Cell Adhesion Molecule 2 and Cannabis Use Vulnerability: Insights from a Neuropsychopharmacological Assessment of a Knockout Mouse Model

Genome-wide association studies identify Cell Adhesion Molecule 2 (CADM2) as a candidate risk gene for lifetime cannabis use and posit its involvement in neurobiological processes that overlap with cannabinoid activity. However, CADM2 polymorphisms also associate with personality traits that are risk factors for substance use, thus obscuring the verity of its role in cannabis phenotypes. In this thesis work, I used a reverse translational approach to assess the role of Cadm2 in behavioral, physiological, and neurobiological features relevant to cannabis vulnerability using a genetically modified knockout (KO) mouse. In Chapter 2, I show that Cadm2 deletion alters cognitive performance in the 5-choice serial reaction time task (5CSRTT), which suggests its expression promotes impulsivity and improves attentional performance. In Chapter 3, I further explore the relationship between Cadm2 and cannabinoid-relevant phenotypes. Preference for Δ9-tetrahydrocannabinol (THC) and cannabis oil containing edibles was lower in KO mice compared to littermates. Cadm2 deletion also induced striking aberrations to THC response, including hyperlocomotion instead of expected hypolocomotion, ablation of hypothermia, and antinociceptive sensitization. These differences did not appear to be consequent of differences in THC pharmacokinetics. Similarly, THC challenge did not impact 5CSRTT performance in KO mice despite evoking hyperlocomotion at the dose administered. To examine the neurobiological correlates of these behavioural and cognitive findings, I investigated the electrophysiological properties of prelimbic layer V pyramidal neurons via whole-cell patch clamp recording and found Cadm2 KO disrupted intrinsic cell properties indicative of ion channel dysfunction. However, THC did not produce genotype-dependent changes in neuron postsynaptic currents and there were no differences in the expression of frontal cortical and striatal ionotropic glutamate and GABA receptor subunits previously correlated with human CADM2 expression. Together, this work implicates a parallel role of Cadm2 in trait impulsivity and pharmacological response to cannabinoids, thus providing support to human genetic associations finding that CADM2 variation directly affects cannabis use liability through multiple phenotypes.