A study of relapse to cocaine seeking in the rat

The primary objective of this study was to determine whether brief exposure to a stressor would provoke relapse to cocaine-trained behaviour and, if so, whether such an effect could be blocked pharmacologically. Rats were initially trained to self-administer cocaine HCl (1.0 mg/kg/infusion, IV; one 3-hour session/day; 9-12 days). Subsequently, extinction conditions were introduced in which lever-pressing resulted in IV infusions of saline rather than of cocaine. Extinction conditions were maintained until animals made 15 or fewer responses in the 3-hour session, after which they received saline infusions at the start of each session until they made 10 or fewer responses in 3 hours. Subsequently, animals were tested for reinstatement of responding for saline infusions following a non-contingent injection of cocaine (2.0 mg/kg, IV) and exposure to intermittent footshock (10 min, 0.5 mA, 0.5 sec on, mean off period of 40 sec). In Experiment 1, footshock stress induced reinstatement of cocaine-trained behaviour after prolonged extinction and after a 4- to 6-week drug-free period; an effect comparable to that induced by a priming injection of cocaine. In Experiment 2, animals were given saline, cocaine, and footshock tests for reinstatement 20 min after pretreatment with saline and diazepam (0.75 or 1.5 mg/kg, IP). In this experiment, diazepam attenuated footshock- but not cocaine-induced reinstatement of cocaine-trained behaviour. These findings suggest that the neurochemical events mediating footshock- and cocaine-induced reinstatement of cocaine-trained behaviour are pharmacologically dissociable

Stress-induced relapse to cocaine seeking in the rat : contributions of central nervous system corticotropin-releasing factor and noradrenaline

The primary objective of the present thesis was to characterize the role of two neurobiological systems, corticotropin-releasing factor (CRF) and noradrenaline (NE), in stress- and cocaine-induced relapse to cocaine seeking, using an animal model of relapse. Rats were allowed to self-administer cocaine (0.5 or 1.0 mg/kg/infusion, i.v.) for 3 hours daily for 10-14 days and were then put on an extinction schedule during which lever pressing was no longer reinforced. Tests for reinstatement were given after intermittent electric footshock (10 or 15 min; 0.5-0.8 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). In a first series of experiments, footshock reinstated cocaine seeking in both intact animals and in animals given corticosterone replacement, but not in adrenalectomized animals. Intracerebroventricular injections of the CRF-receptor antagonist, D-Phe CRF 12-41 , blocked footshock-induced reinstatement in both intact animals and animals given corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF 12-41 . Additionally, systemic injections of the non-peptide CRF-receptor antagonist, CP-154,526, blocked the footshock-induced reinstatement of cocaine seeking. Collectively, these results demonstrate that CRF acting directly in the brain and independent of the hypothalarnic-pituitary-adrenal axis mediates the stress- but not cocaine-induced reinstatement of cocaine seeking. In an attempt to localize where in the brain CRF acts to initiate the behaviors involved in relapse, injections of D-Phe CRF 12-41 were made into the bed nucleus of the stria terminalis (BNST) and the amygdala (AMG), two sites that contain CRF receptors and that have been implicated in behavioral and physiological effects of stress. Injections into the BNST, but not the AMG, blocked the footshock-induced reinstatement of cocaine seeking and injections of CRF into the BNST, but not the AMG, were sufficient to induce reinstatement. These results suggest that the BNST is an import site of action for CRF in mediating the effects of footshock on relapse. In a second series of experiments, an important role for NE in stress-induced relapse was demonstrated. Systemic injections of three alpha-2 adrenergic receptor agonists (clonidine, lofexidine, and gunabenz), which act to block NE cell firing and release, blocked footshock-induced relapse but were without effect on relapse induced by priming injections of cocaine. Together with results of the first series of experiments, these data suggest that an interaction between CRF and NE systems, possibly within the extended AMG, underlies the footshock-induced reinstatement of cocaine seeking. Additionally, the findings argue in favor of a view that different neurobiological systems underlie footshock- and drug-induced relapse to drug seeking and that, therefore, different treatment interventions may be required under different circumstances

Executive functions and borderline personality features in adolescents with major depressive disorder

BackgroundExecutive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF).MethodsWe examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child’s EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity.ResultsOver the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries.ConclusionOn average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03167307

Executive functions and borderline personality features in adolescents with major depressive disorder

BackgroundExecutive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF).MethodsWe examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child’s EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity.ResultsOver the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries.ConclusionOn average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03167307

Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking

The alpha-2 adrenergic receptor agonists, clonidine, lofexidine and guanabenz, blocked stress- but not cocaine-induced reinstatement of cocaine seeking at doses that suppressed footshock-induced release of noradrenaline in prefrontal cortex and amygdala. Rats were trained to self-administer cocaine (0.5 mg/kg/infusion, i.v; 10-12 days) and, after a drug-free period (7-13 days), were returned to the self-administration chambers for daily extinction and reinstatement test sessions. Both intermittent footshock (15 min, 0.6 mA) and cocaine priming (20 mg/kg, i.p.) reinstated extinguished drug seeking. Pretreatment with either clonidine (20, or 40 μg/kg, i.p.) or lofexidine (50, 100, 150, or 200 μg/kg, i.p.) attenuated footshock- but not cocaine-induced reinstatement of cocaine seeking. Guanabenz (640 μg/kg, i.p.), an alpha-2 agonist with low affinity for imidazoline type-1 receptors, also attenuated footshock- but not cocaine-induced reinstatement of cocaine seeking. The results point to an important role for NE systems in the effects of footshock on relapse to cocaine seeking. Copyright (C) 2000 American College of Neuropsychopharmacology

Highly significant improvement of protein sequence alignments with AlphaFold2

Motivation: Protein sequence alignments are essential to structural, evolutionary and functional analysis, but their accuracy is often limited by sequence similarity unless molecular structures are available. Protein structures predicted at experimental grade accuracy, as achieved by AlphaFold2, could therefore have a major impact on sequence analysis. Results: Here, we find that multiple sequence alignments estimated on AlphaFold2 predictions are almost as accurate as alignments estimated on experimental structures and significantly closer to the structural reference than sequence-based alignments. We also show that AlphaFold2 structural models of relatively low quality can be used to obtain highly accurate alignments. These results suggest that, besides structure modeling, AlphaFold2 encodes higher-order dependencies that can be exploited for sequence analysis. Availability and implementation: All data, analyses and results are available on Zenodo (https://doi.org/10.5281/zenodo.7031286). The code and scripts have been deposited in GitHub (https://github.com/cbcrg/msa-af2-nf) and the various containers in (https://cloud.sylabs.io/library/athbaltzis/af2/alphafold, https://hub.docker.com/r/athbaltzis/pred). Supplementary information: Supplementary data are available at Bioinformatics online