Treatment Of Cocaine Use Disorder Research Articles

Barriers and facilitators to medication-assisted treatment for cocaine use disorder among men who have sex with men: a qualitative study

BackgroundRates of cocaine use disorder (CUD) among men who have sex with men (MSM) are high and rising. Among MSM, cocaine use is associated with negative socioeconomic, medical, and psychological outcomes. There are no FDA-approved pharmacotherapy options to treat CUD, and psychosocial interventions demonstrate limited efficacy. While there have been numerous trials evaluating possible medications for CUD, there is a scarcity of qualitative data on the barriers and facilitators of medication-assisted treatment.MethodsSemi-structured interviews were conducted with 16 participants enrolled in a phase II randomized control trial evaluating extended-release lorcaserin among MSM with CUD. Participants were asked about their motivations for enrolling in the study, attitudes towards taking a medication for CUD, barriers and facilitators of study pill adherence, and their general study experience. Interviews were analyzed using an inductive and exploratory approach to thematic analysis.ResultsParticipants were highly motivated to reduce cocaine use and viewed pharmacotherapy as a viable and desirable treatment option. Pharmacotherapy was seen as having fewer access and adherence structural barriers compared to existing psychosocial therapies. Medication reminders facilitated pill taking, while side effects, travel, and active substance use presented barriers to study pill adherence. Disclosure of study participation within social networks was variable pointing to anticipated substance use and treatment stigma.ConclusionsOur study highlights important factors affecting the acceptability and uptake of medication-assisted treatment for CUD among a diverse sample of MSM. These findings can help guide the development and implementation of future pharmacotherapy options for CUD and other substance use disorders in this key population.

Use Of Passiflora Incarnata L. Herba In The Treatment Of Cocaine Use Disorders: The Experience Of An Addiction Center In Monza, Italy.

The authors report a real-world experience on the treatment of cocaine use disorders (craving) in outpatient treatment subjects at the addiction centre in Monza (MB, Italy). 38 patients with Substance Use Disorder (Cocaine) were enrolled over one year for substance craving treatment with Passiflora Incarnata L Herba at a dose of 600 mg/day for a period of two months.

Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity

Cocaine use disorder (CUD) is a chronic neuropsychiatric disorder estimated to effect 1–3% of the population. Activity-dependent neuroprotective protein (ADNP) is essential for brain development and functioning, shown to be protective in fetal alcohol syndrome and to regulate alcohol consumption in adult mice. The goal of this study was to characterize the role of ADNP, and its active peptide NAP (NAPVSIPQ), which is also known as davunetide (investigational drug) in mediating cocaine-induced neuroadaptations. Real time PCR was used to test levels of Adnp and Adnp2 in the nucleus accumbens (NAc), ventral tegmental area (VTA), and dorsal hippocampus (DH) of cocaine-treated mice (15 mg/kg). Adnp heterozygous (Adnp+/−)and wild-type (Adnp+/−) mice were further tagged with excitatory neuronal membrane-expressing green fluorescent protein (GFP) that allowed for in vivo synaptic quantification. The mice were treated with cocaine (5 injections; 15 mg/kg once every other day) with or without NAP daily injections (0.4 µg/0.1 ml) and sacrificed following the last treatment. We analyzed hippocampal CA1 pyramidal cells from 3D confocal images using the Imaris x64.8.1.2 (Oxford Instruments) software to measure changes in dendritic spine density and morphology. In silico ADNP/NAP/cocaine structural modeling was performed as before. Cocaine decreased Adnp and Adnp2 expression 2 h after injection in the NAc and VTA of male mice, with mRNA levels returning to baseline levels after 24 h. Cocaine further reduced hippocampal spine density, particularly synaptically weaker immature thin and stubby spines, in male Adnp+/+) mice while increasing synaptically stronger mature (mushroom) spines in Adnp+/−) male mice and thin and stubby spines in females. Lastly, we showed that cocaine interacts with ADNP on a zinc finger domain identical to ketamine and adjacent to a NAP-zinc finger interaction site. Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD.

Psilocybin administered following extinction sessions does not affect subsequent cocaine cue reinstatement in male and female rats and mice

There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD.

