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In the last decades, the consumption of energy drinks has risen dramatically, especially among young people, adolescents and athletes, driven by the constant search for ergogenic effects, such as the increase in physical and cognitive performance. In parallel, mixed consumption of energy drinks and ethanol, under a binge drinking modality, under a binge drinking modality, has similarly grown among adolescents. However, little is known whether the combined consumption of these drinks, during adolescence, may have long-term effects on central function, raising the question of the risks of this habit on brain maturation. Our study was designed to evaluate, by behavioral, electrophysiological and molecular approaches, the long-term effects on hippocampal plasticity of ethanol (EtOH), energy drinks (EDs), or alcohol mixed with energy drinks (AMED) in a rat model of binge-like drinking adolescent administration. The results show that AMED binge-like administration produces adaptive hippocampal changes at the molecular level, associated with electrophysiological and behavioral alterations, which develop during the adolescence and are still detectable in adult animals. Overall, the study indicates that binge-like drinking AMED adolescent exposure represents a habit that may affect permanently hippocampal plasticity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sexual activity causes differential changes in the expression of markers of neural activation (c-Fos and ΔFosB) and neural plasticity (Arc and BDNF/trkB), as determined either by Western Blot (BDNF, trkB, Arc, and ΔFosB) or immunohistochemistry (BDNF, trkB, Arc, and c-Fos), in the hippocampus of male Roman high (RHA) and low avoidance (RLA) rats, two psychogenetically selected rat lines that display marked differences in sexual behavior (RHA rats exhibit higher sexual motivation and better copulatory performance than RLA rats). Both methods showed (with some differences) that sexual activity modifies the expression levels of these markers in the hippocampus of Roman rats depending on: (i) the level of sexual experience, that is, changes were usually more evident in sexually naïve than in experienced rats; (ii) the hippocampal partition, that is, BDNF and Arc increased in the dorsal but tended to decrease in the ventral hippocampus; (iii) the marker considered, that is, in sexually experienced animals BDNF, c-Fos, and Arc levels were similar to those of controls, while ΔFosB levels increased; and (iv) the rat line, that is, changes were usually larger in RHA than RLA rats. These findings resemble those of early studies in RHA and RLA rats showing that sexual activity influences the expression of these markers in the nucleus accumbens, medial prefrontal cortex, and ventral tegmental area, and show for the first time that also in the hippocampus sexual activity induces neural activation and plasticity, events that occur mainly during the first phase of the acquisition of sexual experience and depend on the genotypic/phenotypic characteristics of the animals., (© 2022 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Oxytocin (100 ng) injected unilaterally into the ventral subiculum of the hippocampus induces penile erection episodes, which started 30 min after treatment and were abolished by the prior injection of d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (2 μg), an oxytocin receptor antagonist, into the ventral subiculum. Oxytocin-induced penile erection occurred 15 min after the increase of the concentration of extracellular dopamine in the dialysate obtained from either the nucleus accumbens or the prelimbic medial prefrontal cortex, which was also abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin. An increase in extracellular glutamic acid concentration was also observed in the same dialysate obtained from the ventral tegmental area, but not from the prelimbic medial prefrontal cortex or the nucleus accumbens in which dopamine concentration was measured, 15 min after the injection of oxytocin into the ventral subiculum. This effect was also abolished by the prior injection of d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin into the ventral subiculum. These results confirm previous findings showing that ventral subiculum oxytocin-induced penile erection is mediated by an increase of glutamic acid neurotransmission in the ventral tegmental area. This in turn increases mesolimbic and mesocortical dopaminergic activity, releasing dopamine in the nucleus accumbens and in the prelimbic medial prefrontal cortex. These results are in line with previous studies supporting the hypothesis that the ventral subiculum participates in a complex neural circuit controlling not only penile erection and copulation, but also sexual motivation, arousal and rewarding., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Oxytocin (100 ng) induces penile erection when injected unilaterally into the ventral subiculum of the hippocampus of male rats. The pro-erectile effect started mostly 30 min after treatment and occurred 15 min after an increase in both nitric oxide (NO) production, measured by the concentration of NO(2)(-) and NO(3)(-), the main metabolites of newly formed NO, and extra-cellular glutamic acid concentration in the dialysate obtained from the ventral subiculum by intracerebral microdialysis. These responses were abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (2 microg), an oxytocin receptor antagonist, S-methyl-L-thiocitrulline (SMTC), a selective inhibitor of neuronal NO-synthase (25 microg), and haemoglobin, a NO scavenger (25 microg), given into the ventral subiculum before oxytocin. Unlike d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin, SMTC and haemoglobin, (+)MK-801 (5 microg), a noncompetitive antagonist of NMDA receptors abolished oxytocin-induced penile erection, but reduced only partially the increase in NO production and extra-cellular glutamic acid. As NMDA (0.25-1 microg) injected into the ventral subiculum induces penile erection episodes, which also occurred with an increase of NO production and extra-cellular glutamic acid, and NMDA responses were abolished by (+)MK-801 (5 microg), but not by SMTC (25 microg) or haemoglobin (25 microg), injected into the ventral subiculum, these results show that oxytocin injected into the ventral subiculum increases NO production by activating its own receptors. NO in turn increases glutamic acid neurotransmission, leading to penile erection, possibly through neural (glutamatergic) efferent projections from the ventral subiculum to extra-hippocampal brain areas (e.g., prefrontal cortex) modulating the activity of mesolimbic dopaminergic neurons., ((c) 2010 Elsevier Ltd. All rights reserved.)

