Long-term administration of cariprazine increases locus coeruleus noradrenergic neurons activity and serotonin1A receptor neurotransmission in the hippocampus

Background: Cariprazine, the novel dopamine (DA) D3-preferring D3/D2 and serotonin (5-HT)1A receptor partial agonist, has activity as an adjunctive therapy in major depressive disorder (MDD). Aims: This study aims to investigate the effects of chronic cariprazine administration in combination with the selective serotonin reuptake inhibitor escitalopram on the activity of monoaminergic systems. Methods: Rats received cariprazine alone and in adjunct to escitalopram for 2 and 14 days and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus norepinephrine (NE) and ventral tegmental area DA neurons was assessed. 5-HT and NE neurotransmission in hippocampus pyramidal neurons was evaluated by assessing tonic activation of their 5-HT1A, and α1- and α2-adrenergic receptors, using their selective antagonists. Results: Two and 14-day cariprazine regimens increased the firing rate of NE, but not 5-HT and DA neurons. Addition of cariprazine to escitalopram reversed the inhibitory effect of escitalopram on NE but not 5-HT and DA neurons. In the hippocampus, there was an increase in neurotransmission at 5-HT1A receptors in cariprazine-treated rats, but no change in overall NE transmission by either regimen. Conclusion: Cariprazine increased NE neuronal firing and reversed the escitalopram-induced inhibition of these neurons. Despite a lack of effect on 5-HT neuronal firing activity, there was an increase in tonic activation of hippocampus 5-HT1A receptors by cariprazine alone but not with the combination. These effects provide a possible rationale for the clinical efficacy of cariprazine as an adjunctive strategy in patients with MDD.

Additional Evidence for Pupil Size as a Measure of Within-Task Learning

This study sought to improve and extend previously conducted research that demonstrated the ability to capture within-task learning by measuring changes in an individual’s peak pupil size across a task. That research had two limitations that needed to be addressed: the use of pixels (an unstandardized pupil size measurement unit) as the primary metric and the lack of inclusion of a pre-stimulus baseline period. Ninety-two Navy and Marine Corps student pilots performed a spatial orientation aptitude test while their pupillary data were recorded. Notably, a new technique was used to convert pupil data from pixels to millimeters and a pre-stimulus baseline period was added between trials to capture tonic activation. Results revealed that peak pupil sizes significantly reduced across trials (r = -.80). The relationship was still very strong after accounting for a reduction in pupillary tonic activation across trials (r = -.59). These findings provide strong support for prior research that showed that reductions in maximum pupil size can demonstrate learning across trials while completing a task. Importantly, this work improved and extended that research by confirming the results using millimeters, a standardized unit of pupil size, instead of pixels, and accounting for tonic activation.

Asymmetric effects of activating and inactivating cortical interneurons

Bidirectional manipulations – activation and inactivation – are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is the notion that tonic activation and inactivation will both produce valid, internally consistent insights into interneurons’ computational roles. Here, using single-unit recordings in auditory cortex of awake mice, we show that this may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed that Sst+ inactivation increased response gain, while Pvalb+ inactivation weakened tuning and decreased information transfer, implying that these neurons support delineable computational functions. But activating Sst+ and Pvalb+ interneurons revealed no such differences. We used a simple network model to understand this asymmetry, and showed how relatively small changes in key parameters, such as spontaneous activity or strength of the light manipulation, determined whether activation and inactivation would produce consistent or paradoxical conclusions regarding interneurons’ computational functions.