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The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor-receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1-15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor-receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

We have previously demonstrated that the ester conjugation of zidovudine (AZT) with ursodeoxycholic acid (UDCA) allows to obtain a prodrug (U-AZT) which eludes the active efflux transporters (AET). This allows the prodrug to more efficiently permeates and remains in murine macrophages than the parent compound. Here we demonstrate that U-AZT can be formulated, by a nanoprecipitation method, as nanoparticle cores coated by bile acid salt (taurocholate or ursodeoxycholate) corona, without any other excipients. The U-AZT nanoparticles appeared spherical with a mean diameter of ∼200 nm and a zeta potential of ∼-55 mV. During the incubation (5 h) in fetal bovine serum, the ursodeoxycholate-coated nanoparticle size did not change. Differently, taurocholate-coated particle size was firstly reduced and then increased up to 800 µm, thus suggesting the high aptitude of these nanoparticles to interact with serum proteins. The in vitro uptake of taurocholate coated particles by murine macrophages was strongly higher than that of ursodeoxycholate-coated particles or free U-AZT (∼500% and ∼7000%, respectively). AZT was also detected in macrophages following the prodrug uptake, with the greatest amounts observed after the taurocholate-coated nanoparticle incubation. As macrophages in the subarachnoid spaces of cerebrospinal fluid (CSF) constitute one of the most unreachable HIV sanctuaries in the body, we also tested the ability of taurocholate-coated nanoparticles (i.e., nanoparticles highly internalized by macrophages) to reach them after their nasal administration in the presence or absence of chitosan. The results indicate that chitosan allowed to obtain a relatively high uptake (up to 4 µg/ml) of U-AZT in CSF. Taking into account that chitosan may promote the direct brain nanoparticle uptake, these findings can be considered an initial step toward the in vivo targeting of the subarachnoid macrophages by U-AZT prodrug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The reinforcing effects of Δ 9 -tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61-8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors (α7nAChRs) and CB1Rs regulate glutamate release. We used in vivo microdialysis and electrophysiology in rats, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the nucleus accumbens shell (NAcS), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAcS. These THC effects were prevented by administration of Ro 61-8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAcS or to the VTA in vivo. These effects were averted by pretreatment with Ro 61-8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and α7nAChR mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway, and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases.

Lipid microparticles (LMs) uncoated or coated with chitosan and containing the neuroprotective polyphenol resveratrol were developed for its targeting to the brain via nasal administration. The lipid microparticles loaded with resveratrol (LMs-Res) were produced by melt emulsification, using stearic acid as lipid material and phosphatidylcholine as the surfactant. The chitosan coated particles LMs-Res-Ch (1.75% w/v chitosan solution) and LMs-Res-Ch-plus (8.75% w/v chitosan solution) were prepared by adding a chitosan solution to the formed particles. The mean diameter of the particles were 68.5 ± 3.1 μm, 76.3 ± 5.2 μm and 84.5 ± 8.1 μm for LMs-Res, LMs-Res-Ch and LMs-Res-Ch-plus respectively, suitable for nasal delivery. Chitosan coating changed the particle surface charge from a negative zeta potential value (-12.7 ± 2.1 mV) for the uncoated particles to a higher positive values respectively, 24.0 ± 4.7 and 44.6 ± 3.1 mV for the chitosan coated LM-Res-Ch and LM-Res-Ch-plus. Permeation studies across human NCM460 cell monolayers demonstrated that their transepithelial electrical resistance (TEER) values were not modified in the presence of free resveratrol, unloaded LMs, loaded LMs-Res or LMs-Res-Ch. On the other hand, the TEER values decreased from 150 ± 7 to 41 ± 3 Ω cm 2 in the presence of LMs-Res-Ch-plus, which corresponded to a significant increase in the apparent permeability (P app ) of resveratrol from 518 ± 8 × 10 -4  cm/min to 750 ± 98 × 10 -4  cm/min. In vivo studies demonstrated that no resveratrol was detected in the rat cerebrospinal fluid (CSF) after an intravenous infusion of the polyphenol. Conversely, the nasal delivery of resveratrol in a chitosan suspension or encapsulated in uncoated LMs-Res dispersed in water achieved the uptake of resveratrol in the CSF with C max after 60 min of 1.30 ± 0.30 μg/ml and 0.79 ± 0.15 μg/ml, respectively. However, a dramatic increase in the levels of resveratrol reaching the CSF was attained by the administration of an aqueous suspension of LMs-Res-Ch-plus with a C max after 60 min of 9.7 ± 1.9 μg/ml. This marked increase in the CSF bioavailability was achieved without any distribution in the systemic circulation, demonstrating a direct and specific nose to brain delivery., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Multiple players are involved in the brain integrative action besides the classical neuronal and astrocyte networks. In the past, the concept of complex cellular networks has been introduced to indicate that all the cell types in the brain can play roles in its integrative action. Intercellular communication in the complex cellular networks depends not only on well-delimited communication channels (wiring transmission) but also on diffusion of signals in physically poorly delimited extracellular space pathways (volume transmission). Thus, the extracellular space and the extracellular matrix are the main players in the intercellular communication modes in the brain. Hence, the extracellular matrix is an 'intelligent glue' that fills the brain and, together with the extracellular space, contributes to the building-up of the complex cellular networks. In addition, the extracellular matrix is part of what has been defined as the global molecular network enmeshing the entire central nervous system, and plays important roles in synaptic contact homeostasis and plasticity. From these premises, a concept is introduced that the global molecular network, by enmeshing the central nervous system, contributes to the brain holistic behavior. Furthermore, it is suggested that plastic 'brain compartments' can be detected in the central nervous system based on the astrocyte three-dimensional tiling of the brain volume and on the existence of local differences in cell types and extracellular space fluid and extracellular matrix composition. The relevance of the present view for neuropsychiatry is discussed. A glossary box with terms and definitions is provided.

