTHOR]

Abstract: This article is focused on understanding the mechanisms for the interactions between the central catecholamine (CA) and oxytocin (OXY) neurons and their relevance for brain function especially social behaviour in the field of pair bonding. Such a topic is analysed under two perspectives namely the intercellular communication modes between CA and OXT neurons and the molecular integrative mechanisms at the plasma membrane level between their respective decoding systems. As a matter of fact, recent observations strongly indicate a major role of volume transmission and receptor–receptor interactions in the CA/OXT neuron interplay in the brain control of social behaviour and pair bonding. This article is part of a Special Issue entitled: Brain Integration. [Copyright &y& Elsevier]

Abstract: The distribution of orexinergic cell bodies and terminal networks within the brains of two species of African mole rat (Cape-dune mole rat –Bathyergus suillus and highveld mole rat –Cryptomys hottentotus) were identified using immunohistochemistry for orexin-A. The aim of the study was to investigate possible differences in the nuclear complement and terminal distribution of this system by comparing those of the mole rats to published studies of other rodents and mammals. The wild-caught mole rats used in this study live a subterranean lifestyle and are well known for their regressed visual system, which may lead to the prediction of differences in the distribution of the cell bodies and the terminal networks; however, we found that both species of mole rat displayed orexinergic nuclei limited to the hypothalamus in regions similar to those previously reported for other rodent and mammalian species. No immunoreactive neurons could be identified, in either species of mole rat within the anterior hypothalamic paraventricular nucleus, as has been reported for Murid rodents. The terminal networks, while remaining similar between the species, are more strongly expressed in the Cape-dune mole rat than in the highveld mole rat. [Copyright &y& Elsevier]

Abstract: The dawn of chemical neuroanatomy in the CNS came with the discovery and mapping of the central dopamine, noradrenaline and 5-hydroxytryptamine neurons by means of transmitter histochemistry using the Falck–Hillarp formaldehyde fluorescence technique in the early 1960s. Our mapping of the central monoamine neurons was continued and further established with tyrosine hydroxylase, dopa decarboxylase and dopamine-beta-hydroxylase immunohistochemistry in collaboration with Menek Goldstein and Tomas Hökfelt. During recent years an evolutionary constraint in the nuclear parcellation of the DA, NA and 5-HT neurons was demonstrated in the order Rodentia and other mammals. The abundant existence of global monoamine varicose nerve terminal networks synthesizing, storing and releasing monoamines in various parts of the CNS, including the release of DA by tubero-infundibular DA neurons as a prolactin inhibitory factor from the external layer of the median eminence into the portal vessels and the appearance of extraneuronal DA fluorescence after, e.g., treatment with amphetamine in nialamide pretreated rats (Falck–Hillarp technique) were also remarkable observations. These observations and others like the discovery of transmitter–receptor mismatches opened up the possibility that monoamines were modulating the wired brain, built up mainly by glutamate and GABA neurons, through diffusion and flow in the extracellular fluid of the extracellular space and in the CSF. This transmission also involved long-distance channels along myelinated fibers and blood vessels and was called volume transmission (VT). The extracellular space (ECS), filled with a 3D matrix, plays a fundamental role in this communication. Energy gradients for signal migration in the ECS are produced via concentration, temperature and pressure gradients, the latter two allowing a flow of the ECF and CSF carrying the VT signals. The differential properties of the wiring transmission (WT) and VT circuits and communication channels will be discussed as well as the role of neurosteroids and oxytocin receptors in volume transmission leading to a new understanding of the integrative actions of neuronal–glial networks. The role of tunneling nanotubes with mitochondrial transfer in CNS inter alia as part of neuron–glia interactions will also be introduced representing a novel type of wiring transmission. The impact of the technicolour approach to the connectome for the future characterization of the wired networks of the brain is emphasized. [Copyright &y& Elsevier]

The intramembrane receptor–receptor interactions among GPCRs demonstrated in the beginning of the 80s in the CNS probably reflect the existence of allosteric mechanisms in receptor heteromers, and the postulated assemblies of multiple GPCRs coined ‘receptor mosaics’ in the early 80s probably represent higher order receptor heteromers, recently demonstrated with novel biophysical techniques in living cells. The receptor interface in the GPCR heteromers is beginning to be characterized and in adenosine A2A–dopamine D2-like heteromers the electrostatic arginine–phosphate salt bridge seems to be a hot spot in the interface with covalent-like stability, possibly participating in the allosteric interactions and making possible integration of heteromer receptor function. We discuss the possible relevance of some putative D2 receptor heteromers in the treatment of Parkinson''s disease and schizophrenia, respectively. [Copyright &y& Elsevier]

