Repeated exposure to drugs of abuse produces long‐term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as ...well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self‐administer drugs and disrupt drug‐associated cue‐induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so‐called proof‐of‐concept studies for drug addiction indications will be discussed.
The focal distribution of the dopamine (DA) D(3) receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will ...review the most recent lines of research in support of the use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D(3) receptor in the rodent and human brain; (2) changes in expression of the DA D(3) receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D(3) receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D(2)/D(3) receptor antagonists or partial D(3) receptor agonists. Growing evidence suggests that selective DA D(3) receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D(3) receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.
The prefrontal cortex in rats can be distinguished anatomically from other frontal cortical areas both in terms of cytoarchitectonic characteristics and neural connectivity, and it can be further ...subdivided into subterritories on the basis of such criteria. Functionally, the prefrontal cortex of rats has been implicated in working memory, attention, response initiation and management of autonomic control and emotion. In humans, dysfunction of prefrontal cortical areas with which the medial prefrontal cortex of the rat is most likely comparable is related to psychopathology including schizophrenia, sociopathy, obsessive-compulsive disorder, depression, and drug abuse. Recent literature points to the relevance of conducting a functional analysis of prefrontal subregions and supports the idea that the area of the medial prefrontal cortex in rats is characterized by its own functional heterogeneity, which may be related to neuroanatomical and neurochemical dissociations. The present review covers recent findings with the intent of correlating these distinct functional differences in the dorso-ventral axis of the rat medial prefrontal cortex with anatomical and neurochemical patterns.
The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and ...receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2–3 ng/ml (corresponding to ≥70% brain
mu
-opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.
•Real-world data analysis of opioid use disorder treatment distribution.•Buprenorphine extended-release increased in organized health systems.•Distribution variation analysis by health system and ...United States geography.•Access and uptake barriers and solutions for health organizations and patients.
Effective medications for opioid use disorder (MOUD) are underutilized. This exploratory study used real-world data to analyze US distribution patterns of buprenorphine extended-release (BUP-XR) within organized health systems (OHS), including the Veterans Health Administration (VHA), Indian Health Service (IHS), criminal justice system (CJS), and integrated delivery networks (IDNs).
National BUP-XR distribution data within each OHS were available from WNS Global Services and were evaluated from July 2019 through July 2020. BUP-XR distribution data by OHS subtype (VHA, IHS, CJS, IDN) and state were aggregated and reported.
The total distribution of BUP-XR increased from 6,721 units in the second half of 2019 (H2’19) to 12,925 in the first half of 2020 (H1’20). OHS distribution increased from H2’19 to H1’20 in every subtype but was primarily driven by IDN distribution growth. IDNs accounted for 73% of total units in H2’19 and continued to grow in H1’20. In H1’20, IDNs accounted for 78%, VHA for 12%, CJS for 6%, and IHS for 4%. IDN distribution for BUP-XR increased from 4,911 to 10,100 units, showing the highest growth rate of 106% within all OHS subtypes. The states with the highest total BUP-XR distribution over the 12-month period were Massachusetts (4,534), Pennsylvania (3,773), and California (1,866).
Overall distribution of BUP-XR, as a treatment option for OUD, is increasing; however, access to MOUD varies greatly across OHS subtypes and geography. Identifying and overcoming barriers to appropriate MOUD use is critical in addressing the opioid crisis.
•The discovery of buprenorphine in 1966 revolutionized care for opioid use disorder.•US government and private industry partnership led to buprenorphine-based medications.•Confronting barriers to use ...these medications is critical to address the opioid crisis.
Buprenorphine-based medications were first approved by the United States Food and Drug Administration in 2002 for the treatment of opioid dependence, or opioid use disorder (OUD) as the condition is presently known. This regulatory milestone was the outcome of 36 years of research and development, which also led to the development and approval of several other new buprenorphine-based medications. In this short review, we first describe the discovery and early development stages of buprenorphine. Second, we review key steps that led to the development of buprenorphine as a drug product. Third, we explain the regulatory approval of several buprenorphine-based medications for the treatment of OUD. We also discuss these developments in the context of the evolution of regulations and policies that have progressively improved OUD treatment availability and efficacy, although challenges remain in removing system-level, provider-level, and local-level barriers to quality treatment, to integrating OUD treatment into routine care and other settings, to reducing disparities in access to treatment, and to optimizing person-centered outcomes.
