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Conditioned stimuli (CS) have multiple psychological functions that can potentially contribute to their effect on memory formation. It is generally believed that CS-induced memory modulation is primarily due to conditioned emotional responses, however, well-learned CSs not only generate the appropriate behavioral and physiological reactions required to best respond to an upcoming unconditioned stimulus (US), but they also serve as signals that the US is about to occur. Therefore, it is possible that CSs can impact memory consolidation even when their ability to elicit conditioned emotional arousal is significantly reduced. To test this, male Sprague-Dawley rats trained on a signaled active avoidance task were divided into "Avoider" and "Non-Avoider" subgroups on the basis of percentage avoidance after 6 d of training. Subgroup differences in responding to the CS complex were maintained during a test carried out in the absence of the US. Moreover, the subgroups displayed significant differences in stress-induced analgesia (hot-plate test) immediately after this test, suggesting significant subgroup differences in conditioned emotionality. Importantly, using the spontaneous object recognition task, it was found that immediate post-sample exposure to the avoidance CS complex had a similar enhancing effect on object memory in the two subgroups. Therefore, to our knowledge, this is the first study to demonstrate that a significant conditioned emotional response is not necessary for the action of a predictive CS on modulation of memory consolidation.

Introduction Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19 , CYP2D6 , CYP3A4 , and ABCB1 , and its effect on these outcomes. Methods The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. Results Eleven cis- SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q =0.027) and serum concentrations of ESCadj (q <0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. Discussion These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored. [ABSTRACT FROM AUTHOR]

To test the hypothesis that drugs of abuse and their conditioned stimuli (CSs) enhance memory consolidation, the effects of post-training exposure to cocaine and nicotine were compared to the effects of post-training exposure to contextual stimuli that were paired with the effects of these drugs. Using the object recognition (OR) task, it was first demonstrated that both 10 and 20 mg/kg cocaine, and 0.2 and 0.4 mg/kg nicotine, enhanced recognition memory when administered immediately after, but not 6 h after the sample phase. To establish the drug CSs, rats were confined for 2 h in a chamber (the CS+) after injections of 20 mg/kg cocaine, or 0.4 mg/kg nicotine, and in another chamber (the CS-) after injections of vehicle. This was repeated over 10 d (5 drug/CS+ and 5 vehicle/CS- pairings in total). At the end of this conditioning period, when tested in a drug-free state, rats displayed conditioned hyperactivity in the CS+ relative to the CS-. More important, immediate, but not delayed, post-sample exposure to the cocaine CS+, or nicotine CS+, enhanced OR memory. Therefore, this study reports for the first time that contextual stimuli paired with cocaine and nicotine, like the drugs themselves, have the ability to enhance memory consolidation.

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The P‐glycoprotein efflux pump, encoded by the ABCB1 gene, has been shown to alter concentrations of various antidepressants in the brain. In this study, we conducted a systematic review and meta‐analysis to investigate the association between six ABCB1 single‐nucleotide polymorphisms (SNPs; rs1045642, rs2032582, rs1128503, rs2032583, rs2235015, and rs2235040) and antidepressant treatment outcomes in individuals with major depressive disorder (MDD), including new data from the Canadian Biomarker and Integration Network for Depression (CAN‐BIND‐1) cohort. For the CAN‐BIND‐1 sample, we applied regression models to investigate the association between ABCB1 SNPs and antidepressant treatment response, remission, tolerability, and antidepressant serum levels. For the meta‐analysis, we systematically summarized pharmacogenetic evidence of the association between ABCB1 SNPs and antidepressant treatment outcomes. Studies were included in the meta‐analysis if they investigated at least one ABCB1 SNP in individuals with MDD treated with at least one antidepressant. We did not find a significant association between ABCB1 SNPs and antidepressant treatment outcomes in the CAN‐BIND‐1 sample. A total of 39 studies were included in the systematic review. In the meta‐analysis, we observed a significant association between rs1128503 and treatment response (T vs. C‐allele, odds ratio = 1.30, 95% confidence interval = 1.15–1.48, P value (adjusted) = 0.024, n = 2,526). We did not find associations among the six SNPs and treatment remission nor tolerability. Our findings provide limited evidence for an association between common ABCB1 SNPs and antidepressant outcomes, which do not support the implementation of ABCB1 genotyping to inform antidepressant treatment at this time. Future research, especially on rs1128503, is recommended. [ABSTRACT FROM AUTHOR]