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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 by L-3,4-dihydroxyphenylalanin (i.-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. Patchdamp experiments in NAc slices reveal that both in vivo systemic l-DOPA administration and in vitro exposure 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the reduction in NMDAR-mediated synaptic currents and rectify the altered NMDAR/AMPAR ratio observed in alcohol-withdrawn rats.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 vivo microdialysis experiments show that blunted dopaminergic signaling is revived after l-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. [ABSTRACT FROM AUTHOR]

PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction. [ABSTRACT FROM AUTHOR]

The aim of this research was to study the role of dopamine D1 receptors in caffeine elicited ERK phosphorylation in the prefrontal and other cortical (cingulate and motor) and subcortical (shell and core of the nucleus accumbens) regions. To this end, caffeine (3 and 10 mg/kg) was administered before phosphoERK immunohistochemistry. Caffeine dose-dependently increased the number of phosphoERK-positive neurons in the prefrontal and cingulate cortices but not in the secondary motor cortex and in the nucleus accumbens shell and core. The dopamine D1 receptor antagonist, SCH 39166 (50 μg/kg), fully prevented phosphoERK activation by caffeine (10 mg/kg) in the superficial and deep layers of the prefrontal cortex but failed to prevent it in the cingulate cortex. Given that phosphoERK can be regarded as a postsynaptic marker of neuronal activation, the present results indicate that psychotropic properties of caffeine may result from the activation of prefrontal, via dopamine D1 receptors, and cingulate cortices. Failure of caffeine to activate ERK in the nucleus accumbens further supports, indirectly, the observation that caffeine fails to activate dopamine transmission in this structure and is consistent with the tenet that caffeine lacks of true addictive properties. Synapse 64:341-349, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Exercise and antioxidants have health benefits that improve cognitive impairment and may act synergistically. In this study, we examined the effects of treadmill exercise (TE) and mitochondria-targeted antioxidant mitoquinone (MitoQ), individually or combined, on learning and memory, mitochondrial dynamics, NADPH oxidase activity, and neuroinflammation and antioxidant activity in the hippocampus of D-galactose-induced aging rats. TE alone and TE combined with MitoQ in aging rats reduced mitochondrial fission factors (Drp1, Fis1) and increased mitochondrial fusion factors (Mfn1, Mfn2, Opa1). These groups also exhibited improved NADPH oxidase activity and antioxidant activity (SOD-2, catalase). TE or MitoQ alone decreased neuroinflammatory response (COX-2, TNF-α), but the suppression was greater with their combination. In addition, aging-increased neuroinflammation in the dentate gyrus was decreased in TE but not MitoQ treatment. Learning and memory tests showed that, contrarily, MitoQ alone demonstrated some similar effects to TE but not a definitive improvement. In conclusion, this study demonstrated that MitoQ exerted some positive effects on aging when used as an isolated treatment, but TE had a more effective role on cognitive impairment, oxidative stress, inflammation, and mitochondria dysfunction. Our findings suggest that the combination of TE and MitoQ exerted no synergistic effects and indicated regular exercise should be the first priority in neuroprotection of age-related cognitive decline. [ABSTRACT FROM AUTHOR]

In the last decade, the trend of drug consumption has completely changed, and several new psychoactive substances (NPS) have appeared on the drug market as legal alternatives to common drugs of abuse. Designed to reproduce the effects of illegal substances like cannabis, ecstasy, cocaine, or ketamine, NPS are only in part controlled by UN conventions and represent an emerging threat to global public health. The effects of NPS greatly differ from drug to drug and relatively scarce information is available at present about their pharmacology and potential toxic effects. Yet, compared to more traditional drugs, more dangerous short- and long-term effects have been associated with their use, and hospitalizations and fatal intoxications have also been reported after NPS use. In the era of cyberculture, the Internet acts as an ideal platform to promote and market these compounds, leading to a global phenomenon. Hidden by several aliases, these substances are sold across the web, and information about consumption is shared by online communities through drug fora, YouTube channels, social networks, and smartphone applications (apps). This review intends to provide an overview and analysis of social media that contribute to the popularity of NPS especially among young people. The possibility of using the same channels responsible for their growing diffusion to make users aware of the risks associated with NPS use is proposed. [ABSTRACT FROM AUTHOR]

