Intronic single nucleotide polymorphisms (SNPs) in the CACNA1C gene, which encodes for the Cav1.2 protein, have been identified as risk factors for a number of neuropsychiatric disorders including bipolar disorder, major depressive disorder, and schizophrenia (1). Recent studies have revealed that these intronic SNPs can lead to both higher and lower levels of CACNA1C mRNA (2, 3) suggesting that a gain or loss of Cav1.2 function can contribute to neuropsychiatric conditions. Anxiety is a common core underlying symptom across all neuropsychiatric conditions in which CACNA1C has been implicated. Additionally, altered brain reward circuitry and addictive behavior is a common, co-morbid condition often observed in patients with anxiety disorders. Many studies have revealed overlapping anatomical pathways and molecular mechanisms involved in mood disorders and addiction (4). Recently, human carriers of the bipolar disorder and schizophrenia-associated SNP rs1006737 were found to be associated with altered reward responsiveness compared to non-carriers (5), suggesting that variants in CACNA1C may predispose individuals to anxiety disorders and addiction. Thus, to better understand the role of CACNA1C in mediating neuropsychiatric-related behavioral phenotypes we have utilized a combination of cacna1c (Cav1.2) genetic knockout mice, viral vector-mediated focal knockouts and behavioral assays to map the Cav1.2 brain circuitry in anxiety- and addiction-related behaviors. Our studies have revealed that Cav1.2 channels within glutamatergic neurons of the forebrain regulate anxiety-related behaviors in mice as measured by the open field, light-dark, and elevated plus maze tests (6). Stereotaxic delivery of adenoassociated viral vector (AAV) expressing Cre recombinase under the control of the CaMK2 promoter in Cav1.2 floxed mice, has further identified glutamatergic neurons within the prefrontal cortex (PFC) in regulating anxiety-like behaviors. This is consistent with human and rodent studies that have established the PFC as a critical brain center involved in emotional regulation. As carriers of CACNA1C SNPs have been shown to have altered brain reward responsivity (5), we tested cacna1c knockout mice in cocaine conditioned place preference (CPP), a behavioral test used to measure cocaine reward. We find that cacna1c knockout mice that exhibit high anxiety have higher preference for cocaine than control wildtype mice. AAV-Cre-mediated conditional knockout of Cav1.2 further demonstrates that loss of Cav1.2 in the hippocampus (HPC) results in a long-lasting maintenance of cocaine preference compared to control mice. Taken together our data using mouse models suggests that loss of Cav1.2 channel function within key brain regions contributes to anxiety and addiction-related behaviors and that similarly, SNPs in CACNA1C may predispose humans to anxiety disorders and addiction.