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Social and emotional experiences differently shape individual’s neurodevelopment inducing substantial changes in neurobiological substrates and behavior, particularly when they occur early in life. In this scenario, the present study was aimed at (i) investigating the impact of early social environments on emotional reactivity of adolescent male and female rats and (ii) uncovering the underlying molecular features, focusing on the cortical endocannabinoid (eCB) and glucocorticoid systems. To this aim, we applied a protocol of environmental manipulation based on early postnatal socially enriched or impoverished conditions. Social enrichment was realized through communal nesting (CN). Conversely, an early social isolation (ESI) protocol was applied (post-natal days 14–21) to mimic an adverse early social environment. The two forms of social manipulation resulted in specific behavioral and molecular outcomes in both male and female rat offspring. Despite the combination of CN and ESI did not affect emotional reactivity in both sexes, the molecular results reveal that the preventive exposure to CN differently altered mRNA and protein expression of the main components of the glucocorticoid and eCB systems in male and female rats. In particular, adolescent females exposed to the combination of CN and ESI showed increased corticosterone levels, unaltered genomic glucocorticoid receptor, reduced cannabinoid receptor type-1 and fatty acid amide hydrolase protein levels, suggesting that the CN condition evokes different reorganization of these systems in males and females. [ABSTRACT FROM AUTHOR]

Background and Purpose: Psychotic disorders have been reported in long‐term users of synthetic cannabinoids. This study aims at investigating the long‐lasting effects of repeated JWH‐018 exposure. Experimental Approach: Male CD‐1 mice were injected with vehicle, JWH‐018 (6 mg·kg−1), the CB1‐antagonist NESS‐0327 (1 mg·kg−1) or co‐administration of NESS‐0327 and JWH‐018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH‐018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) and their main synthetic and degrading enzymes in the striatum and hippocampus. Key Results: The repeated treatment with JWH‐018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH‐018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH‐018, reduced hippocampal CB1 receptor density and induced a long‐term alteration in AEA and 2‐AG levels and their degrading enzymes, FAAH and MAGL, in the striatum. Conclusion and Implications: Our findings suggest that repeated administration of a high dose of JWH‐018 leads to the manifestation of psychotic‐like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system. [ABSTRACT FROM AUTHOR]

Drug addiction is a devastating disorder with a huge economic and social burden for modern society. Although an individual may slip into drug abuse throughout his/her life, adolescents are at higher risk, but, so far, only a few studies have attempted to elucidate the underlying cellular and molecular bases of such vulnerability. Indeed, preclinical evidence indicates that psychostimulants and adolescence interact and contribute to promoting a dysfunctional brain. In this review, we have focused our attention primarily on changes in neuroplasticity brought about by cocaine, taking into account that there is much less evidence from exposure to cocaine in adolescence, compared with that from adults. This review clearly shows that exposure to cocaine during adolescence, acute or chronic, as well as contingent or non‐contingent, confers a vulnerable endophenotype, primarily, by causing changes in neuroplasticity. Given the close relationship between drug abuse and psychiatric disorders, we also discuss the translational implications providing an interpretative framework for clinical studies involving addictive as well as affective or psychotic behaviours. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc [ABSTRACT FROM AUTHOR]

Background and Purpose: It is well established that the nucleus accumbens and glutamate play a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin (5‐HT) transporter (SERT−/− rats) show increased cocaine intake reminiscent of compulsivity. Experimental Approach By comparing SERT−/− to SERT+/+ rats, we set out to explore whether SERT deletion influences glutamate neurotransmission under control conditions as well as after short access (1 h/session) or long access (6 h/session) to cocaine self‐administration. Key Results: Rats were killed at 24 h after the final self‐administration session for ex vivo molecular analyses of the glutamate system (vesicular and glial transporters, post‐synaptic subunits of NMDA and AMPA receptors and their related scaffolding proteins). Such analyses were undertaken in the nucleus accumbens core. In cocaine‐naïve animals, SERT deletion evoked widespread abnormalities in markers of glutamatergic neurotransmission that, overall, indicate a reduction of glutamate signalling. These results suggest that 5‐HT is pivotal for the maintenance of accumbal glutamate homeostasis. We also found that SERT deletion altered glutamate homeostasis mainly after long access, but not short access, to cocaine. Conclusion and Implications: Our findings reveal that SERT deletion may sensitize the glutamatergic synapses of the nucleus accumbens core to the long access but not short access, intake of cocaine. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc [ABSTRACT FROM AUTHOR]