Differential effects of deep brain stimulation on reinstatement of cocaine seeking in male and female rats

There are currently no FDA-approved treatments for cocaine use disorder. Recent preclinical and clinical studies showed that deep brain stimulation (DBS) in limbic regions reduced drug seeking behavior. Our previous work indicated that DBS of the nucleus accumbens shell attenuated reinstatement of cocaine seeking, a model of relapse, in male rats. The current experiments were designed to evaluate the effect of electrical DBS on cocaine reinstatement in female rats across the estrous cycle. Rats were allowed to self-administer cocaine and lever responding was subsequently extinguished. Cocaine seeking was reinstated by an acute injection of experimenter-delivered cocaine. The effect of nucleus accumbens shell DBS vs. sham stimulation on cocaine-primed reinstatement was evaluated in female and male rats using a within-subjects counterbalanced design. Consistent with previous work, accumbens shell DBS suppressed cocaine seeking in male rats. In sharp contrast, accumbens shell DBS had no effect on cocaine reinstatement in female rats evaluated in either the estrus or non-estrus phases. These results suggest that changes across the estrous cycle are not responsible for the differences in the effect of DBS on cocaine reinstatement between female and male rats.

In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase

It is recognized as a promising therapeutic strategy for cocaine use disorder to develop an efficient enzyme which can rapidly convert cocaine to physiologically inactive metabolites. We have designed and discovered a series of highly efficient cocaine hydrolases, including CocH5-Fc(M6) which is the currently known as the most efficient cocaine hydrolase with both the highest catalytic activity against (−)-cocaine and the longest biological half-life in rats. In the present study, we characterized the time courses of protein appearance, pH, structural integrity, and catalytic activity against cocaine in vitro and in vivo of a CocH5-Fc(M6) bulk drug substance produced in a bioreactor for its in vitro and in vivo stability after long-time storage under various temperatures (− 80, − 20, 4, 25, or 37 °C). Specifically, all the tested properties of the CocH5-Fc(M6) protein did not significantly change after the protein was stored at any of four temperatures including − 80, − 20, 4, and 25 °C for ~ 18 months. In comparison, at 37 °C, the protein was less stable, with a half-life of ~ 82 days for cocaine hydrolysis activity. Additionally, the in vivo studies further confirmed the linear elimination PK profile of CocH5-Fc(M6) with an elimination half-life of ~ 9 days. All the in vitro and in vivo data on the efficacy and stability of CocH5-Fc(M6) have consistently demonstrated that CocH5-Fc(M6) has the desired in vitro and in vivo stability as a promising therapeutic candidate for treatment of cocaine use disorder.

Exercise Influences the Brain's Metabolic Response to Chronic Cocaine Exposure in Male Rats.

Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors.

Improving Attention as a Treatment for Cocaine Use Disorder: Initial, Mechanistic Steps

Improving Attention as a Treatment for Cocaine Use Disorder: Initial, Mechanistic Steps

Ketamine for Adults With Substance Use Disorders

What Is the Issue
 
 Accumulating research has demonstrated that subanesthetic doses of ketamine have rapid and sustained antidepressant effects. In 2019, the US FDA approved the S-enantiomer of ketamine (esketamine) for the treatment of patients with treatment-resistant depression.
 Since then, there has been interest in the development of ketamine for the treatment of a broad range of mental health conditions beyond depression, including substance use disorders (SUDs).
 Decision-makers want to know if there is any evidence to support the use of ketamine for treating SUDs in adults.
 
 What Did We Do?
 
 To inform decisions about using ketamine for treating SUDs, we sought to identify and summarize the literature comparing the clinical and cost-effectiveness of ketamine with placebo or no treatment, with alternative interventions, or among ketamine administered via different routes for SUDs. We also searched for evidence-based recommendations for the use of ketamine for SUDs.
 A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2018, and November 28, 2023. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.
 
 What Did We Find?
 
 We found 2 systematic reviews (SRs) and 1 randomized controlled trial (RCT) on the use of ketamine for the treatment of patients with alcohol use disorder (AUD), cocaine use disorder (CUD), and opioid use disorder (OUD).
 Evidence from 2 SR suggests that a combination of ketamine infusion and psychotherapy treatment may be effective in promoting abstinence and reduced consumption of alcohol and cocaine use. There were mixed results regarding the effect of ketamine on withdrawal and craving.
 The effects of ketamine on OUD were inconclusive as the results were derived from a single study with a small sample size. Similarly, the effects of ketamine on health care utilization (e.g., hospital readmission, emergency department visit) in patients with severe AUD reported in a RCT were also inconclusive due to the small sample size.
 Adverse events associated with ketamine treatment included the dissociative and psychotomimetic effects and nondissociative effects. The authors of the included SR reported that these events were mild and transient.
 We did not find any studies on the cost-effectiveness or evidence-based guidelines of ketamine for treating SUDs that met our criteria for this review.
 