Our previous results demonstrated that a prodrug obtained by the conjugation of the antiretroviral drug zidovudine (AZT) with ursodeoxycholic acid (UDCA) represents a potential carrier for AZT in the central nervous system, thus possibly increasing AZT efficiency as an anti-HIV drug. Based on these results and in order to enhance AZT brain targeting, the present study focuses on solid lipid microparticles (SLMs) as a carrier system for the nasal administration of UDCA-AZT prodrug. SLMs were produced by the hot emulsion technique, using tristearin and stearic acid as lipidic carriers, whose mean diameters were 16 and 7 μm, respectively. SLMs were of spherical shape, and their prodrug loading was 0.57 ± 0.03% (w/w, tristearin based) and 1.84 ± 0.02% (w/w, stearic acid based). The tristearin SLMs were able to control the prodrug release, whereas the stearic acid SLMs induced a significant increase of the dissolution rate of the free prodrug. The free prodrug was rapidly hydrolyzed in rat liver homogenates with a half-life of 2.7 ± 0.14 min (process completed within 30 min). The tristearin SLMs markedly enhanced the stability of the prodrug (75% of the prodrug still present after 30 min), whereas the stabilization effect of the stearic acid SLMs was lower (14% of the prodrug still present after 30 min). No AZT and UDCA-AZT were detected in the rat cerebrospinal fluid (CSF) after an intravenous prodrug administration (200 μg). Conversely, the nasal administration of stearic acid based SLMs induced the uptake of the prodrug in the CSF, demonstrating the existence of a direct nose-CNS pathway. In the presence of chitosan, the CSF prodrug uptake increased six times, up to 1.5 μg/mL within 150 min after nasal administration. The loaded SLMs appear therefore as a promising nasal formulation for selective zidovudine brain uptake.

The tridecapeptide neurotensin (NT) acts as neurotransmitter in the central nervous system and in the periphery. NT and NT receptors are largely localized in dopamine (DA)-enriched regions of the mammalian brain. Accordingly, numerous studies indicate the presence of close functional interactions between DA neurons and the peptide. Among others mechanisms, it has been suggested that NT could modulate nigrostriatal, mesolimbic and meso-cortical DA transmission through an antagonistic receptor-receptor interaction between the NT receptor subtype 1 (NTS1) and the dopamine D2 receptor (D2R). In particular, it was originally demonstrated that the peptide reduces the D2R agonist affinity in striatal sections and in striatal membrane preparations. These effects could be a consequence of the direct allosteric NTS1/D2 receptor interactions leading to a decrease in the DA agonist affinity at the D2 receptor. Several neurochemical, biochemical and co-immunoprecipitation data have successively reinforced the indication of the presence of direct NTS1-D2 receptor interactions in the mammalian brain. The present mini-review attempts to provide a summary of current knowledge, mainly emerging from our microdialysis studies, supporting the presence of a NTS1/D2 receptor heteromer in the brain. The pre and post-synaptic mechanisms underlying the involvement of this heteromer in the striatopallidal GABA and mesocorticolimbic DA neurotransmission are discussed especially for their relevance in Parkinson's disease and schizophrenia, respectively.

The objective of this study was to investigate the effect of polymeric microcarriers on the in vivo intranasal uptake of an anti-migraine drug for brain targeting. Mucoadhesive powder formulations consisted of antimigraine drug, zolmitriptan, and chitosans (various molecular weights and types) or hydroxypropyl methylcellulose (HPMC). Their suitability for nasal administration was evaluated by in vitro and ex vivo mucoadhesion and permeation tests. The formulations based on chitosan glutamate (CG) or HPMC were tested in vivo because they showed good mucoadhesive properties and altered the permeation rate of the drug. The in vivo results from intravenous infusion and nasal aqueous suspension of the drug or nasal particulate powders were compared. The plasmatic AUC values obtained within 8h following intravenous administration appeared about three times higher than those obtained by nasal administration, independent of the formulations. Zolmitriptan concentrations in the cerebrospinal fluid obtained from nasal and intravenous administrations were, respectively, 30 and 90 times lower than the concentrations of the drug in the blood. Thus, nasal administration potentiated the central zolmitriptan activity, allowing a reduction in the drug peripheral levels, with respect to the intravenous administration. Among nasally administered formulations, CG microparticles showed the highest efficacy in promoting the central uptake of zolmitriptan within 1h., (Copyright © 2012 Elsevier B.V. All rights reserved.)