Methoxetamine (MXE) is a dissociative substance of the arylcyclohexylamine class that has been present on the designer drug market as a ketamine-substitute since 2010. We have previously shown that MXE (i) possesses ketamine-like discriminative and positive rewarding effects in rats, (ii) affects brain processing involved in cognition and emotional responses, (iii) causes long-lasting behavioral abnormalities and neurotoxicity in rats and (iv) induces neurological, sensorimotor and cardiorespiratory alterations in mice. To shed light on the mechanisms through which MXE exerts its effects, we conducted a multidisciplinary study to evaluate the various neurotransmitter systems presumably involved in its actions on the brain. In vivo microdialysis study first showed that a single administration of MXE (0.25 and 0.5 mg/kg, i.v.) is able to significantly alter serotonin levels in the rat medial prefrontal cortex (mPFC) and nucleus accumbens. Then, we observed that blockade of the serotonin 5-HT 2 receptors through two selective antagonists, ketanserin (0.1 mg/kg, i.p.) and MDL 100907 (0.03 mg/kg, i.p.), at doses not affecting animals behavior per se, attenuated the facilitatory motor effect and the inhibition on visual sensory responses induced by MXE (3 mg/kg, i.p.) and ketamine (3 mg/kg, i.p.), and prevented MXE-induced reduction of the prepulse inhibition in rats, pointing to the 5-HT 2 receptors as a key target for the recently described MXE-induced sensorimotor effects. Finally, in-vitro electrophysiological studies revealed that the GABAergic and glutamatergic systems are also likely involved in the mechanisms through which MXE exerts its central effects since MXE inhibits, in a concentration-dependent manner, NMDA-mediated field postsynaptic potentials and GABA-mediated spontaneous currents. Conversely, MXE failed to alter both the AMPA component of field potentials and presynaptic glutamate release, and seems not to interfere with the endocannabinoid-mediated effects on mPFC GABAergic synapses. Altogether, our results support the notion of MXE as a NMDA receptor antagonist and shed further lights into the central mechanisms of action of this ketamine-substitute by pointing to serotonin 5-HT 2 receptors as crucial players in the expression of its sensorimotor altering effects and to the NMDA and GABA receptors as potential further important targets of action., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Preclinical and clinical studies indicate that synthetic psychoactive substances, in addition to having abuse potential, may elicit toxic effects of varying severity at the peripheral and central levels. Nowadays, toxicity induced by synthetic psychoactive substances poses a serious harm for health, since recreational use of these substances is on the rise among young and adult people. The present review summarizes recent findings on the peripheral and central toxicity elicited by "old" and "new" synthetic psychoactive substances in humans and experimental animals, focusing on amphetamine derivatives, hallucinogen and dissociative drugs and synthetic cannabinoids., Competing Interests: None

The aim of this research was to study the role of dopamine D(1) receptors in caffeine elicited ERK phosphorylation in the prefrontal and other cortical (cingulate and motor) and subcortical (shell and core of the nucleus accumbens) regions. To this end, caffeine (3 and 10 mg/kg) was administered before phosphoERK immunohistochemistry. Caffeine dose-dependently increased the number of phosphoERK-positive neurons in the prefrontal and cingulate cortices but not in the secondary motor cortex and in the nucleus accumbens shell and core. The dopamine D(1) receptor antagonist, SCH 39166 (50 microg/kg), fully prevented phosphoERK activation by caffeine (10 mg/kg) in the superficial and deep layers of the prefrontal cortex but failed to prevent it in the cingulate cortex. Given that phosphoERK can be regarded as a postsynaptic marker of neuronal activation, the present results indicate that psychotropic properties of caffeine may result from the activation of prefrontal, via dopamine D(1) receptors, and cingulate cortices. Failure of caffeine to activate ERK in the nucleus accumbens further supports, indirectly, the observation that caffeine fails to activate dopamine transmission in this structure and is consistent with the tenet that caffeine lacks of true addictive properties.