Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics.

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

Opioid Activity in the Locus Coeruleus Is Modulated by Chronic Neuropathic Pain.

Pain affects both sensory and emotional aversive responses, often provoking depression and anxiety-related conditions when it becomes chronic. As the opioid receptors in the locus coeruleus (LC) have been implicated in pain, stress responses, and opioid drug effects, we explored the modifications to LC opioid neurotransmission in a chronic constriction injury (CCI) model of short- and long-term neuropathic pain (7 and 30 days after nerve injury). No significant changes were found after short-term CCI, yet after 30 days, CCI provoked an up-regulation of cAMP (cyclic 5'-adenosine monophosphate), pCREB (phosphorylated cAMP response element binding protein), protein kinase A, tyrosine hydroxylase, and electrical activity in the LC, as well as enhanced c-Fos expression. Acute mu opioid receptor desensitization was more intense in these animals, measured as the decline of the peak current caused by [Met5]-enkephalin and the reduction of forskolin-stimulated cAMP produced in response to DAMGO. Sustained morphine treatment did not markedly modify certain LC parameters in CCI-30d animals, such as [Met5]-enkephalin-induced potassium outward currents or burst activity and c-Fos rebound after naloxone precipitation, which may limit the development of some typical opioid drug-related adaptations. However, other phenomena were impaired by long-term CCI, including the reduction in forskolin-stimulated cAMP accumulation by DAMGO after naloxone precipitation in morphine dependent animals. Overall, this study suggests that long-term CCI leads to changes at the LC level that may contribute to the anxiodepressive phenotype that develops in these animals. Furthermore, opioid drugs produce complex adaptations in the LC in this model of chronic neuropathic pain.

Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation.

Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT1AR activation might predispose to a high anxious phenotype and an impaired stress coping behavior.