N(6)-cyclopentyladenosine (CPA) has neuronal anti-ischemic properties, but it is not absorbed into the brain from the bloodstream, where it shows poor stability and induces side effects. Microparticulate drug delivery systems designed for CPA nasal administration and constituted by mannitol or chitosan, were prepared by spray-drying and characterized. Mannitol-lecithin microparticles showed high CPA dissolution rate, whereas chitosan microparticles controlled its release rate. In vitro mucoadhesion studies indicated that CPA-loaded chitosan microparticles had higher mucoadhesive properties compared to mannitol particles. Ex vivo studies on sheep nasal mucosa showed that mannitol microparticles promoted CPA permeation across the mucosa, whereas chitosan microparticles controlled CPA permeation rate in comparison with CPA raw material. In vivo studies were carried out on rats. No CPA was detected in rat cerebrospinal fluid (CSF) and brain sections after intravenous administration. In contrast, after nasal administration of loaded microparticles CPA was found in the CSF at concentrations ranging from high nM to microM values and up to two order of magnitude higher than those obtained at systemic level. CPA was also found in the olfactory bulb at concentrations around 0.1 ng/mg of tissue. These results can open new perspectives for the employment of CPA against brain damages following stroke.

In view of a postulated role of the vigilance-promoting drug modafinil in depression, the interaction of modafinil and two classical antidepressant drugs, fluoxetine and imipramine, were studied in 5-HT levels in the dorsal raphe-cortical system using dual-probe microdialysis. Fluoxetine (1-10 mg/kg) dose-dependently increased dorsal raphe-cortical 5-HT levels. Modafinil at a very low dose (3 mg/kg), by itself ineffective, enhanced the fluoxetine (5 mg/kg)-induced increases of 5-HT levels in both brain areas. A synergistic interaction was observed in the prefrontal cortex with fluoxetine (1 mg/kg) in terms of 5-HT release, but not in the dorsal raphe. Imipramine (1.3 mg/kg) increased 5-HT levels in the dorsal raphe, but not in the prefrontal cortex, while the higher doses (10.9-21.8 mg/kg) caused substantial increases in both brain areas. Modafinil (3 mg/kg), injected before imipramine (1.3 mg/kg), which by itself was ineffective on cortical 5-HT levels, increased cortical 5-HT levels. On other hand, modafinil failed to affect the high-dose imipramine (10.9 mg/kg)-induced increase of 5-HT levels in the prefrontal cortex and the imipramine (1.3; 10.9 mg/kg)-induced increase of 5-HT levels in the dorsal raphe nucleus. These results demonstrate that modafinil in low doses enhances the acute effects of fluoxetine and imipramine on 5-HT levels in the dorsal raphe nucleus (fluoxetine only) and especially in the prefrontal cortex of the awake rat. These findings suggest a therapeutic potential of low doses of modafinil in the treatment of depression when combined with low doses of classical antidepressants, especially by increasing 5-HT transmission in cortical regions., ((c) 2005 Wiley-Liss, Inc.)

The present in vivo microdialysis study evaluates the possible existence of a differential regulation of serotonergic transmission by the antinarcoleptic drug modafinil [(diphenyl-methyl)-sulfinyl-2-acetamide; Modiodal] among various brain regions of the awake rat. The results show that, in the cerebral cortex, the central amygdala, and the dorsal raphe nucleus, modafinil in the dose range of 10-100 mg/kg i.p. dose-dependently increases dialysate serotonin (5-HT) levels. In other brain areas, such as the medial preoptic area and the posterior hypothalamus, the modafinil-induced increase in dialysate 5-HT levels is observed only at tenfold higher doses (100 mg/kg), 10-30 mg/kg being ineffective. Together these data suggest that, in the frontal cortex, the amygdala, and the dorsal raphe, modafinil is more potent in enhancing extracellular 5-HT levels and presumably 5-HT transmission than in the medial preoptic area and the posterior hypothalamus. In view of the role of ascending 5-HT pathways in arousal and depression, it seems likely that the antinarcoleptic drug modafinil may also have an antidepressant potential in addition to its wakefulness-promoting action, both actions involving enhancement of 5-HT neurotransmission., (Copyright 2002 Wiley-Liss, Inc.)