Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

Shorter, Daryl; Domingo, Coreen; Kosten, Thomas R.

doi:10.1517/14728214.2015.985203

Cited by 52 publications

(35 citation statements)

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“…Although knowledge of reward mechanisms has significantly increased in recent decades, there are currently no approved medications for the treatment of cocaine dependence and behavioural treatment has shown limited efficacy (Shorter et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Papale

Morella

Indrigo

et al. 2016

eLife

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Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.DOI: http://dx.doi.org/10.7554/eLife.17111.001

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Section: Discussionmentioning

confidence: 99%

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Papale

Morella

Indrigo

et al. 2016

eLife

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“…Given the need for more direct coordination across disciplines in life sciences discovery (e.g., Zerhouni), concerns about the ability of animal models to inform the management of human conditions (e.g., Collins, 2011), and the demand for medications to treat cocaine use disorder (Kampman, 2010; Shorter et al, 2015), the goal of this and the companion study described in this issue (Johnson et al, 2016) was to back-translate a drug versus non-drug choice procedure in humans to rhesus monkeys, in order to establish a pipeline for cocaine use disorder medications development. These parallel studies demonstrated similar patterns of choice for cocaine and a non-drug alternative reinforcer under matching self-administration schedules and experimental session conditions in humans and rhesus monkeys.…”

Section: Discussionmentioning

confidence: 99%

“…Despite intense efforts, an effective and acceptable medication for treating cocaine use disorder has yet to be identified (Kampman, 2010; Shorter et al, 2015). A recent review of the literature revealed that, of the more than 60 medications evaluated in randomized controlled clinical trials for cocaine use disorder, only 10 had also been screened using both animal and human laboratory self-administration procedures (Czoty et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans

Lile

Stoops

Rush

et al. 2016

Drug and Alcohol Dependence

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Background A medication for treating cocaine use disorder has yet to be approved. Laboratory-based evaluation of candidate medications in animals and humans is a valuable means to demonstrate safety, tolerability and initial efficacy of potential medications. However, animal-to-human translation has been hampered by a lack of coordination. Therefore, we designed homologous cocaine self-administration studies in rhesus monkeys (see companion article) and human subjects in an attempt to develop linked, functionally equivalent procedures for research on candidate medications for cocaine use disorder. Methods Eight (N=8) subjects with cocaine use disorder completed 12 experimental sessions in which they responded to receive money ($0.01, $1.00 and $3.00) or intravenous cocaine (0, 3, 10 and 30 mg/70 kg) under independent, concurrent progressive-ratio schedules. Prior to the completion of 9 choice trials, subjects sampled the cocaine dose available during that session and were informed of the monetary alternative value. Results The allocation of behavior varied systematically as a function of cocaine dose and money value. Moreover, a similar pattern of cocaine choice was demonstrated in rhesus monkeys and humans across different cocaine doses and magnitudes of the species-specific alternative reinforcers. The subjective and cardiovascular responses to IV cocaine were an orderly function of dose, although heart rate and blood pressure remained within safe limits. Conclusions These coordinated studies successfully established drug vs. non-drug choice procedures in humans and rhesus monkeys that yielded similar cocaine choice behavior across species. This translational research platform will be used in future research to enhance the efficiency of developing interventions to reduce cocaine use.

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“…Comorbidity with other psychiatric conditions, including depression and anxiety disorders, is commonly seen in substance use disorders, including cocaine abuse (Volkow, 2004;Vorspan et al, 2015). Pharmacotherapies developed for treating cocaine abuse have been largely unsuccessful (Shorter et al, 2015) and some purported treatment mechanisms elicit or exacerbate unwanted symptoms (eg, depression, anxiety, increased impulsivity, cognitive impairments, or psychosis) (Homayoun et al, 2004;Kishi et al, 2013;Moore et al, 2014). Developing pharmacotherapies targeting cocaine addiction and associated comorbidities while lacking adverse effects may provide greater therapeutic efficacy as well as medication compliance, increased abstinence rates and improved overall treatment success.…”

Section: Introductionmentioning

confidence: 99%

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Gould

Amato

Bubser

et al. 2015

Neuropsychopharmacol

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Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5 ) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.

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Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

Cited by 52 publications

References 125 publications

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

Development of a translational model to screen medications for cocaine use disorder II: Choice between intravenous cocaine and money in humans

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

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