Melatonin, the major regulator of the sleep/wake cycle, also plays important physiological and pharmacological roles in the control of neuronal plasticity and neuroprotection. Accordingly, the secretion of this hormone reaches the maximal extent during brain development (childhood-adolescence) while it is greatly reduced during aging, a condition associated to altered sleep pattern and reduced neuronal plasticity. Altogether, these properties of melatonin have allowed us to demonstrate in both experimental models and clinical studies the great chronobiotic efficacy and sleep promoting effects of exogenous melatonin. Thus, the prolonged release formulation of melatonin, present as a drug in the pharmaceutical market, has been recently recommended for the treatment of insomnia in over 55 years old subjects.

Post-weaning social isolation (SI) is a model of prolonged mild stress characterized by behavioral and neurochemical alterations. We used SI in C57BL/6J mice to investigate the effects of ethanol (EtOH) in the free-choice drinking paradigm on gene expression and function of γ-aminobutyric acid type A receptors (GABA_ARs) and the role of neuroactive steroids in the actions of EtOH in the hippocampus. SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA_AR. The gene expression of the α₄ and δ subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the γ₂ subunit was decreased whereas that of the α₁ did not change. Patch-clamp recordings in dentate gyrus (DG) granule cells obtained from SI C57BL/6J mice revealed a greater enhancement of tonic currents induced by α-(4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) compared to that in control C57BL/6J mice. These neurochemical, molecular and functional changes observed in SI C57BL/6J mice were associated with an increased EtOH intake and EtOH preference. Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the α₄ subunit but not those of the δ and γ₂ subunits induced by SI. In addition, EtOH self-administration did not block the SI-induced changes in GABA_AR-mediated tonic inhibition in hippocampal granule cells but increased the frequency of basal GABAergic sIPSCs in DG granule cells. We conclude that self-administration of EtOH selectively abolishes the increase of α₄ subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

Alcohol abuse leads to aberrant forms of emotionally salient memory, i.e., limbic memory, that promote escalated alcohol consumption and relapse. Accordingly, activity-dependent structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing chronic alcohol consumption. Here we show that alcohol-dependent male rats fail to perform an emotional-learning task during abstinence but recover their functioning byl-3,4-dihydroxyphenylalanin (l-DOPA) administration during early withdrawal.l-DOPA also reverses the selective loss of dendritic “long thin” spines observed in medium spiny neurons of the nucleus accumbens (NAc) shell of alcohol-dependent rats during abstinence, as well as the reduction in tyrosine hydroxylase immunostaining and postsynaptic density-95-positive elements. Patch-clamp experiments in NAc slices reveal that bothin vivosystemicl-DOPA administration andin vitroexposure to dopamine can restore the loss of long-term depression (LTD) formation, counteract the reduction in NMDAR-mediated synaptic currents and rectify the altered NMDAR/AMPAR ratio observed in alcohol-withdrawn rats. Further,in vivomicrodialysis experiments show that blunted dopaminergic signaling is revived afterl-DOPA treatment during early withdrawal. These results suggest a key role of an efficient dopamine signaling for maintaining, and restore, neural trophism, NMDA-dependent LTD, and ultimately optimal learning.SIGNIFICANCE STATEMENTBlunted dopamine signaling and altered glutamate connectivity in the nucleus accumbens represent the neuroanatomical basis for the impairment in aversive limbic memory observed during withdrawal in alcohol dependence. Supplyingl-DOPA during withdrawal re-establishes synaptic morphology and functional neuroadaptations, suggesting a complete recovery of nucleus accumbens glutamatergic synaptic plasticity when dopamine is revived. Importantly, restoring dopamine transmission allows those synapses to encode emotionally relevant information and rescue flexibility in the neuronal circuits that process limbic memory formation. Under these conditions, drugs capable of selectively boosting the dopaminergic function during the “fluid” and still responsive state of the early withdrawn maladaptive synapses may help in the treatment of alcohol addiction.

Loss-of-function mutations in the KCNA1 (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by KCNA1 mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation–induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a knock-in mouse model of EA1 and restored the neuromuscular transmission and climbing ability in Shaker (Kv1.1) mutant Drosophila melanogaster flies ( Sh ⁵ ). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.

The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague–Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions.