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.

Alzheimer's disease (AD) is a chronic, neurodegenerative and devastating disorder affecting a high percentage of the population over 65 years of age and causing a relevant emotional, social and economic burden. Clinically, it is characterized by a prominent cognitive deficit associated with language and behavioral impairments. The molecular pathogenesis of AD is multifaceted and involves changes in neurotransmitter levels together with alterations of inflammatory, oxidative, hormonal and synaptic pathways, which may represent a druggable target for both prevention and treatment; however, an effective treatment for AD still represents an unmet goal.Since neurotrophic factors participate in the modulation of the above-mentioned pathways, they have been pointed out as critical contributors of AD etiology, whose modulation might be beneficial for AD. We here focused on the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) providing several lines of evidence pointing to BDNF as a plausible endophenotype of cognitive deficit in AD, illustrating some among the most recent possibilities to modulate the expression of this neurotrophin in the brain in an attempt to ameliorate cognition and delay the progression of AD.This review shows that otherwise disparate pharmacologic or non-pharmacologic approaches converge on BDNF providing a means whereby apparently unrelated medical approaches may nevertheless produce similar synaptic and cognitive outcomes in AD pathogenesis through its modulation, suggesting that BDNF-based synaptic repair may represent a modifying strategy to ameliorate cognition in AD. Key points:1) The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) represents a plausible endophenotype of cognitive deficit in Alzheimer's disease (AD) and a mechanistic underpinning to be targeted to offset the cognitive decline of AD.2) Otherwise disparate pharmacologic or non-pharmacologic approaches converge on BDNF, influencing synaptic plasticity and ameliorating the cognitive deficit 3) BDNF-based synaptic repair may represent an interesting modifying strategy to improve cognition in AD patients.

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Modulation of αCaMKII expression and phosphorylation is a feature shared by drugs of abuse with different mechanisms of action. Accordingly, we investigated whether αCaMKII expression and activation could be altered by self-administration of ketamine, a non-competitive antagonist of the NMDA glutamate receptor, with antidepressant and psychotomimetic as well as reinforcing properties. Rats self-administered ketamine at a sub-anesthetic dose for 43 days and were sacrificed 24 h after the last drug exposure; reward-related brain regions, such as medial prefrontal cortex (PFC), ventral striatum (vS), and hippocampus (Hip), were used for the measurement of αCaMKII-mediated signaling. αCaMKII phosphorylation was increased in these brain regions suggesting that ketamine, similarly to other reinforcers, activates this kinase. We next measured the two main targets of αCaMKII, i.e., GluN2B (S1303) and GluA1 (S831), and found increased activation of GluN2B (S1303) together with reduced phosphorylation of GluA1 (S831). Since GluN2B, via inhibition of ERK, regulates the membrane expression of GluA1, we measured ERK2 phosphorylation in the crude synaptosomal fraction of these brain regions, which was significantly reduced suggesting that ketamine-induced phosphorylation of αCaMKII promotes GluN2B (S1303) phosphorylation that, in turn, inhibits ERK 2 signaling, an effect that results in reduced membrane expression and phosphorylation of GluA1. Taken together, our findings point to αCaMKII autophosphorylation as a critical signature of ketamine self-administration providing an intracellular mechanism to explain the different effects caused by αCaMKII autophosphorylation on the post-synaptic GluN2B- and GluA1-mediated functions. These data add ketamine to the list of drugs of abuse converging on αCaMKII to sustain their addictive properties.

