The Role of Potassium Channels in Working Memory Impairments of Chronic Cocaine Users

The study aims to address the neurobiological basis of cognitive impairments in chronic cocaine users by investigating the potential impact of an acute potassium channel blockade on working memory performance and other cognitive functions.

Chronic cocaine use is associated with impairments in cognitive functions, particularly in working memory, which are thought to contribute to the persistence of addictive behaviors and high relapse rates. Despite the clinical relevance of these cognitive deficits, the underlying neuropharmacological mechanisms remain insufficiently understood. Preclinical and clinical evidence suggests that potassium channels may play an important role in the regulation of neuronal excitability and cognitive processes, including working memory. However, their contribution to cognitive impairments in individuals with cocaine use disorder has not yet been systematically investigated in humans. The present study aims to investigate the role of potassium channel modulation in working memory performance in individuals with chronic cocaine use. The study addresses the following key research questions: (1) Does modulation of potassium channels influence working memory performance in individuals with chronic cocaine use? and (2) How are potential effects related to behavioral responses observed during the experimental sessions? To address these questions, a randomized, controlled, cross-over study will be conducted in participants with a history of chronic cocaine use. Participants will complete a series of neurocognitive tasks assessing working memory and related cognitive domains under controlled experimental conditions. Blood samples will be collected at multiple time points to quantify substance levels and to support the interpretation of behavioral findings. The results of this study may contribute to a better understanding of the neurobiological mechanisms underlying cognitive impairments in cocaine use and inform future research on cognitive dysfunction in substance use disorders.

Inclusion Criteria: * Current diagnosis of mild, moderate, or severe CoUD according to DSM-5 * Minimum cocaine use of 1g/month in the last three months * Cocaine as the primary drug of consumption * Willingness to abstain from cocaine use at least 72 hours before prior to each study visit * Ability to read, understand and provide written informed consent * To be sufficiently fluent in German * Age between 20 and 50 years * Body mass index (BMI) between 19 and 30 kg/m2 * If applicable: luteal phase of the menstrual cycle * For individuals with childbearing potential: use of contraceptive measures Exclusion Criteria: * Presence or history of severe neurological disorders or head injuries * Current diagnosis of an acute or chronic infectious disease * If applicable: pregnancy and breastfeeding * Lifetime history of any epileptic seizures * Lifetime diagnosis of a cardiovascular disease, specifically arrhythmia and long QT syndrome * Clinically significant laboratory or ECG abnormality that could be a safety issue in the study * Lifetime diagnosis of liver or kidney disease including moderate or severe renal impairment (creatinine clearance \< 50 ml/min) * Known hypersensitivity or allergy to 4-aminopyridine * Use of potassium channel blockers within the last 3 months * Use of psychotropic medication within the last 7 days * Use of inhibitors of the organic cation transporter 2 (OCT2), such as cimetidine * Lifetime diagnosis of schizophrenia, bipolar disorder, obsessive-compulsive disorder, or autism spectrum disorder according to DSM-5 * Diagnosis of a current episode of depression * Current diagnosis of a moderate or severe substance use disorder other than CoUD according than DSM-5 * Daily cannabis consumption in the past three months * (E-Cigarette) Fagerström Test of Nicotine Dependence Score \> 5 (strong nicotine dependence) * Inability to follow the procedures of the study, e.g., due to language problems * Being related to or in any form dependent on the investigator * Prior participation (less than two years ago) in a study investigating working memory using the n-back task, the SWM, PAL, RVP, or LNST * Participation in another study with investigational drugs within the 30 days preceding and during the present study