Dissociating the Psychoactive Effects of Distinct Cannabis Compounds in the Mesocorticolimbic Circuitry

................................................................................................................................. ii ACKNOWLEDGEMENTS.........................................................................................................iii LIST OF FIGURES .....................................................................................................................vi LIST OF ABBREVIATIONS ....................................................................................................vii Chapter 1. General Introduction ........................................................................................ 1 1.1 The endocannabinoid system .....................................................................................................2 1.1.1 Role of CB1 receptors in emotional processing ...........................................................................3 1.1.2 eCB interactions with the dopamine system .................................................................................4 1.1.3 The eCB system in neuropsychiatric disorders ............................................................................5 1.1.4 Schizophrenia ..........................................................................................................................................6 1.2 Cannabis and phytocannabinoids .............................................................................................8 1.2.1 Cannabis use as a risk factor for schizophrenia............................................................................9 1.3 Research Purpose and Hypotheses ........................................................................................ 10 Chapter 2. Cannabidiol produces rewarding effects in the nucleus accumbens shell via serotonergic and dopaminergic signaling mechanisms .........................12 2.1 Introduction ................................................................................................................................ 12 2.2 Materials and Methods ............................................................................................................. 13 2.2.1 Animals and Surgery ..........................................................................................................................13 2.2.2 Post-Surgery SOP................................................................................................................................14 2.2.3 Conditioned Place Preference .........................................................................................................14 2.2.4 Drug administration ............................................................................................................................15 2.2.5 VTA neuronal activity recording ...................................................................................................15 2.2.6 Histology ................................................................................................................................................17 2.2.7 Data analysis .........................................................................................................................................17 2.3 Results .......................................................................................................................................... 17 2.3.1 Histological analysis...........................................................................................................................17 2.3.2 Intra-NASh CBD microinfusions display behaviourally rewarding properties..............19 2.3.3 Intra-NASh 5-HT1A receptor blockade switches the motivational valence of CBD from rewarding to aversive ....................................................................................................................................21 2.3.4 Intra-NASh 5-HT1B receptor antagonism blocks the acquisition of CBD reward memory ..............................................................................................................................................................21 2.3.7 Intra-NASh CBD modulates GABAergic neuronal activity in the VTA..........................25 2.3.8 Intra-VTA GABAA/B receptor antagonism blocks the acquisition of intra-NASh CBD reward memory ...............................................................................................................................................28 2.4 Discussion .................................................................................................................................... 29 2.4.1 Intra-NASh CBD produces a reward memory in a dose-dependent manner...................29 2.4.2 CBD reward signals through 5-HT receptor transmission in the NASh ...........................30 2.4.3 CBD reward signals through DA receptor transmission in the NASh...............................32 2.4.4 CBD modulates intra-VTA DA and GABA neuronal activity.............................................32 2.5 Summary...................................................................................................................................... 34 Chapter 3. Cannabidiol and Δ9-­tetrahydrocannbinol differentially modulate the acquisition of an associative fear memory in the nucleus accumbens shell ......................................................................................................................................................35