Abstract: Common architecture of cytokine receptors and G-protein coupled receptors (GPCRs) may underlie pathological receptor heteromer formation and signaling. Here, we clarify how chemokines and cytokines can participate in pathogenic processes of Parkinson''s disease, especially in dopaminergic neurons of substantia nigra. Possible common architecture of GPCRs and cytokine receptors suggests that they may act as molecular switches similar to the prototypical innate immune receptors: Toll-like receptors. Thus, pathological signaling (as well as trafficking and internalization) of receptors may be initiated by their incorrect dimerization depending on direct or indirect (via adaptor proteins) receptor–receptor interactions, leading to neuroinflammatory responses. [Copyright &y& Elsevier]

Abstract: Receptor assemblies seem to play a key role in the integration and modulation of molecular signals of cell–cell communications. This may be confirmed by recent discoveries of the immunological synapse and cytokine networks which can be also treated within a sort of meta-system—neuroimmune molecular network. On the examples of receptor superfamilies expressed both in the neural and immune cells, our review paper aims to show some implications of receptor–receptor interactions for basal ganglia functions in health and disease. [Copyright &y& Elsevier]

Abstract: The distribution, morphology and nuclear subdivisions of the cholinergic, putative catecholaminergic and serotonergic systems within the brains of two species of African mole-rat (Cape dune mole-rat –Bathyergus suillus; highveld mole-rat –Cryptomys hottentotus pretoriae) were identified following immunohistochemistry for acetylcholinesterase, tyrosine hydroxylase and serotonin. The aim of the present study was to investigate possible differences in the complement of nuclear subdivisions of these systems by comparing those of the mole-rats to published studies of other rodents. The mole-rats used exhibit a major reduction of the visual system and live a subterranean lifestyle. These wild caught animals also have differing social systems, the Cape dune mole-rat is strictly solitary whereas the highveld mole-rat occurs in social familial units. While these differences, especially that of phenotype, may lead to the prediction of significant differences in the nuclear complement of these systems, we found that all nuclei identified in all three systems in the laboratory rat and other rodents had direct homologs in the brains of the mole-rats studied. There were no additional nuclei in the brains of the mole-rats that are not found in the laboratory rat or other rodents and vice versa. The mole-rats are phylogenetically distant from the laboratory rat, but are still part of the order Rodentia. We conclude that changes in the nuclear organization of the systems studied appear to demonstrate a form of constraint related to the phylogenetic level of the order. [Copyright &y& Elsevier]

Abstract: Corticosterone hormones mediate the stress response and function in the survival of hippocampal neurons via activation of gluco-(GR) and mineralocorticoid (MR) receptors. Activated GR and MR couple the corticosterone signal through immediate early genes (IEGs) to the late expression of downstream genes, such as neurotrophic factors. The potential importance of IEGs in GR/MR-dependent plasticity in the brain is largely unknown. We examined the region- and time-dependent transcriptional profiles of six IEGs (c-fos, fosB, fra-1, junB, c-jun and egr-1) by in situ hybridization after acute corticosterone challenge in the hippocampus and the primary somatosensory cortex (S1). Adrenalectomized rats and subsequent hormone injections were used as a model system to eliminate interference of endogenous corticosterone on IEG expression. In the hippocampus, a single corticosterone dose (10 mg/kg, s.c.) caused a widespread and transient reduction of fosB mRNA after 0.8 h, whereas changes in both c-fos and fra-1 mRNA levels were restricted to the dentate gyrus region. Corticosterone treatment gave rise to a delayed and significant reduction of junB mRNA signals after 2 h in all hippocampal regions, which reversed to increase at 4 h. c-jun and egr-1 mRNA levels were unaffected by corticosterone treatment. On the contrary, in the S1, IEG expression seems to be unaffected by corticosterone treatment, with the exception of a transient increase of junB transcripts at 0.8 h. The early reduction in c-fos family and junB transcripts may contribute to the GR/MR-dependent changes on hippocampal plasticity and may be dependent on rapid corticosteroid signaling. [Copyright &y& Elsevier]

Abstract: The dopamine D1 and D2 receptors are major receptors in the regulation of striatal function and striatal adenosine A1 and A2A receptors are major modulators of their signaling. The evidence suggests the existence of antagonistic A1–D1 heteromeric receptor complexes in the basal ganglia and prefrontal cortex and especially in the direct striatonigral–striatoentopeduncular GABA pathways. The neurochemical and behavioral findings showing antagonistic A1–D1 receptor interactions can be explained by the existence of such A1–D1 heteromeric receptor complexes and of antagonistic interactions at the level of the second messengers. In contrast, A2A–D2 receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A2A receptors reduces D2 receptor recognition, coupling and signaling. As a result of the A2A receptor-induced reduction of D2 receptor signaling, the activity of these GABA neurons is increased resulting in reduced motor and reward functions mediated via the indirect pathway, causing a reduced glutamate drive to the prefrontal and motor areas of the cerebral cortex. Thus, A2A receptor antagonists and A2A receptor agonists, respectively, may offer novel treatments of Parkinson''s disease (reduced D2 receptor signaling) and of schizophrenia and drug addiction (increased D2 receptor signaling). [Copyright &y& Elsevier]

