Rationale: The mesocorticolimbic dopamine (DA) system is critically involved in mediating reinstatement of drug-seeking behaviour. Substance P (SP) is a neuropeptide that significantly interacts with the mesocorticolimbic system, therefore suggesting a possible role for the SP system in the mediation of relapse.
Objectives: This study examined the effects of injections of the SP analogue, DiMe-C7, into the ventral tegmental area (VTA) on reinstatement of cocaine-seeking behaviour, as well as on locomotor activity in rats. Additionally, this study examined whether these effects are DA-dependent.
Methods: Rats were trained to self-administer cocaine for 15 days followed by 15 days of extinction. Reinstatement of cocaine-seeking behaviour was then measured in response to bilateral intra-VTA microinjections of DiMe-C7 (0, 0.1, 0.5 and 2.5 microg). In a separate group of rats, locomotor activity was measured in response to intra-VTA injections of DiMe-C7 (0, 0.5, 1.5 and 3 microg). The effects of pre-treatment with DA receptor antagonists on DiMe-C7-induced reinstatement and locomotor activity were also examined. Animals were pre-treated with the D(1) and D(2) receptor antagonists, SCH23390 and haloperidol (0, 0.01 and 0.03 mg/kg, IP), respectively, prior to receiving intra-VTA injections of DiMe-C7 (0 and 2.5 microg).
Results: Infusion of DiMe-C7 into the VTA increased locomotor activity and induced reinstatement of cocaine-seeking behaviour. Both SCH23390 and haloperidol blocked intra-VTA DiMe-C7-induced locomotor activation. In addition, SCH23390 attenuated DiMe-C7-induced reinstatement of cocaine-seeking behaviour, while haloperidol had no effect.
Conclusions: These results suggest that interactions between SP and the mesocorticolimbic DA system may play a role in mediating reinstatement of cocaine-seeking behaviour and that the involvement of these interactions in reinstatement are dependent upon D(1) receptor mechanisms.
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Article Synopsis
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- 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.
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Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics.
Annu Rev Pharmacol Toxicol
January 2025
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
January 2025
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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