Maria Florencia Constantin, Emilce Artur de la Villarmois, José Leonardo Bravo, Aida Marcotti, Marisa Ghersi, Facundo Castro, Gastón Diego Calfa, María Dolores Rubianes, Mariela Fernanda Pérez
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引用次数: 0
Abstract
Rationale: Sildenafil, a phosphodiesterase-5 inhibitor, crosses the blood-brain barrier, enhancing cGMP signaling, dopamine neurotransmission, and hippocampal plasticity-key mechanisms for learning and memory.
Objectives: This study aimed to (1) determine whether sildenafil influences hippocampal dopamine levels by modulating dopamine transporter (DAT) function in naïve young rats; (2) assess sildenafil-induced dopamine increases by evaluating its impact on hippocampal-dependent memories in non-aversive and aversive tasks; and (3) examine the effects of acute sildenafil administration on hippocampal synaptic plasticity.
Methods: DAT function was assessed through ex-vivo dopamine reuptake analysis in the hippocampus and nucleus accumbens of rats sacrificed 2 h post-administration. Memory effects were evaluated by administering sildenafil 2 h before training in non-aversive (novel object recognition-NOR, Y-maze, Barnes maze) and aversive (step-down inhibitory avoidance, fear conditioning) tasks. To examine D3 receptor (D3R) involvement, a subset of animals received the selective D3R antagonist FAUC-365 before NOR training. Synaptic plasticity was analyzed via electrophysiology and dendritic spine density.
Results: Sildenafil reduced dopamine reuptake, likely by inhibiting DAT. It impaired NOR performance, an effect prevented by D3R antagonism, while leaving working and long-term spatial memory unaffected. Additionally, sildenafil enhanced aversive memory expression, facilitated hippocampal long-term potentiation, and increased dendritic spine density.
Conclusions: Sildenafil differentially affected hippocampal-dependent memory, potentially by increasing dopamine transmission. In young, healthy individuals, sildenafil may impair recognition memory and alter responses to non-threatening stimuli, influencing cognitive and emotional processes.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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