 What Does It Mean?
 
 The conclusions on the positive effects of ketamine for AUD and CUD should be interpreted with caution due to the high risk of bias of the studies included in the SRs.
 There is a need for more robust clinical trials with larger sample sizes, blinding, and low risk of bias to provide more accurate findings on clinical efficacy, dosing strategies, and safety profile of ketamine for the treatment of AUD, CUD, and OUD.
 Additional studies on other substances of abuse (e.g., nicotine, amphetamines, and cannabis) may provide important insights into the overall efficacy of ketamine in the treatment of SUDs.

Enhanced peripheral levels of BDNF and proBDNF: elucidating neurotrophin dynamics in cocaine use disorder

Brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF, are known to significantly contribute to brain homeostasis, neuroplasticity, and neuronal remodeling. Although these neurotrophins are thought to have opposing roles, both play a critical part in shaping long-lasting behavioral changes following substance use. In this context, our study sought to explore the implications of these neurotrophins in the pathophysiology of cocaine use disorder (CUD). We conducted a case-control study, which included 28 individuals seeking treatment for CUD and 38 matched healthy participants. We measured peripheral neurotrophin concentrations via an enzyme-linked immunosorbent assay. Additionally, all participants were screened for cocaine-associated pathways (e.g., cocaine intake, craving intensity), along with associated psychopathological data. Our findings highlighted an increased concentration of BDNF and proBDNF in CUD individuals when compared to healthy controls (BDNF: 18092.80 ± 6844.62 vs. 11334.42 ± 5061.85 pg/ml, p < 0.001; proBDNF: 87.03 ± 33.23 vs. 55.70 ± 23.26 ng/ml, p < 0.001). We further corroborated the relationship between neurotrophin levels and CUD using a linear regression model. Nevertheless, there was no significant difference in the proBDNF to BDNF ratio between the two groups. Interestingly, our study also demonstrated the influence of factors like usage of psychotropic medications, history of psychiatric hospitalizations, and psychiatric diagnoses on neurotrophin dynamics. In conclusion, our study underscores the significance of neurotrophin fluctuations in CUD. The observed increase in BDNF and proBDNF levels could play a pivotal role in driving craving and relapse risk. Thus, a nuanced understanding of these neurobiological underpinnings in CUD might contribute to the development of more targeted and effective therapeutic strategies.

Contingency management plus acceptance and commitment therapy for initial cocaine abstinence: Results of a sequential multiple assignment randomized trial (SMART)

BackgroundThis study tested an adaptive intervention for optimizing abstinence outcomes over phases of treatment for cocaine use disorder using a SMART design. Phase 1 assessed whether 4 weeks of contingency management (CM) improved response with the addition of Acceptance and Commitment Therapy (ACT). Phase 2 assessed pharmacological augmentation with modafinil (MOD) vs. placebo (PLA) for individuals not achieving abstinence during Phase 1. MethodFor Phase 1 of treatment, participants (N=118) were randomly allocated to ACT+CM or Drug Counseling (DC+CM), the comparison condition. At week 4, treatment response was defined as the submission of six consecutive cocaine-negative urine drug screens (UDS). Phase 1 non-responders were re-randomized to MOD or PLA as adjunct to their initial treatment. Phase 1 responders continued receiving their initial treatment. Primary outcomes included response rate and proportion of cocaine-negative UDS for Phase 1 and 2. Analyses used Bayesian inference with 80% pre-specified as the posterior probability (PP) threshold constituting moderate evidence that an effect exists. ResultsPhase 1 response was higher in the ACT+CM group (24.5%) compared to the DC+CM group (17.5%; PP = 84.5%). In Phase 2, the proportion of cocaine-negative UDS among Phase 1 responders did not differ by initial treatment (PP = 61.8%) but remained higher overall compared to Phase 1 non-responders (PPs > 99%). No evidence of an effect favoring augmentation with MOD was observed. DiscussionAdding ACT to CM increased abstinence initiation. Initial responders were more likely to remain abstinent compared to initial non-responders, for whom modafinil was not an effective pharmacotherapy augmentation strategy.

