Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Miriam Melis,Liana Fattore,Salvatore Lecca,Marco Pistis,Marta De Felice

doi:10.3389/fnint.2013.00093

Abstract

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction.

Highlights

Drug addiction is defined as a chronic relapsing brain disease characterized by compulsive drug seeking and taking, despite negative consequences
Given the strong GABA background input arising from diverse districts, endocannabinoids – by silencing one or more inhibitory inputsmight sensitize DA cells towards excitatory inputs evoked by rewarding stimuli, such as those associated with drugs of abuse (Melis and Pistis, 2012; Melis et al, 2012)
Our findings reveal a tonic 2-AG signaling, which modulates inhibitory afferents impinging upon ventral tegmental area (VTA) DA neurons in female Lister Hooded (LH) rats. 2-AG by differently depressing inhibitory synapses in a sex specific fashion might indirectly alter DA neuron functional state, and enhance their responsiveness towards excitatory inputs evoked by external stimuli, such as those associated with drugs of abuse

Summary

Introduction

Drug addiction is defined as a chronic relapsing brain disease characterized by compulsive drug seeking and taking, despite negative consequences. Addictive drugs share the property of being self-administered by laboratory animals, and acquisition of drug taking behavior depends on several variables including aversive characteristics intrinsic to many addictive drugs (Stolerman, 1992). Aversive properties of drugs of abuse, such as cannabinoids and alcohol, play a key role in acquisition phases of self-administration in laboratory animals (Quinn et al, 2008; Rezvani et al, 2010). Vulnerability to drug abuse and dependence might result from diminished responses to harmful consequences of compulsive drug taking (Riley, 2011)

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