Ketamine and MK-801 by blocking NMDA receptors may induce reinforcing effects as well as schizophrenia-like symptoms. Recent results showed that ketamine can also effectively reverse depressive signs in patients’ refractory to standard therapies. This evidence clearly points to the need of characterization of effects of these NMDARs antagonists on relevant brain areas for mood disorders. The aim of the present study was to investigate the molecular changes occurring at glutamatergic synapses 24 h after ketamine or MK-801 treatment in the rat medial prefrontal cortex (mPFC) and hippocampus (Hipp). In particular, we analyzed the levels of the glutamate transporter-1 (GLT-1), NMDA receptors, AMPA receptors subunits, and related scaffolding proteins. In the homogenate, we found a general decrease of protein levels, whereas their changes in the post-synaptic density were more complex. In fact, ketamine in the mPFC decreased the level of GLT-1 and increased the level of GluN2B, GluA1, GluA2, and scaffolding proteins, likely indicating a pattern of enhanced excitability. On the other hand, MK-801 only induced sparse changes with apparently no correlation to functional modification. Differently from mPFC, in Hipp, both substances reduced or caused no changes of glutamate receptors and scaffolding proteins expression. Ketamine decreased NMDA receptors while increased AMPA receptors subunit ratios, an effect indicative of permissive metaplastic modulation; conversely, MK-801 only decreased the latter, possibly representing a blockade of further synaptic plasticity. Taken together, these findings indicate a fine tuning of glutamatergic synapses by ketamine compared to MK-801 both in the mPFC and Hipp.

During adolescence, the medial prefrontal cortex (mPFC) is still developing. We have previously shown that developmental cocaine exposure alters mPFC's ability to cope with challenging events. In this manuscript, we exposed rats developmentally treated with cocaine to a novelty task and analyzed the molecular changes of mPFC. Rats were exposed to cocaine from post-natal day (PND) 28 to PND 42 and sacrificed at PND 43, immediately after the novel object recognition (NOR) test. Cocaine-treated rats spent more time exploring the novel object than saline-treated counterparts, suggesting an increased response to novelty. The messenger RNA (mRNA) and protein levels of the immediate early gene Arc/Arg3.1 were reduced in both infralimbic (IL) and prelimbic (PL) cortices highlighting a baseline reduction of mPFC neuronal activity as a consequence of developmental exposure to cocaine. Intriguingly, significant molecular changes were observed in the IL, but not PL, cortex in response to the combination of cocaine exposure and test such as a marked upregulation of both Arc/Arg3.1 mRNA and protein levels only in cocaine-treated rats. As for proteins, such increase was observed only in the post-synaptic density and not in the whole homogenate, suggesting psychostimulant-induced changes in trafficking of Arc/Arg3.1 or an increased local translation. Notably, the same profile of Arc/Arg3.1 was observed for post-synaptic density (PSD)-95 leading to the possibility that Arc/Arg3.1 and PSD-95 bridge together to promote aberrant synaptic connectivity in IL cortex following repeated exposure to cocaine during brain development.

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.

Background and Purpose Amphetamine (AMPH) use disorder is a serious health concern, but, surprisingly, little is known about the vulnerability to the moderate and compulsive use of this psychostimulant and its underlying mechanisms. Previous research showed that inherited serotonin transporter (SERT) down‐regulation increases the motor response to cocaine, as well as moderate (as measured during daily 1‐h self‐administration sessions) and compulsive (as measured during daily 6‐h self‐administration sessions) intake of this psychostimulant. Here, we sought to investigate whether these findings generalize to AMPH and the underlying mechanisms in the nucleus accumbens. Experimental Approach In serotonin transporter knockout (SERT−/−) and wild‐type control (SERT+/+) rats, we assessed the locomotor response to acute AMPH and i.v. AMPH self‐administration under short access (ShA: 1‐h daily sessions) and long access (LgA: 6‐h daily sessions) conditions. Twenty‐four hours after AMPH self‐administration, we analysed the expression of glutamate system components in the nucleus accumbens shell and core. Key Results We found that SERT−/− animals displayed an increased AMPH‐induced locomotor response and increased AMPH self‐administration under LgA but not ShA conditions. Further, we observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits, and their respective postsynaptic scaffolding proteins as function of SERT genotype and AMPH exposure (baseline, ShA, and LgA), specifically in the nucleus accumbens shell. Conclusion and Implications We demonstrate that SERT gene deletion increases the psychomotor and reinforcing effects of AMPH and that the latter is potentially mediated, at least in part, by homeostatic changes in the glutamatergic synapse of the nucleus accumbens shell and/or core.