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27/11/2015 | Neuropsychopharmacology   IF 7.8
Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.
Martin-Garcia E, Bourgoin L, Cathala A, Kasanetz F, Mondesir M, Gutierrez-Rodriguez A, Reguero L, Fiancette JF, Grandes P, Spampinato U, Maldonado R, Piazza PV, Marsicano G, Deroche-Gamonet V

The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine-seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.Neuropsychopharmacology accepted article preview online, 27 November 2015. doi:10.1038/npp.2015.351.

03/01/2014 | Science   IF 34.7
Pregnenolone can protect the brain from cannabis intoxication.
Vallee M, Vitiello S, Bellocchio L, Hebert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarriere V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV

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Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Delta(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

15/10/2013 | Mol Psychiatry   IF 15
BDNF-TrkB signaling through Erk1/2 phosphorylation mediates the enhancement of fear memory induced by glucocorticoids.
Revest JM, Le Roux A, Roullot-Lacarriere V, Kaouane N, Vallee M, Kasanetz F, Rouge-Pont F, Tronche F, Desmedt A, Piazza PV

Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2MAPK signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GRNesCre). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2MAPK responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2MAPK signaling pathways as one of the core effectors of stress-related effects of GC.Molecular Psychiatry advance online publication, 15 October 2013; doi:10.1038/mp.2013.134.

15/05/2012 | Mol Psychiatry   IF 15
Prefrontal synaptic markers of cocaine addiction-like behavior in rats.
Kasanetz F*, Lafourcade M*, Deroche-Gamonet V*, Revest JM, Berson N, Balado E, Fiancette JF, Renault P, Piazza PV*, Manzoni OJ*

Defining the drug-induced neuroadaptations specifically associated with the behavioral manifestation of addiction is a daunting task. To address this issue, we used a behavioral model that differentiates rats controlling their drug use (Non-Addict-like) from rats undergoing transition to addiction (Addict-like). Dysfunctions in prefrontal cortex (PFC) synaptic circuits are thought to be responsible for the loss of control over drug taking that characterizes addicted individuals. Here, we studied the synaptic alterations in prelimbic PFC (pPFC) circuits associated with transition to addiction. We discovered that some of the changes induced by cocaine self-administration (SA), such as the impairment of the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) was similarly abolished in Non-Addict- and Addict-like rats and thus unrelated to transition to addiction. In contrast, metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) was specifically suppressed in Addict-like rats, which also show a concomitant postsynaptic plasticity expressed as a change in the relative contribution of AMPAR and NMDAR to basal glutamate-mediated synaptic transmission. Addiction-associated synaptic alterations in the pPFC were not fully developed at early stages of cocaine SA, when addiction-like behaviors are still absent, suggesting that pathological behaviors appear once the pPFC is compromised. These data identify specific synaptic impairments in the pPFC associated with addiction and support the idea that alterations of synaptic plasticity are core markers of drug dependence.Molecular Psychiatry advance online publication, 15 May 2012; doi:10.1038/mp.2012.59.

25/06/2010 | Science   IF 34.7
Transition to addiction is associated with a persistent impairment in synaptic plasticity.
Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O, Piazza PV



Precise control of synaptic strength is critical for maintaining accurate network activity and normal brain functions. Several major brain diseases are related to synaptic alterations in the adult brain. Detailed descriptions of the normal physiological properties of adult synapses are scarce, mainly because of the difficulties in performing whole cell patch-clamp recording in brain slices from adult animals. Here we present the portrait of excitatory synapses and intrinsic properties of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a central structure of the mesocorticolimbic system, from youth (P14) to adulthood (P120). We found that intrinsic neuronal excitability decreased over development, mainly due to an enhancement of potassium conductance and the consequent reduction in membrane resistance. The ratio between paired-pulse synaptic responses was similar in juvenile, adolescent, and adult MSNs, suggesting that the probability of neurotransmitter release was unaltered. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) decayed more slowly in adult MSN. In contrast, the kinetic properties and the subunit composition of N-methyl-d-aspartate receptor (NMDAR)-mediated EPSC in the NAc were conserved from youth to adulthood. Changes in synaptic strength were estimated from the ratio of AMPAR to NMDAR evoked and spontaneous EPSCs (AMPAR/NMDAR ratio). Although both AMPAR and NMDAR EPSCs decreased over development, there was an increase of the AMPAR/NMDAR ratio that was linked to changes in NMDAR EPSC. Furthermore, distribution of the AMPAR/NMDAR ratio was more heterogeneous in MSNs from adults, suggesting that synaptic strength is continuously refined during life.