Abstract: Learning and memory seem to be inherent to a biological neural network. To emerge, they need an extensive functional connectivity, enabling a large repertoire of possible responses to stimuli, and sensitivity of the connectivity to activity, allowing for the selection of adaptive responses. According to the classical view about the organization of the CNS, the connectivity issue is realized by the huge amount of synaptic contacts each neuron establishes, while the adaptation of the network to specific tasks is obtained by mechanisms of activity-dependent synaptic plasticity. The discovery of direct receptor–receptor interactions at the level of the plasma membrane and the existence in the brain of two main modes of communication, the wiring transmission (such as the synaptic transmission) and the volume transmission (based on the diffusion of signals in the extracellular space), provided a broader view of the functional organization of the CNS with potential important consequences on the understanding of learning and memory processes. Owing to receptor–receptor interactions clusters of receptors, the receptor mosaics (RM), can be formed at the plasma membrane where they can work as collective functional units. As a consequence, the connections between the cells become themselves networks (molecular networks) able to adapt their function according to the stimuli they receive. Learning, therefore, can occur also at the level of RMs. Thus, memory formation seems not only to be a distributed process, but also to follow a hierarchical morpho-functional organization. Furthermore, the combination of the two different forms of transmission could allow processes of correlation and coordination to be established between networks and network elements without the need of additional physical connections, leading to a significant increase of the degrees of freedom available to the CNS for learning. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: The present study was designed to provide results aimed at testing whether the interneurons with choline acetyltransferase immunoreactivity (ChAT), probably representing GABA interneurons, found in the cerebral cortex of the rat represent a common feature of the order Rodentia. Initially we verified the presence of ChAT immunoreactive bipolar cell bodies, axons and terminal-like fibres in pigmented (Long-Evans) and non-pigmented (Sprague-Dawley) strains of Rattus norvegicus, confirming that the ChAT polyclonal antibodies (AB144P and AB143, Chemicon; VChAT, Sigma) with the immunohistochemical techniques used provided the same staining as previously described for this species. We then examined pigmented (AKR3) and non-pigmented (C3H) strains of Mus musculus, wild caught striped mice (Rhabdomys pumilio), bushveld gerbil (Tatera brantsii), greater canerat (Thryonomys swinderianus) and common molerat (Cryptomys hottentotus). The AB144P antibody revealed cortical interneurons in both strains of M. musculus and in R. pumilio, but not in the other species. In all species/strains cortical ChAT immunoreactive axons and terminal-like fibres were localized with the AB144P antibody. In the non-Rattus species/strains there was no evidence for localization of ChAT immunoreactivity in any cortical cell bodies using the AB143 and vesicular acetylcholine transporter (VChAT) antibodies despite extensive localization in axons and terminal-like fibres. It is concluded that bipolar cortical GABA interneurons in certain rodent species may develop ChAT immunoreactivity but not VChAT immunoreactivity making the cholinergic relevance of ChAT in the GABA interneurons uncertain and may exclude these neurons from being part of the traditionally defined cholinergic system. [Copyright &y& Elsevier]

Abstract: The present paper details our findings following immunohistochemical examination of the midbrain and pons of the Highveld molerat (Cryptomys hottentotus) using antibodies for vesicular acetylcholine transporter (cholinergic neurons), tyrosine hydroxylase (dopaminergic and noradrenergic neurons), and serotonin (serotonergic neurons). The aim was to see if, in this microphthalmic rodent that lacks a distinct circadian rhythm, the nuclei involved in aspects of visual processing and the sleep–wake cycle exhibited specific loss or morphological alteration. For all of the neural systems investigated we found nuclei that can be considered direct homologues of those found in the laboratory rat. There was no specific loss of any nuclear group of any of the systems investigated, but there was significant reduction (as judged qualitatively) in the number of neurons in the visual associated nuclei. The fact that we could identify all nuclear groupings from three systems in this species is suggestive of an evolutionary constraint acting at the level of the organization of the neural system. [Copyright &y& Elsevier]

