Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

Abstract

Whether metabotropic glutamate 7 (mGluR7) -activation enhances or diminishes the reinforcing properties of psychostimulants remains unclear. We have previously shown that systemic mGluR7 activation reduced alcohol consumption and preference as well as locomotorstimulating and rewarding properties of ethanol. In this study, we further examined the contribution of mGluR7 on the effect of ethanol within the nucleus accumbens (NAcc), a neural target for many drugs of abuse. Using short hairpin RNA (shRNA)-expressing lentiviral vectors (LV) to alter locally the activity of mGluR7 in male rats, we have shown that blocking mGluR7 expression increased ethanol consumption and preference in a two-bottle choice drinking paradigm with no effect either on saccharin or on quinine used for taste discrimination. In addition, mGluR7 knockdown increases preference for environments previously paired with low doses of ethanol in the conditioned place preference (CPP) test, as it shifted the dose-response curve for ethanol CPP to the left, indicating alterations in the rewarding effects of alcohol. More importantly, mGluR7 blockade in the dorsal striatum (DS) neither affected ethanol consumption nor ethanol-elicited CPP. These results show that levels of mGluR7 in the NAcc regulate responsiveness to alcohol. Taken together, these findings clearly demonstrate that mGluR7 signaling within the NAcc is a key modulator of functional responses to ethanol and offer an important target for regulating the addictive effects of alcohol.

Modelos animales de adicción a las drogas

“…Dentro de los modelos animales de refuerzo utilizados para evaluar la preferencia que lleva a un sujeto a consumir encontramos el paradigma de consumo voluntario: sistema de dos botellas, más conocido por su término en inglés "two-bottle choice". Existen diferentes modalidades o variedades dentro de dicho procedimiento pero el objetivo principal del mismo es medir la preferencia del animal por la sustancia de abuso (normalmente alcohol) y su consumo oral frente a otra sustancia no adictiva (como el agua) (Bahi, 2012(Bahi, , 2013a(Bahi, , 2013b. Para medir esta preferencia los animales son expuestos a ambas sustancias durante días, ofreciéndoseles la posibilidad de beber únicamente agua, únicamente alcohol o ambas sustancias al mismo tiempo.…”

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

“…Cells were harvested 72 h later and viruses were concentrated from the supernatant by ultracentrifugation. Vectors were resuspended in PBS-BSA and stored at À80 C until use (Bahi, 2013;Bahi and Dreyer, 2013). The three distinct Drd1a-siRNA sequences were successfully used to knock-down the expression Drd1a mRNA in the NAc (Bahi and Dreyer, 2012) and proteins in the hippocampus (Ortiz et al, 2010).…”

Viral-mediated overexpression of the Myelin Transcription Factor 1 (MyT1) in the dentate gyrus attenuates anxiety- and ethanol-related behaviors in rats

“…The typical two-bottle choice drinking paradigm procedure described previously (Bahi 2013) was used with minor modifications. In brief, the rats were weighed and given access to two-bottles, one containing tap water and the other containing 5% ethanol.…”

“…The tubes were centrifuged and the plasma was separated and stored at −20°C. BECs were measured in milligrams per deciliter (BioVision Research Products, CA, USA) as described previously (Bahi 2013). …”