Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors
Abstract
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.
INTRODUCTION
As a reward-related behavior, cocaine taking involves interacting psychological components, including reinforcement, reward, motivation, response inhibition, and response to drug discriminative or conditioned cues (Berridge et al, 2009). Although the picture is still fragmented, these psychological components appear to rely on interconnected prefrontal-subcortical neuronal circuits that process motivational and discriminative value of the drug and drug-related stimuli (Goldstein and Volkow, 2011) vs cognitive inhibitory control (Kober et al, 2010; Mihindou et al, 2013; Volkow et al, 2010). In these circuits, notably within the nucleus accumbens (Kalivas, 2009; Wolf and Ferrario, 2010) (NAc), glutamate (Glu) and GABA have major roles in controlling cocaine self-administration by modulating mesolimbic dopamine (DA), the primary neurochemical substrate for cocaine’s reinforcing/rewarding properties. Converging data point to a specific role of cortical Glu projections in controlling drug seeking through learning processes (Bowers et al, 2010; Briand et al, 2014; Pierce and Wolf, 2013; Schmidt and Pierce, 2010; Suto et al, 2013; Xi et al, 2006). Alternatively, subcortical forebrain GABA transmission is thought to be indirectly involved in the reinforcing properties of cocaine and cocaine-related stimuli (Roberts, 2005; Vlachou and Markou, 2010) by modulating the perception of drug-related rewards (Tachibana and Hikosaka, 2012).
The endocannabinoid system, mainly through type 1 cannabinoid receptors (CB1) located on glutamatergic (glutamatergic CB1) and GABAergic neurons (GABAergic CB1), control both excitatory and inhibitory neurotransmission, thereby modulating dopaminergic-dependent behaviors (Melis and Pistis, 2012; Dubreucq et al, 2013), including cocaine seeking (De Vries and Schoffelmeer, 2005). Full pharmacological antagonism of CB1 decreases the influence of conditioned factors on cocaine seeking and on extracellular Glu and DA in the NAc (Caillé and Parsons, 2006; Cheer et al, 2007; Oleson and Cheer, 2012; De Vries et al, 2001; Xi et al, 2006), as well as expression of cocaine-induced behavioral sensitization in a context-specific manner (Gerdeman et al, 2008). Differently, full pharmacological blockade or complete genetic deletion of CB1 does not affect, or only marginally affect (Chaperon et al, 1998; Soria et al, 2005), the primary reinforcing (Cossu et al, 2001; De Vries et al, 2001; Caillé and Parsons, 2006) and rewarding properties of cocaine (Houchi et al, 2005; Martin et al, 2000), as well as the underlying DA and GABA mechanisms (Caillé and Parsons, 2006; Soria et al, 2005; De Vries and Schoffelmeer, 2005). Together these data suggest that the primary role of the endocannabinoid system in cocaine self-administration is to control conditioning-related processes that largely depend on glutamatergic transmission (De Vries and Schoffelmeer, 2005; Wiskerke et al, 2008).
However, full genetic deletion or pharmacological blockade of CB1 might produce a biased effect and obscure the combined functions of the glutamatergic and GABAergic CB1 pools. When targeted genetic deletion of CB1 is applied in feeding-, novelty-, and fear-related behaviors (Bellocchio et al, 2010; Dubreucq et al, 2012; Metna-Laurent et al, 2012), deletion localized to cortical glutamatergic neurons (Glu-CB1-KO mice) produces similar effects to full CB1 blockade, apparently confirming that CB1 exclusively controls glutamatergic-dependent processes (Bellocchio et al, 2010; Dubreucq et al, 2012; Metna-Laurent et al, 2012). However, deletion of CB1 in forebrain GABAergic neurons (GABA-CB1-KO mice) is not without effect. Interestingly, it can produce opposing or qualitatively different results as compared with deletion in cortical glutamatergic neurons (Bellocchio et al, 2010; Dubreucq et al, 2012; Metna-Laurent et al, 2012).
Considering the specific contribution of excitatory or inhibitory neurotransmission in distinct components of cocaine self-administration, we explored the specific roles of CB1 located in glutamatergic and GABAergic neurons. We used the two mutant mouse lines targeting CB1 deletion in cortical glutamatergic (Glu-CB1-KO) and forebrain GABAergic (GABA-CB1-KO) neurons (Marsicano et al, 2003) to test complementary components of cocaine self-administration, involving primary and secondary reinforcing properties of cocaine. In the Glu-CB1-KO mice, the CB1 gene is primarily absent in cortical glutamatergic neurons in the dorsal telencephalon, including neurons located in neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In the GABA-CB1-KO mice, the CB1 gene is primarily absent in forebrain GABAergic neurons, that is, in several cortical and non-cortical regions, eg the striatum, NAc and some thalamic and hypothalamic nuclei (Marsicano and Lutz, 1999; Monory et al, 2006; Marsicano and Kuner, 2008; Bellocchio et al, 2010).
Considering the role of meso-accumbal DA in mediating cocaine primary reinforcing effects (Di Chiara et al, 2004), freely moving naïve rodents were tested for cocaine-induced extracellular DA in the NAc using in vivo microdialysis. Last, because cocaine produces sustained alterations in glutamatergic-dependent synaptic plasticity in the NAc (Guercio et al, 2015; Kalivas and Volkow, 2011; Ortinski et al, 2012; Pascoli et al, 2014; Ma et al, 2014) that are critical for associative learning (Pierce and Wolf, 2013; Schmidt and Pierce, 2010), we quantified AMPAR/NMDAR ratio as a maker of synaptic plasticity in the NAc of cocaine-experienced mice, using ex vivo electrophysiology.
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