Abstract
The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; PFWE < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.
Highlights
Cognitive deficits are a core symptom of schizophrenia, but currently available antipsychotic drugs improve mainly positive symptoms, leaving patients with often debilitating cognitive dysfunction and negative symptoms
We previously reported that healthy adults who carry the CACNA1C SNP rs1006737 A allele, which is associated with risk for schizophrenia and bipolar disorder, had increased activation in the prefrontal cortex during the N-back working memory task, compared to non-risk genotype carriers[1]
In healthy subjects, nimodipine administration significantly decreased neural activity in parietal and frontal cortices during the N-back working memory task, despite fixed performance on the task. This is a pattern of change that suggests that nimodipine improves the physiological efficiency of cortical processing of working memory information
Summary
Cognitive deficits are a core symptom of schizophrenia, but currently available antipsychotic drugs improve mainly positive symptoms (e.g. hallucinations and delusions), leaving patients with often debilitating cognitive dysfunction and negative symptoms (e.g. apathy, avolition, anhedonia). The CACNA1C gene (alpha 1C subunit of the L-type voltage-gated calcium channel) has been identified by several independent studies as a genome-wide associated risk gene for both schizophrenia[1,2,3,4] and bipolar disorder[5,6]. We previously reported that healthy adults who carry the CACNA1C SNP rs1006737 A allele, which is associated with risk for schizophrenia and bipolar disorder, had increased activation in the prefrontal cortex during the N-back working memory task, compared to non-risk genotype carriers[1]. Increased activation of the prefrontal cortex during working memory without change in performance on the task (i.e. inefficient cortical engagement) has been previously reported in patients with schizophrenia and their healthy siblings (who are at increased genetic risk for schizophrenia, but without illness)[7].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