Oxytocin (20-100 ng) was found to be able to induce penile erection when injected unilaterally into the ventral subiculum or the posteromedial cortical nucleus of the amygdala of male rats. The pro-erectile effect started mostly 30 min after treatment and was abolished by the prior injection of d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin (1-2 microg), an oxytocin receptor antagonist, into the ventral subiculum or posteromedial cortical nucleus. Oxytocin-induced penile erection occurred 15 min after the increase in the concentration of extracellular dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the dialysate obtained from the nucleus accumbens, which was also abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin. The pro-erectile effect of oxytocin was also reduced by cis-flupentixol (2 and 5 microg), a dopamine receptor antagonist, injected into the nucleus accumbens, and by (+)MK-801 (5 microg), a noncompetitive N-methyl-d-aspartate receptor antagonist, injected into the ventral tegmental area, but not into the nucleus accumbens. Together with studies showing that glutamatergic efferents from the ventral subiculum/posteromedial cortical nucleus of the amygdala to other areas of the limbic system modulate the activity of mesolimbic dopaminergic neurons, these findings suggest that oxytocin injected into these areas increases glutamatergic neurotransmission in the ventral tegmental area. This, in turn, activates mesolimbic dopaminergic neurons, leading to penile erection. These results provide evidence that the ventral subiculum and the posteromedial cortical nucleus of the amygdala participate in a neural circuit that controls not only the consummatory aspects of sexual behaviour (e.g. penile erection and copulatory performance), but also its motivational/reward aspects, confirming a key role of oxytocin and dopamine in these processes.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson's and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders. [ABSTRACT FROM AUTHOR]

Abstract: Oxytocin (80ng) induces yawning when injected into the caudal part of the ventral tegmental area, the hippocampal ventral subiculum and the posteromedial nucleus of the amygdala of male rats. The behavioural response occurred concomitantly with an increase in the concentration of extracellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate obtained from the shell of the nucleus accumbens and of the prelimbic medial prefrontal cortex by means of intracerebral microdialysis. Both oxytocin responses were significantly reduced by d(CH2)5Tyr(Me)2-Orn8-vasotocin, a selective oxytocin receptor antagonist, injected in the above brain areas 15min before oxytocin. Similar results were obtained by activating central oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to the ventral tegmental area, the hippocampus and the amygdala, with the dopamine agonist apomorphine given at a dose that induces yawning when injected into the paraventricular nucleus. Since oxytocin is considered a key regulator of emotional and social reward that enhances amygdala-dependent, socially reinforced learning and emotional empathy, mesolimbic and mesocortical dopamine neurons play a key role in motivation and reward, and yawning in mammals is considered a primitive, unconscious form of empathy, the present results support the hypothesis that oxytocinergic neurons originating in the paraventricular nucleus of the hypothalamus and projecting to the above brain areas and mesolimbic and mesocortical dopaminergic neurons participate in the complex neural circuits that play a role in the above mentioned functions. [Copyright &y& Elsevier]

The Roman High-Avoidance (RHA) and the Roman Low-Avoidance (RLA) rats, represent two psychogenetically-selected lines that are, respectively, resistant and prone to displaying depression-like behavior, induced by stressors. In the view of the key role played by the neurotrophic factors and neuronal plasticity, in the pathophysiology of depression, we aimed at assessing the effects of acute stress, i.e., forced swimming (FS), on the expression of brain-derived neurotrophic factor (BDNF), its trkB receptor, and the Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), in the dorsal (dHC) and ventral (vHC) hippocampus of the RHA and the RLA rats, by means of western blot and immunohistochemical assays. A 15 min session of FS elicited different changes in the expression of BDNF in the dHC and the vHC. In RLA rats, an increment in the CA2 and CA3 subfields of the dHC, and a decrease in the CA1 and CA3 subfields and the dentate gyrus (DG) of the vHC, was observed. On the other hand, in the RHA rats, no significant changes in the BDNF levels was seen in the dHC and there was a decrease in the CA1, CA3, and DG of the vHC. Line-related changes were also observed in the expression of trkB and PSA-NCAM. The results are consistent with the hypothesis that the differences in the BDNF/trkB signaling and neuroplastic mechanisms are involved in the susceptibility of RLA rats and resistance of RHA rats to stress-induced depression. [ABSTRACT FROM AUTHOR]