Vulnerability to drug addiction relies on substantial individual differences. We previously demonstrated that serotonin transporter knockout (SERT-/- ) rats show increased cocaine intake and develop signs of compulsivity. However, the underlying neural mechanisms are not fully understood. Given the pivotal role of glutamate and prefrontal cortex in cocaine-seeking behavior, we sought to investigate the expression of proteins implicated in glutamate neurotransmission in the prefrontal cortex of naïve and cocaine-exposed rats lacking SERT. We focused on the infralimbic (ILc) and prelimbic (PLc) cortices, which are theorized to exert opposing effects on the control over subcortical brain areas. SERT-/- rats, which compared to wild-type (SERT+/+ ) rats show increased ShA and LgA intake short-access (ShA) and long-access (LgA) cocaine intake, were sacrificed 24 h into withdrawal for ex vivo molecular analyses. In the ILc homogenate of SERT-/- rats, we observed a sharp increase in glial glutamate transporter 1 (GLT-1) after ShA, but not LgA, cocaine intake. This was paralleled by ShA-induced increases in GluN1, GluN2A, and GluN2B NMDA receptor subunits and their scaffolding protein SAP102 in the ILc homogenate, but not postsynaptic density, of these knockout animals. In the PLc, we found no major changes in the homogenate; conversely, the expression of GluN1 and GluN2A NMDA receptor subunits was increased in the postsynaptic density under ShA conditions and reduced under LgA conditions. These results point to SERT as a critical regulator of glutamate homeostasis in a way that differs between the subregions investigated, the duration of cocaine exposure as well as the cellular compartment analyzed. [ABSTRACT FROM AUTHOR]

Objectives: Long-term abstinence following cocaine exposure up-regulates brain-derived neurotrophic factor (BDNF) expression in the mesocorticolimbic pathway. Given the increased vulnerability to drug abuse typical of adolescence, we hypothesized that changes in BDNF expression may become manifest early after the end of cocaine treatment in the adolescent brain. Methods: Rats received cocaine injections from postnatal day 28 (PND28) to PND42 and the mesocorticolimbic expression of BDNF was measured by real-time PCR and Western blotting at PND43. Results: In the ventral tegmental area, BDNF-tropomyosin receptor kinase B (TrΚB) expression and phosphorylation are enhanced while the intracellular signaling is unaltered. In the nucleus accumbens (NAc) shell and core, BDNF and its signaling were down-regulated. In the prelimbic (PL) cortex, we found reduced BDNF expression and increased phosphoprylation of TrΚB, ERK and AKT. In the infralimbic (IL) cortex, increased BDNF expression was coupled with reduced activity and expression of its downstream targets. To evaluate the role of glutamate on BDNF-independent changes, we investigated the expression of the transporter GLT-1 and the activation of the NMDA receptor subunit GluN2B, which were both increased in the PL cortex while reduced in the IL cortex. Conclusions: Our results show that adolescent cocaine exposure modulates BDNF system early after treatment in the mesocorticolimbic pathway, identifying a complex but specific set of changes that could provide clues for treatment. [ABSTRACT FROM AUTHOR]

Ketamine is a non-competitive antagonist of the NMDA glutamate receptor with psychotomimetic and reinforcing properties, although recent work has pointed out its antidepressant action following acute exposure. Our aim was to investigate the expression of crucial components of the glutamate synapse following chronic ketamine self-administration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders. Rats self-administered ketamine at a sub-anesthetic dose for 5-6 weeks and were sacrificed 24 h after the last drug exposure. We found a general downregulation of glutamate receptor expression that was brain region-dependent. In fact, in the mPFC, we found reduced expression of NMDA receptor subunits, whereas AMPA receptor protein levels were reduced in Hip; of note, specific scaffolding proteins of NMDA and AMPA receptors were also reduced in mPFC and Hip, respectively. Moreover, the metabotropic mGluR5 receptor was similarly downregulated in these brain regions. These findings reveal a dynamic impairment of glutamate homeostasis in the mPFC and Hip that may represent a signature of long-term exposure to ketamine S/A. Further, this decrement, similarly observed in humans and animal models of schizophrenia may represent a specific feature of the human disease endophenotype. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying the action of lithium (LiCl) in bipolar disorder (BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities., Objective: In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure., Results: We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca 2+ -permeable AMPA receptors., Conclusion: Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)