Various dopaminergic drugs have been studied for their efficacy in the treatment of cocaine addiction. Pretreatment with either selective dopamine D1 receptor agonists or selective dopamine D2 receptor antagonists prevents reinstatement of cocaine-seeking in animal models of drug craving and relapse. We tested a novel ergoline derivative with combined D1 agonistic and D2 antagonistic effects, 9,10-didehydro- N-methyl- N-(2-propynyl)-6-methyl-8beta-aminomethylergoline bimaleate (LEK-8829), for its effects on cocaine-seeking in the intravenous cocaine self-administration model in rats. Pretreatment with systemic injections of LEK-8829 attenuated reinstatement of cocaine-seeking induced by cocaine priming injections and diminished cocaine intake in cocaine self-administration sessions. LEK-8829 itself did not induce reinstatement of cocaine-seeking and did not maintain intravenous self-administration. The results of our study indicate that LEK-8829 is a candidate medication for the treatment of cocaine craving in cocaine addiction.
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Article Synopsis
- Cocaine use disorder (CUD) is a major public health issue, and there's currently no FDA-approved medication to treat it, highlighting the need for new treatments.
- RDS04-010, a novel atypical dopamine transporter inhibitor, shows promise in animal models by significantly reducing cocaine-seeking behavior without producing addictive effects, unlike its analog RDS03-094 which has more cocaine-like properties.
- The study’s results emphasize the importance of the binding conformation to the dopamine transporter and suggest RDS04-010 could be a potential therapeutic option for CUD due to its ability to lower motivation for cocaine use.
Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics.
Annu Rev Pharmacol Toxicol
October 2024
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA; email:
The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models.
View Article and Find Full Text PDFBackground: Repeated cocaine use produces neuroadaptations that support drug craving and relapse in substance use disorders (SUDs). Powerful associations formed with drug-use environments can promote a return to active drug use in SUD patients, but the molecular mechanisms that control the formation of these prepotent drug-context associations remain unclear.
Methods: In the rat intravenous cocaine self-administration (SA) model, we examined the role and regulation of histone deacetylase 5 (HDAC5) in the prelimbic (PrL) and infralimbic (IL) cortices in context-associated drug seeking.
The ventral tegmental area dopamine to basolateral amygdala projection supports acquisition of cocaine self-administration.
Neuropharmacology
December 2024
Department of Psychiatry, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA, 15219, USA; Center for Neuroscience, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA, 15213, USA. Electronic address:
Article Synopsis
- Dopamine signaling in the amygdala is crucial for associative learning, particularly in linking environmental cues to the effects of drugs like cocaine.
- Researchers used chemogenetics to alter dopamine inputs from the ventral tegmental area (VTA) to the basolateral amygdala (BLA) during cocaine-related behaviors, revealing that inhibiting dopamine reduced the motivation to seek cocaine when exposed to previously associated cues.
- The findings suggest that targeting dopamine pathways in the amygdala could lead to new treatments for substance use disorders by potentially modifying the associations formed between cues and drug use.
Sequential physical and cognitive training disrupts cocaine-context associations via multi-level stimulation of adult hippocampal neurogenesis.
Prog Neuropsychopharmacol Biol Psychiatry
September 2024
Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, Spain; Instituto de Investigación Biomédica de Málaga y Plataforma de Nanomedicina (IBIMA Plataforma BIONAND), Spain. Electronic address:
Cocaine-related contextual cues are a recurrent source of craving and relapse. Extinction of cue-driven cocaine seeking remains a clinical challenge, and the search for adjuvants is ongoing. In this regard, combining physical and cognitive training is emerging as a promising strategy that has shown synergistic benefits on brain structure and function, including enhancement of adult hippocampal neurogenesis (AHN), which has been recently linked to reduced maintenance of maladaptive drug seeking.
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