Eleanor Blair Towers, Ivy L Williams, Emaan I Qillawala, Ben Setaro, Kyle A Hsu, Wendy J Lynch
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引用次数: 0
Abstract
Rationale: The telescoping effect, where females progress more rapidly than males from initial drug use to developing a substance use disorder, is a widely cited sex/gender difference, yet its molecular basis remains unknown.
Objectives: To test whether calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc) contribute to the development of enhanced motivation for cocaine, a defining feature of addiction, which emerges earlier in females than in males.
Methods: Motivation for cocaine was measured under a progressive-ratio schedule before and after extended-access self-administration (4 trials/h, 24 h/day, 10 days) and a 7-day abstinence period. During abstinence, females received SYN119 (0 or 10 mg/kg) to block, and males received JNJ16259685 (0 or 5 mg/kg) to enhance, NAc CP-AMPAR recruitment, consistent with a hypothesis-driven, sex-informed design. After stable motivation was established, intra-NAc infusions of the CP-AMPAR antagonist naspm (40 µg/side) were administered.
Results: Females, but not males, developed enhanced cocaine motivation after 7 days of abstinence, replicating the telescoping effect. This effect was persistently blocked by SYN in females and reproduced in males by JNJ treatment for over three weeks. Subsequently, intra-NAc naspm reduced motivation in JNJ-treated males, but not SYN-treated females, supporting a role for CP-AMPARs in the development of an enhanced motivation for cocaine.
Conclusion: These findings suggest that CP-AMPAR recruitment in the NAc, a mechanism classically linked to the incubation of cocaine craving, may also contribute to abstinence-dependent increases in drug motivation that emerge earlier in females.
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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