mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism

Abstract

Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism.

The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators

“…In other words, MTEP attenuates cocaine-seeking in animals that typically show sustained elevation of drugseeking and resistance to extinction, behavior previously described as 'incubation of cocaine craving' (Grimm et al 2001;Lu et al 2003;Freeman et al 2008). We hypothesize that systemic MTEP is partially targeting the NAc to control drug seeking as previous studies report that MTEP microinfused into the NAc is sufficient to reproduce the effects of systemic MTEP administration (Knackstedt et al, 2014;Li et al, 2018;Wang et al, 2013). However, mGlu5…”

“…Due to potentially severe adverse side effects of ionotropic glutamate receptor antagonists, pharmacological modulation of postsynaptic metabotropic glutamate receptor 5 (mGlu5) has been explored as a viable approach for the development of anti-relapse therapies (Olive 2009). A large number of preclinical studies demonstrate that systemic and intra-accumbens administration of mGlu5 antagonists or negative allosteric modulators (NAMs) selectively limit cocaine reward and reduce cocaine-seeking, broadening the appeal of mGlu5 inhibitors as therapeutics for CUD (Chiamulera et al, 2001;Keck et al, 2013Keck et al, , 2014Kenny et al, 2005;Knackstedt et al, 2014;Knackstedt & Schwendt, 2016;Kumaresan et al, 2009;Lee et al, 2005;Li et al, 2018;Martin-Fardon et al, 2009;Wang et al, 2013), Despite this evidence advocating for the use of mGlu5 inhibitors in anti-relapse therapy, there are potential complications that may prevent clinical use of these compounds. As mGlu5 receptors play a central role in certain forms of synaptic plasticity (such as long-term depression), it is not surprising that brain-wide inhibition, or ablation of mGlu5 can produce learning and memory side-effects (for review see: Simonyi et al 2005;Olive 2010).…”

El modulador alostérico negativo de los mGluR5, MPEP, potencia la reinstauración de la preferencia condicionada inducida con priming de cocaína

“…Se ha sugerido una acción potencialmente terapéutica de los moduladores alostéricos negativos, como MPEP (Mihov y Hasler, 2106), porque esta droga reduce la autoadministración de cocaína en dosis que no impiden la autoadministración de alimentación. De manera específica, el MPEP atenuó, de forma significativa, la reinstauración de la búsqueda de cocaína en el paradigma de autoadministración tanto cuando estaba inducido por claves asociadas con la droga (Backstrom y Hyytia, 2006;Li et al, 2018) como por una inyección de priming con cocaína (Kumaresan et al, 2009;Lee, Platt, Rowlett, Adewale y Spealman, 2005;Li et al, 2018), sin afectar los refuerzos naturales, tales como la comida o la sacarosa (Herzig et al, 2005). Parece ser que su acción sobre él subyacen estos resultados, porque la administración de MPEP directamente al NAcc atenuó la reinstauración de la búsqueda de droga inducida por priming de cocaína (Schmidt et al, 2015).…”

“…En particular, el MPEP (2-metil-6-(fenil etanol)-piridina), un modulador alostérico negativo de mGluR5 (Olive, 2009), es un ligando activo es un ligando activo que administrado a nivel sistémico provoca un potente y selectivo antagonismo, no competitivo, de los mGluR5 (Gasparini et al, 1999;Pomierny-Chamioło et al, 2014), y que ha mostrado ser eficaz para reducir el consumo, el refuerzo y la recaída a la cocaína. (Li et al, 2018). Una revisión sistemática reciente concluyó que el MPEP reduce la autoadministración de cocaína, como muestra de su potencial terapéutica para el tratamiento de trastornos adictivos (Mihov y Hasler, 2016).…”

Neurophysiological and neuropsychological damages produced by cocaine in adult populations

“…15 The small cognitive and executive changes that adult cocaine users present from the first time must be measured with neuropsychological batteries that can quantify these changes and compare them with other stages of consumption. 16 Mortality rates in adult populations consuming cocaine are up to 15% higher than the rest of the world population. While the risks of stroke increases by up to 6%, which means that the consumption of cocaine puts people's lives at high risk.…”