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02/2017 | Neuropsychopharmacology   IF 7.8
Individual Variations in the Mechanisms of Nicotine Seeking: A Key for Research on Nicotine Dependence.
Garcia-Rivas V, Cannella N, Deroche-Gamonet V


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.

17/03/2014 | Neuropsychopharmacology   IF 7.8
Frequency of Cocaine Self-Administration Influences Drug Seeking in the Rat: Optogenetic Evidence for a Role of the Prelimbic Cortex.
Martin-Garcia E, Courtin J, Renault P, Fiancette JF, Wurtz H, Simonnet A, Levet F, Herry C, Deroche-Gamonet V

High-frequency intake and high drug-induced seeking are associated with cocaine addiction in both human and animals. However, their relationships and neurobiological underpinnings remain hypothetical. The medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and nucleus accumbens (NAc) have been shown to have a role in cocaine seeking. However, their involvement in regulating high-frequency intake and high cocaine-induced seeking is unclear. We manipulated frequency of cocaine self-administration and investigated whether it influenced cocaine seeking. The contribution of the aforementioned structures was evaluated using changes in expression of the immediate early gene c-Fos and targeted optogenetic manipulations. Rats that self-administered at High frequency (short inter-infusion intervals allowed by short time-out) showed higher cocaine-induced seeking than low frequency rats (long inter-infusions intervals imposed by long time-out), as measured with cocaine-induced reinstatement. c-Fos was enhanced in High frequency rats in the prelimbic (PL) and infralimbic (IL) areas of the mPFC, the BLA, and the NAc core and shell. Correlational analysis of c-Fos revealed that the PL was a critical node strongly correlated with both the IL and NAc core in High frequency rats. Targeted optogenetic inactivation of the PL decreased cocaine-induced reinstatement, but increased cocaine self-administration, in High frequency rats. In contrast, optogenetic activation of the PL had no effect on Low frequency rats. Thus, high-frequency intake promotes a PL-dependent control of cocaine seeking, with the PL exerting a facilitatory or inhibitory effect, depending on operant contingencies. Individual differences in cocaine-induced PL activation might be a source of vulnerability for poorly controlled cocaine-induced seeking and/or cocaine intake.Neuropsychopharmacology advance online publication, 16 April 2014; doi:10.1038/npp.2014.66.

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.

Transition to addiction is the shift from controlled to uncontrolled drug use that occurs after prolonged drug intake in a limited number of drug users. A major challenge of addiction research in recent years has been to develop models for studying this pathological transition. Toward this goal, a DSM-IV/5-based multi-symptomatic model of cocaine addiction has been developed in the rat. It is based on an operational translation of the main features of the disease. 1. Addiction is not just taking drug; it is a non-adaptive drug use: The procedure models addiction in relation to its clinical definition. 2. All drug users do not face the same individual risk of developing addiction: The model includes an individual-based approach. 3. Addiction develops after protracted periods of controlled drug use: This procedure allows for the study of the long-term shift from controlled drug use to addiction. We describe this model in detail and show how it can contribute to our understanding of the pathophysiology of cocaine addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

10/2013 | Psychopharmacology (Berl)   IF 4.1
A multistep general theory of transition to addiction.
Piazza PV, Deroche-Gamonet V

BACKGROUND: Several theories propose alternative explanations for drug addiction. OBJECTIVES: We propose a general theory of transition to addiction that synthesizes knowledge generated in the field of addiction into a unitary explanatory frame. MAJOR PRINCIPLES OF THE THEORY: Transition to addiction results from a sequential three-step interaction between: (1) individual vulnerability; (2) degree/amount of drug exposure. The first step, sporadic recreational drug use is a learning process mediated by overactivation of neurobiological substrates of natural rewards that allows most individuals to perceive drugs as highly rewarding stimuli. The second, intensified, sustained, escalated drug use occurs in some vulnerable individuals who have a hyperactive dopaminergic system and impaired prefrontal cortex function. Sustained and prolonged drug use induces incentive sensitization and an allostatic state that makes drugs strongly wanted and needed. Habit formation can also contribute to stabilizing sustained drug use. The last step, loss of control of drug intake and full addiction, is due to a second vulnerable phenotype. This loss-of-control-prone phenotype is triggered by long-term drug exposure and characterized by long-lasting loss of synaptic plasticity in reward areas in the brain that induce a form of behavioral crystallization resulting in loss of control of drug intake. Because of behavioral crystallization, drugs are now not only wanted and needed but also pathologically mourned when absent. CONCLUSIONS: This general theory demonstrates that drug addiction is a true psychiatric disease caused by a three-step interaction between vulnerable individuals and amount/duration of drug exposure.

09/2013 | Neuropsychopharmacology   IF 7.8
The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior.
Cannella N, Halbout B, Uhrig S, Evrard L, Corsi M, Corti C, Deroche-Gamonet V, Hansson AC, Spanagel R

Medication development for cocaine-addicted patients is difficult, and many promising preclinical candidates have failed in clinical trials. One reason for the difficulty in translating preclinical findings to the human condition is that drug testing is typically conducted in behavioral procedures in which animals do not show addiction-like traits. Recently, a DSM-IV-based animal model has been developed that allows studying the transition to an addiction-like behavior. Changes in synaptic plasticity are involved in the transition to cocaine addiction. In particular, it has been shown that metabotropic glutamate receptor 2/3 (mGluR2/3)-mediated long-term depression is suppressed in the prelimbic cortex in addict-like rats. We therefore hypothesized that cocaine-seeking in addict-like rats could be treated with an mGluR2/3 agonist. Indeed, addict-like rats that were treated systemically with the mGluR2/3 agonist LY379268 (0, 0.3, and 3 mg/kg) showed a pronounced reduction in cue-induced reinstatement of cocaine-seeking. In an attempt to dissect the role played by mGluR2 and mGluR3 in cue-induced reinstatement, we analyzed the mRNA expression patterns in several relevant brain areas but did not find any significant differences between cocaine addict-like and non-addict-like rats, suggesting that the behavioral differences observed are due to translational rather than transcriptional regulation. Another possibility to study the contributions of mGluR2 and mGluR3 in mediating addictive-like behavior is the use of knockout models. Because mGluR2 knockouts cannot be used in operant procedures due to motoric impairment, we only tested mGluR3 knockouts. These mice did not differ from controls in reinstatement, suggesting that mGluR2 receptors are critical in mediating addictive-like behavior.

Epidemiological studies have revealed striking associations between several distinct behavioral/personality traits and drug addiction, with a large emphasis on the sensation-seeking trait and the associated impulsive dimension of personality. However, in human studies, it is difficult to identify whether personality/behavioral traits actually contribute to increased vulnerability to drug addiction or reflect psychobiological adaptations to chronic drug exposure. Here we show how animal models, including the first multi-symptomatic model of addiction in the rat, have contributed to a better understanding of the relationships between different subdimensions of the sensation-seeking trait and different stages of the development of cocaine addiction, from vulnerability to initiation of cocaine self-administration to the transition to compulsive drug intake. We argue that sensation seeking predicts vulnerability to use cocaine, whereas novelty seeking, akin to high impulsivity, predicts instead vulnerability to shift from controlled to compulsive cocaine use, that is, addiction.

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.