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.

Localization of the cannabinoid type‐1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus

“…Loss of function in mutant mice lacking CB 1 receptors in specific cell types allowed insights into their anatomical localization and a deeper understanding of their necessary role for several brain functions (Bénard et al, ; Han et al, ; Koch et al, ; Marsicano et al, ; Martín‐García et al, ; Monory et al, ; Monory, Polack, Remus, Lutz, & Korte, ; Soria‐Gómez et al, ). Conditional mutant mice lacking CB 1 receptors in astrocytes exhibit neither in vivo hippocampal long‐term depression nor the impairment of spatial working memory typically observed following acute cannabinoid treatment (Han et al, ).…”

Anatomical characterization of the cannabinoid CB1 receptor in cell‐type–specific mutant mouse rescue models

“…However, CB 1 receptor density is not uniform through the regions expressing it. Actually, the use of mutant mice lacking the CB 1 receptor in specific brain cell populations served to identify low CB 1 receptor expression in cellular, subcellular, or intracellular compartments and to understand its physiological functions in those compartments (Monory et al, 2006(Monory et al, , 2007Puighermanal et al, 2009;Bellocchio et al, 2010;B enard et al, 2012;Han et al, 2012;Steindel et al, 2013;Ruehle et al, 2013;Soria-G omez et al, 2014;Busquets-Garcia et al, 2015;Mart ın-Garc ıa et al, 2015;Oliveira da Cruz et al, 2015). In this study, the hippocampus was chosen because it is one of the structures with the highest CB 1 receptor immunoreactivity in the brain (Herkenham et al, 1990;Mailleux and Vanderhaeghen, 1992;Matsuda et al, 1993;Tsou et al, 1998;Marsicano and Lutz, 1999;Egertov a and Elphick, 2000;Katona et al, 2006;Kawamura et al, 2006;Lud anyi et al, 2008;Katona and Freund, 2012;Steindel et al, 2013;Hu and Mackie, 2015).…”

“…The specificity of CB 1 receptor antibody (Table ) was assessed in previous publications (Bellocchio et al, ; Reguero et al, ; Bénard et al, ; Hebert‐Chatelain et al, ; Soria‐Gómez et al, ; Martín‐García et al, ). Furthermore, the specificity was tested in this study by applying the antibody to CB 1 ‐KO hippocampus.…”

“…CB 1 receptor expression is very high in inhibitory GABAergic synaptic terminals (Katona et al, ; Kawamura et al, ; Ludányi et al, ; Marsicano and Kuner, ; Katona and Freund, ; De‐May and Ali, ; Steindel et al, ; Hu and Mackie, ), and it is also expressed in glutamatergic neurons (Marsicano et al, ; Domenici et al, ; Takahashi and Castillo, ; Katona et al, ; Monory et al, ; Kamprath et al, ; Bellocchio et al, ; Puente et al, ; Reguero et al, ; Ruehle et al, ; Soria‐Gómez et al, ) and in brain astrocytes (Navarrete and Araque, ; Stella, ; Han et al, ; Bosier et al, ; Metna‐Laurent and Marsicano, ; Oliveira da Cruz et al, ; Viader et al, ). Subcellularly, CB 1 receptors are localized in the plasma membranes, where they play crucial roles in brain function, dysfunction, and cognition (Marsicano et al, ; Monory et al, , 2015; Bellocchio et al, ; Puente et al, ; Castillo, ; Katona and Freund, ; Steindel et al, ; Ruehle et al, ; Soria‐Gómez et al, ; Hu and Mackie, ; Katona, ; Lutz et al, 2015; Martín‐García et al, ) and in intracellular organelles, such as brain mitochondria (Bénard et al, ; Hebert‐Chatelain et al, ; Koch et al, ).…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…However, other interactions with the eCB/CB1 system could alter drug reward and intake. Indeed, one recent study demonstrated that deletion of CB1 from forebrain GABAergic neurons (including striatal MSNs) enhances DA release (Martín-García et al, 2016), indicating that CB1 receptors at multiple synapses regulate the neurochemical effects of cocaine, and perhaps other abused drugs (Miller et al, 2007). …”