SB-399885 (N-3,5-dichloro-2-(methoxy)phenyl-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide) has high affinity for human recombinant and native 5-HT(6) receptors, with pK(i) values 9.11+/-0.03 and ...9.02+/-0.05, respectively and is a potent competitive antagonist (pA(2) 7.85+/-0.04). It displays over 200-fold selectivity for the 5-HT(6) receptor over all other receptors, ion channels and enzymes tested to date. SB-399885 inhibited ex vivo (125)ISB-258585 (4-Iodo-N-4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl-benzenesulfonamide) binding with an ED(50) of 2.0+/-0.24 mg/kg p.o. in rats. It had a minimum effective dose of 1 mg/kg p.o. in a rat maximal electroshock seizure threshold test and a long duration of action, overall demonstrating an excellent pharmacokinetic-pharmacodynamic correlation. Repeated administration of this agent (10 mg/kg p.o., b.i.d. for 7 days) significantly reversed a scopolamine-induced deficit (0.5 mg/kg i.p.) in a rat novel object recognition paradigm. Moreover, in aged rats (22 months old) SB-399885 (10 mg/kg p.o., b.i.d. for 7 days) fully reversed the age-dependent deficit in water maze spatial learning compared to vehicle-treated age-matched controls and significantly improved recall of the task measured by increases in the searching of the target quadrant on post-training days 1, 3 and 7. In vivo microdialysis in the rat medial prefrontal cortex demonstrated that acute SB-399885 (10 mg/kg p.o.) significantly increased extracellular acetylcholine levels. These data demonstrate that SB-399885 is a potent, selective, brain penetrant, orally active 5-HT(6) receptor antagonist with cognitive enhancing properties that are likely to be mediated by enhancements of cholinergic function. These studies provide further support for the potential therapeutic utility of 5-HT(6) receptor antagonists in disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.
In rats, acute administration of SB‐277011A, a highly selective dopamine (DA) D3 receptor antagonist, blocks cocaine‐enhanced brain stimulation reward, cocaine‐seeking behaviour and reinstatement of ...cocaine‐seeking behaviour. Here, we investigated whether SB‐277011A attenuates cocaine reinforcement as assessed by cocaine self‐administration under variable‐cost–variable‐payoff fixed‐ratio (FR) and progressive‐ratio (PR) reinforcement schedules. Acute i.p. administration of SB‐277011A (3–24 mg/kg) did not significantly alter cocaine (0.75 mg/kg/infusion) self‐administration reinforced under FR1 (one lever press for one cocaine infusion) conditions. However, acute administration of SB‐277011A (24 mg/kg, i.p.) progressively attenuated cocaine self‐administration when: (a) the unit dose of self‐administered cocaine was lowered from 0.75 to 0.125–0.5 mg/kg, and (b) the work demand for cocaine reinforcement was increased from FR1 to FR10. Under PR (increasing number of lever presses for each successive cocaine infusion) cocaine reinforcement, acute administration of SB‐277011A (6–24 mg/kg i.p.) lowered the PR break point for cocaine self‐administration in a dose‐dependent manner. The reduction in the cocaine (0.25–1.0 mg/kg) dose–response break‐point curve produced by 24 mg/kg SB‐277011A is consistent with a reduction in cocaine's reinforcing efficacy. When substituted for cocaine, SB‐277011A alone did not sustain self‐administration behaviour. In contrast with the mixed DA D2/D3 receptor antagonist haloperidol (1 mg/kg), SB‐277011A (3, 12 or 24 mg/kg) failed to impede locomotor activity, failed to impair rearing behaviour, failed to produce catalepsy and failed to impair rotarod performance. These results show that SB‐277011A significantly inhibits acute cocaine‐induced reinforcement except at high cocaine doses and low work requirement for cocaine. If these results extrapolate to humans, SB‐277011A or similar selective DA D3 receptor antagonists may be useful in the treatment of cocaine addiction.
A rapid liquid chromatography/tandem mass spectrometry (LC–MS/MS) method has been developed for the measurement of dopamine (DA), 5-hydroxytryptamine (5HT) and norepinephrine (NE) in brain ...microdialysates. The assay has also been utilised for the simultaneous measurement of these neurotransmitters and cocaine in brain dialysates. The neurotransmitters and cocaine were resolved in a single 4-min run using a binary gradient elution profile. The analytes were detected using tandem mass spectrometry in the positive ion electrospray mode. The limits of detection for DA, NE, 5HT and cocaine were 200, 1000, 900
pM and 1
pg
ml
−1, respectively.
Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation ...to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.
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