Molecular BiologyCellular and Molecular NeurosciencePsychiatry and Mental Health
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Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment. The emphasis is on studies at the interface of pre-clinical and clinical research, including studies at the cellular, molecular, integrative, clinical, imaging and psychopharmacology levels.
Marco Colizzi, Nathalie Weltens, Philip McGuire, David J. Lythgoe, Steven Williams, Lukas Van Oudenhove, Sagnik Bhattacharyya
AbstractThe neurobiological mechanisms underlying the association between cannabis use and acute or long-lasting psychosis are not completely understood. While some evidence suggests altered striatal dopamine may underlie the association, direct evidence that cannabis use affects either acute or chronic striatal dopamine is inconclusive. In contrast, pre-clinical research suggests that cannabis may affect dopamine via modulation of glutamate signaling. A double-blind, randomized, placebo-controlled, crossover design was used to investigate whether altered striatal glutamate, as measured using proton magnetic resonance spectroscopy, underlies the acute psychotomimetic effects of intravenously administered delta-9-tetrahydrocannabinol (Δ9-THC; 1.19 mg/2 ml), the key psychoactive ingredient in cannabis, in a set of 16 healthy participants (7 males) with modest previous cannabis exposure. Compared to placebo, acute administration of Δ9-THC significantly increased Glutamate (Glu) + Glutamine (Gln) metabolites (Glx) in the left caudate head (P = 0.027). Furthermore, compared to individuals who were not sensitive to the psychotomimetic effects of Δ9-THC, individuals who developed transient psychotic-like symptoms (~70% of the sample) had significantly lower baseline Glx (placebo; P 7= 0.023) and a 2.27-times higher increase following Δ9-THC administration. Lower baseline Glx values (r = −0.55; P = 0.026) and higher previous cannabis exposure (r = 0.52; P = 0.040) were associated with a higher Δ9-THC-induced Glx increase. These results suggest that an increase in striatal glutamate levels may underlie acute cannabis-induced psychosis while lower baseline levels may be a marker of greater sensitivity to its acute psychotomimetic effects and may have important public health implications.
Elsmarieke van de Giessen, Jodi J. Weinstein, Clifford M. Cassidy, Margaret Haney, Zheng Dong, Rassil Ghazzaoui, Najate Ojeil, Lawrence S. Kegeles, Xijin Xu, Nehal P. Vadhan, Nora D. Volkow, Mark Slifstein, Anissa Abi‐Dargham
Rajiv Radhakrishnan, Patrick D. Skosnik, Mohini Ranganathan, Mika Naganawa, Takuya Toyonaga, Sjoerd J. Finnema, Ansel T. Hillmer, Irina Esterlis, Yiyun Huang, Nabeel Nabulsi, Richard E. Carson, Deepak Cyril D’Souza
H. Thomazeau, Miquel Bosch, Sofia Essayan-Perez, Stephanie A. Barnes, Hector De Jesús‐Cortés, Mark F. Bear
AbstractMany neurodevelopmental disorders are characterized by impaired functional synaptic plasticity and abnormal dendritic spine morphology, but little is known about how these are related. Previous work in the Fmr1-/y mouse model of fragile X (FX) suggests that increased constitutive dendritic protein synthesis yields exaggerated mGluR5-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus, but an effect on spine structural plasticity remains to be determined. In the current study, we used simultaneous electrophysiology and time-lapse two photon imaging to examine how spines change their structure during LTD induced by activation of mGluRs or NMDA receptors (NMDARs), and how this plasticity is altered in Fmr1-/y mice. We were surprised to find that mGluR activation causes LTD and AMPA receptor internalization, but no spine shrinkage in either wildtype or Fmr1-/y mice. In contrast, NMDAR activation caused spine shrinkage as well as LTD in both genotypes. Spine shrinkage was initiated by non-ionotropic (metabotropic) signaling through NMDARs, and in wild-type mice this structural plasticity required activation of mTORC1 and new protein synthesis. In striking contrast, NMDA-induced spine plasticity in Fmr1-/y mice was no longer dependent on acute activation of mTORC1 or de novo protein synthesis. These findings reveal that the structural consequences of mGluR and metabotropic NMDAR activation differ, and that a brake on spine structural plasticity, normally provided by mTORC1 regulation of protein synthesis, is absent in FX. Increased constitutive protein synthesis in FX appears to modify functional and structural plasticity induced through different glutamate receptors.
Alo C. Basu, G E Tsai, C-L Ma, Jeffrey T. Ehmsen, Asif K. Mustafa, Liqun Han, Z I Jiang, Michael A. Benneyworth, Mark Froimowitz, Nicholas Lange, Solomon H. Snyder, Richard Bergeron, Joseph T. Coyle
Pascal Steullet, Jan-Harry Cabungcal, Joseph T. Coyle, Michael Didriksen, Kathryn Gill, Anthony A. Grace, Takao K. Hensch, A-S. LaMantia, Lothar Lindemann, Thomas M. Maynard, Urs Meyer, Hirofumi Morishita, Patricio O’Donnell, Matthew D. Puhl, Michel Cuénod, Kim Q.