Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

Treatment for illegal drug use disorders: the role of comorbid mood and anxiety disorders.

International audienceBACKGROUND: Our aim was to examine whether comorbid mood and anxiety disorders influence patterns of treatment or the perceived unmet need for treatment among those not receiving treatment for illegal drug use disorders. METHODS: Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, 2001-2002 and 2004-2005, n = 34,653). Lifetime DSM-IV illegal drug use disorder (abuse and dependence), as well as comorbid mood (major depression, dysthymia, manic disorder, hypomanic disorder) and anxiety disorders (panic disorder, agoraphobia, social phobia, specific phobia, generalized anxiety) were ascertained by a standardized psychiatric interview. Treatment for illegal drug use disorders and perceived unmet need for treatment were assessed among individuals with illegal drug use disorder. Odds of treatment and odds of perceived unmet need for treatment were assessed using logistic regression, adjusting for socio-demographic characteristics, treatment for mood and anxiety disorders, and comorbid alcohol use disorder. RESULTS: Out of 34,653 participants, 1114 (3.2%) had a diagnosis of lifetime illegal drug use disorder: 21.2% had a comorbid mood disorder only, 11.8% a comorbid anxiety disorder only, and 45.9% comorbid mood and anxiety disorders. Comorbid mood and anxiety disorders were not related to treatment for illegal drug use disorders but were associated with an elevated likelihood of unmet need for treatment: compared to participants with no comorbidities, multivariate ORs were 2.21 (95% CI: 1.23- 4.10) for mood disorder only, 2.38 (95% CI: 1.27-4.45) for anxiety disorder only, and 2.90 (95% CI: 1.71-4.94) for both mood and anxiety disorders. CONCLUSIONS: Individuals with an illegal drug use disorder and comorbid mood or anxiety disorders are disproportionately likely to report unmet need for treatment. Integrated mental health and substance use programs could prove effective in addressing their treatment needs