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Neuronal events are regulated by the integration of several complex signaling networks in which G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) are considered key players of an intense bidirectional cross-communication in the cell, generating signaling mechanisms that, at the same time, connect and diversify the traditional signal transduction pathways activated by the single receptor. For this receptor-receptor crosstalk, the two classes of receptors form heteroreceptor complexes resulting in RTKs transactivation and in growth-promoting signals. In this review, we describe heteroreceptor complexes between GPCR and RTKs in the central nervous system (CNS) and their functional effects in controlling a variety of neuronal effects, ranging from development, proliferation, differentiation and migration, to survival, repair, synaptic transmission and plasticity. In this interaction, RTKs can also recruit components of the G protein signaling cascade, creating a bidirectional intricate interplay that provides complex control over multiple cellular events. These heteroreceptor complexes, by the integration of different signals, have recently attracted a growing interest as novel molecular target for depressive disorders. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Treatment with resveratrol (RSV) has been shown to protect vulnerable neurons after various brain injuries and in neurodegenerative diseases. The mechanisms for the effects of RSV in brain are not fully understood, but RSV may affect the expression of various gene products. RSV is structurally related to the synthetic estrogen, diethylstilbestrol so the effects of RSV may be gender-specific. Here we studied the role of RSV in the regulation of dopamine transporter (DAT) in the striatum using male and female mice. The basic levels of DAT in the striatum showed no sex difference, but the levels increased significantly by RSV (20 mg/kg i.p.) in female but not in male mice. Pretreatment of mice with the selective estrogen receptor (ER), ERα- and ERβ antagonist ICI 182,780, led to a complete block of RSV effect on DAT protein levels, suggesting that ERs are involved in the up-regulation of DAT by RSV. Similar data was also obtained in culture using human MESC2.10 and mouse SN4741 dopaminergic cells after treatment with RSV. Data further showed that RSV specifically induced gene transcription of DAT in the dopaminergic cells. These results show that estrogen receptors are involved in the up-regulation of DAT by RSV in the dopaminergic neurons, demonstrating a sex-dependent effect of RSV in the brain that may be of clinical importance. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In the present study we aimed to verify if the enhancement of glial cell line-derived neurotrophic factor (GDNF) production in mouse striatum following treatment with LY379268 may also induce in the nigrostriatal system a time-related activation of RET receptor and its specific intracellular signaling. For this purpose, we have investigated the effects of LY379268 treatment on RET phosphorylation at the Tyr1062 and on downstream signaling Erk1/2, Akt and PLCγ1 pathway activation. The results showed that treatment with LY379268 (3 mg/kg) induces a significant increase of GDNF levels and time-related RET and Erk1/2 phosphorylation in the striatum. These increases were detected at 24 h and 48 h following LY379268 treatment. No changes were observed in the Akt and PLCγ1 phosphorylation levels. Similar results for p-Erk1/2 were observed in the substantia nigra. A complete block of LY379268 effect on striatal RET and p-Erk1/2 phosphorylation was observed in mice intrastriatal injected with anti-GDNF antibodies, suggesting a correlation between GDNF upregulation and RET activation. Overall, with present data we have shown that activation of mGluR2/3 receptors by LY379268 may be particularly promising for nigrostriatal dopaminergic system protection by enhancing striatal levels of GDNF/RET trophic system activity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Carbenoxolone (CBX), the succinyl ester of glycyrrhetinic acid, is an inhibitor of gap junctional intercellular communication. We have tested its possible effects upon two genetic animal models of epilepsy (WAG/Rij rats and lethargic (lh/lh) mice). Systemic administration of CBX was unable to significantly affect the occurrence of absence seizures in WAG/Rij rats. In particular, intravenous (5-40 mg/kg) or intraperitoneal (i.p.; 10-80 mg/kg) administration of CBX was unable to significantly modify the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats, whereas the bilateral microinjection (0.05, 0.1, 0.5 and 1 microg/0.5 microl) of CBX into nucleus reticularis thalami (NRT) and nucleus ventralis posterolateralis (VPL) thalami produced a decrease in the duration and the number of SWDs. Bilateral microinjection of CBX into nucleus ventroposteromedial (VPM) thalami did not produce any significant decrease in the number and duration of SWDs. On the contrary, i.p. (5-40 mg/kg) or intracerebroventricular (0.5, 1, 2 and 4 microg/2 microl) administration of CBX in lh/lh mice induced a marked decrease in the number and duration of SWDs in a dose-dependent manner. At the doses used no movement disorders, or other behavioural changes, were recorded in both WAG/Rij rats and lh/lh mice. No effects were observed in both animal models following systemic or focal administration of glycyrrhizin into the same brain areas where CBX was shown to be effective.

Carbenoxolone (CBX), the succinyl ester of glycyrrhetinic acid, is an inhibitor of gap junctional intercellular communication. Systemic administration of CBX was able to decrease the seizure severity score and to increase the latency time of seizure onset in genetically epilepsy prone rats (GEPRs). In particular, intravenous or intraperitoneal administration of carbenoxolone (5-30 mg/kg) produced a dose-dependent and significant reduction in the clonic and tonic phases of the audiogenic seizures in GEPRs. The anticonvulsant doses were not associated with an impairment of motor coordination. The bilateral microinjection of CBX (0.001-0.50 microg/0.5 microl) into the inferior colliculi, the substantia nigra (pars reticulata or compacta) and the inferior olivary complex was able to reduce the seizure severity score in a dose-dependent manner. The anticonvulsant effects were longer lasting after focal microinjection than after systemic administration. No anticonvulsant effects were observed following focal bilateral microinjections of glycyrrhizin into the same brain areas where CBX was shown to be effective.