Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented—in order of decreasing affinity for the catecholamine—by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing—in turn—a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large number of experimental and clinical findings, a major challenge will be to adapt this hypothesis to integrate the role of other neurotransmitters released during stress in a centralized fashion, like serotonin, acetylcholine, and histamine, as well as those released in a non-centralized fashion, like purines and cytokines.

Autism spectrum disorder (ASD) is a syndrome of diverse neuropsychiatric diseases of growing incidence characterized by repetitive conduct and impaired social behavior and communication for which effective pharmacological treatment is still unavailable. While the mechanisms and etiology of ASD are still unknown, a consensus is emerging about the synaptic nature of the syndrome, suggesting a possible avenue for pharmacological treatment with synaptogenic compounds. The peptidic mixture cerebrolysin (CBL) has been successfully used during the last three decades in the treatment of stroke and neurodegenerative disease. Animal experiments indicate that at least one possible mechanism of action of CBL is through neuroprotection and/or synaptogenesis. In the present study, we tested the effect of CBL treatment (daily injection of 2.5 mL/Kg i.p. during 15 days) on a rat model of ASD. This was based on the offspring (43 male and 51 female pups) of a pregnant female rat injected with valproic acid (VPA, 600 mg/Kg) at the embryonic day 12.5, which previous work has shown to display extensive behavioral, as well as synaptic impairment. Comparison between saline vs. CBL-injected VPA animals shows that CBL treatment improves behavioral as well as synaptic impairments, measured by behavioral performance (social interaction, Y-maze, plus-maze), maximal response of inhibitory γ-amino butyric acid type A receptor (GABA R)-mediated synaptic currents, as well as their kinetic properties and adrenergic and muscarinic modulation. We speculate that CBL might be a viable and effective candidate for pharmacological treatment or co-treatment of ASD patients. © 2017 Wiley Periodicals, Inc.

The pro-inflammatory cytokine interleukin 6 (IL-6) interacts with the central nervous system in a largely unknown manner. We used a genetically modified mouse strain (GFAP-sgp130Fc, TG) and wild type (WT) mice to determine whether IL-6 trans-signaling contributes to basal properties of synaptic transmission. Postsynaptic currents (PSCs) were studied by patch-clamp recording in cortical layer 5 of a mouse prefrontal cortex brain slice preparation. TG and WT animals displayed differences mainly (but not exclusively) in excitatory synaptic responses. The frequency of both action potential-independent (miniature) and action potential-dependent (spontaneous) excitatory PSCs (EPSCs) were higher for TG vs. WT animals. No differences were observed in inhibitory miniature, spontaneous, or tonic inhibitory currents. The pair pulse ratio (PPR) of electrically evoked inhibitory as well as of excitatory PSCs were also larger in TG animals vs. WT ones, while no changes were detected in electrically evoked excitatory-inhibitory synaptic ratio (eEPSC/eIPSC), nor in the ratio between the amino-propionic acid receptor (AMPAR)-mediated and N-methyl D aspartate-R (NMDAR)-mediated components of eEPSCs (I /I ). Evoked IPSC rise times were shorter for TG vs. WT animals. We also compared the sensitivity of TG and WT animals to pentylenetetrazole (PTZ)-induced seizures. We found that TG animals were more sensitive to PTZ injections, as they displayed longer and more severe seizures. We conclude that the absence of basal IL-6 trans-signaling contributes to increase the basal excitability of the central nervous system, at the system level as well at the synaptic level, at least in the prefrontal cortex.

Nicotine is the major addictive component of cigarettes, reaching a brain concentration of ~300 nM during smoking of a single cigarette. The prefrontal cortex (PFC) mechanisms underlying temporary changes of working memory during smoking are incompletely understood. Here, we investigated whether 300 nM nicotine modulates γ‐aminobutyric acid (GABA) ergic synaptic transmission from pyramidal neurons of the output layer (V) of the murine medial PFC. We used patch clamp in vitro recording from C57BL/6 mice in the whole‐cell configuration to investigate the effect of nicotine on pharmacologically isolated GABAergic postsynaptic currents (IPSCs) in the absence or presence of methyllycaconitine (MLA) or dihydro‐β‐erythroidine (DHβE), selective antagonists of α7‐ and β2‐containing (α7* and β2*) nicotinic acetylcholine receptors (AChRs), respectively. Our results indicated that nicotine, alone or in the presence of MLA, decreases electrically evoked IPSC (eIPSC) amplitude, whereas in the presence of DHβE, nicotine elicited either an eIPSCs amplitude increase or a decrease. In the presence of DHβE, nicotine increased membrane conductance leaving the paired pulse ratio unchanged in all conditions, suggesting a non‐β2* mediated effect. In the presence of MLA, nicotine decreased the mean spontaneous IPSC (sIPSC) frequency but increased their rise time, suggesting a non‐α7* AChR‐mediated synaptic modulation. Also, in the presence of DHβE, nicotine decreased both eIPSC rise and decay times. No receptors other than α7* and β2* appear to be involved in the nicotine effect. Our results indicate that nicotine smoking concentrations modulate GABAergic synaptic currents through mixed pre‐ and post‐synaptic mechanisms by activation of α7* and β2* AChRs.

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