It has been demonstrated that receptor–receptor interactions between G-protein-coupled receptors (GPCRs) occur at the plasma-membrane level. It has also been shown that clustering of GPCRs in aggregates or receptor mosaics (RMs) results in the reciprocal modulation of their binding and decoding characteristics. It is hypothesized that cooperativity plays an important part in the decoding of signals processed by RMs of GPCRs. Thus, the binding of the ligand at one receptor alters the likelihood of the same ligand binding at the next site, in the case of RMs, formed by identical receptors and/or by iso-receptors (receptors that bind the same ligand). [Copyright &y& Elsevier]

To understand the morphological substrate of the nicotine effect on nigral FGF-2 expression, a stereological analysis of FGF-2 immunoreactive neuronal and glial profiles has been performed in the substantia nigra of the rat after acute intermittent nicotine treatment. The major finding of this paper is the demonstration that this type of nicotine treatment produces a significant reduction in the total number of nuclear FGF-2 immunoreactive astroglial profiles in the substantia nigra. A parallel analysis of nigral FGF-1 and FGF-5 immunoreactivities showed no effect of this type of nicotine treatment. The results may be explained by an inhibition of FGF-2 synthesis in a subpopulation of nigral astroglia by nicotinic receptor activation, favouring a reduction of astroglial neurotrophism in the substantia nigra. [Copyright &y& Elsevier]

The aim of this work was to investigate the modulation of the cardiovascular effects of neuropeptide Y (NPY) in the nucleus tractus solitarii (NTS) by angiotensin II (Ang II) and to determine the NPY receptor subtype involved in this modulation. Anesthesized Sprague–Dawley rats received microinjections in the NTS of Ang II (threshold and ED50 doses) with NPY Y1 agonist Leu31Pro34NPY and NPY Y2 agonist NPY(13–36) (threshold and ED50 doses). The changes in mean arterial pressure (MAP) and heart rate (HR) recorded in the femoral artery were analyzed during 60 min after the microinjections. The injection of threshold doses of Ang II, Y1 agonist or Y2 agonist alone did not produce any change in cardiovascular parameters. However, the co-injections into the NTS of threshold doses of both Ang II and the Y1 agonist elicited significant increases of MAP and HR of about 12 and 10%, respectively. The co-administration of threshold doses of Ang II with the Y2 agonist also induced a significant vasopressor response. The vasodepressor and bradycardiac effect of an ED50 dose of the Y1 agonist was significantly counteracted (P<0.01) by a threshold dose of Ang II. The vasopressor effect elicited by an ED50 dose of the Y2 agonist was significantly enhanced by a threshold dose of Ang II (P<0.01). No significant change of cardiovascular responses elicited by an ED50 dose of Ang II was observed in the presence of threshold doses of the Y1 agonist or of the Y2 agonist. The present study gives functional evidences for a differential modulatory activity of Ang II on the cardiovascular responses mediated by Y1 and Y2 receptor subtypes, which may be of relevance for central cardiovascular regulation in the NTS. [Copyright &y& Elsevier]

Purinergic signaling modulates dopaminergic neurotransmission in health and disease. Classically adenosine A 1 and A 2A receptors have been considered key for the fine tune control of dopamine actions in the striatum, the main CNS motor control center. The main adenosine signaling mechanism is via the cAMP pathway but the future will tell whether calcium signaling is relevant in adenosinergic control of striatal function. Very relevant is the recent approval in Japan of the adenosine A 2A receptor antagonist, istradefylline, for use in Parkinson's disease patients. Purine nucleotides are also regulators of striatal dopamine neurotransmission via P2 purinergic receptors. In parallel to the alpha-synuclein hypothesis of Parkinson's disease etiology, purinergic P2X 1 receptors have been identified as mediators of accumulation of the Lewy-body enriched protein alpha-synuclein. Of note is the expression in striatum of purinergic-receptor-containing heteromers that are potential targets of anti-Parkinson's disease therapies and should be taken into account in drug discovery programs. This article is part of the Special Issue entitled ‘Purines in Neurodegeneration and Neuroregeneration’. [ABSTRACT FROM AUTHOR]

The serotonin and neurotrophic factor hypotheses of depression are well known. The discovery of brain fibroblast growth factor receptor 1 (FGFR1)–5 hydroxytryptamine receptor 1A (5-HT1A) heteroreceptor complexes, and their enhancement of neuroplasticity, offers an integration of these hypotheses at the molecular level. They were first described in the hippocampus and later in midbrain 5-HT neurons, where these heterocomplexes are enriched in 5-HT1A autoreceptors. Combined FGF2 and 5-HT1A agonist treatment increased the formation of these heterocomplexes and the facilitatory allosteric receptor–receptor interactions within them led to the enhancement of FGFR1 signaling and was associated with the development of antidepressant effects. We discuss these findings with regard to a theory of motifs critically involved in these interactions and suggest that these complexes represent novel targets for antidepressants. [ABSTRACT FROM AUTHOR]