Endogenous opioid system modulates conditioned cocaine reward in a sex-dependent manner.

Cocaine predictive cues and contexts exert powerful control over behaviour and can incite cocaine seeking and taking. This type of conditioned behaviour is encoded within striatal circuits, and these circuits and behaviours are, in part, regulated by opioid peptides and receptors expressed in striatal medium spiny neurons. We previously showed that augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP), while opioid receptor antagonists attenuate expression of cocaine CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. To address this, we generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing medium spiny neurons and tested them in a cocaine CPP paradigm. Low striatal enkephalin levels did not attenuate acquisition of CPP. However, expression of preference, assessed after acute administration of the opioid receptor antagonist naloxone, was blocked in females, regardless of genotype. When saline was paired with the cocaine context during extinction sessions, females, regardless of genotype, extinguished preference faster than males, and this was prevented by naloxone when paired with the cocaine context. We conclude that while striatal enkephalin is not necessary for acquisition, expression, or extinction of cocaine CPP, expression and extinction of cocaine preference in females is mediated by an opioid peptide other than striatal enkephalin. The unique sensitivity of females to opioid antagonists suggests sex should be a consideration when using these compounds in the treatment of cocaine use disorder.

Chronic administration of a norepinephrine antagonist prevents and partially reverses escalation of cocaine self-administration.

Anxiety is a critical component of the development and maintenance of drug addiction; however, anti-anxiety medications such as benzodiazepines and beta-blockers (β-adrenergic receptor antagonists) are not used for the treatment of substance use disorder, except for the management of acute withdrawal syndrome. Preclinical studies have shown that beta-blockers may reduce stress-induced relapse; however, the effect of beta blockers on the escalation and maintenance of drug intake has not been tested. To address this issue, we chronically administered the β-adrenergic receptor antagonist propranolol during the escalation or maintenance of cocaine intake in a model of extended access (6h) to cocaine self-administration (0.5mg/kg). The behavioural specificity of propranolol was tested using a non-drug reward (saccharin). Daily administration of propranolol (15 mg/kg) prevented the development of escalation of cocaine self-administration and partially reversed self-administration after the establishment of escalation of intake. Moreover, propranolol dose-dependently decreased the motivation for cocaine tested under a progressive ratio schedule of reinforcement during the development of escalation and after maintenance. Finally, propranolol administration had no effect on the escalation and maintenance of saccharin self-administration. These results demonstrate that chronic treatment with propranolol provides therapeutic efficacy in reducing cocaine self-administration during the development and after the establishment of escalation of cocaine self-administration in an animal model relevant to cocaine use disorder. These results suggest that beta blockers should be further investigated as a target for medication development for the treatment of cocaine use disorder.

Estradiol enhances the mirtazapine effects on the expression of cocaine-induced locomotor sensitization in female rats.

Epidemiological studies have mentioned that cocaine use disorder (CUD) has increased in the last decade among women; these show endocrine and reproductive disorders and a high propensity to stress and depression disorders. Mirtazapine-a tetracyclic antidepressant-decreases cocaine-induced locomotor activity and locomotor sensitization in male rats. The objective of this study was to evaluate if estradiol alters the efficacy of mirtazapine to decrease cocaine-induced locomotor activity in sham and ovariectomized female rats. Three hundred and twenty adult female Wistar rats were assigned to three experimental protocols. For experiments, 1-3, female rats were daily dosed with 10 mg/kg of cocaine during the 10 days of induction and expression of locomotor sensitization. During drug withdrawal (30 days), cocaine was withdrawn and the groups received daily mirtazapine, estradiol, or saline. In addition, the females underwent sham or ovariectomy surgery. Tamoxifen was administered during the antagonism phase. After each administration, locomotor activity for each animal was recorded for 30 min in activity chambers. The dosage of mirtazapine reduces estradiol-induced enhancement in cocaine-dependent locomotor activity during the expression of locomotor sensitization in sham and ovariectomized female rats. As well as they showed that estradiol co-dosed with mirtazapine enhances the efficacy of mirtazapine to decrease cocaine-induced locomotor activity. Finally, tamoxifen enhanced the estradiol and mirtazapine-induced decrease in the cocaine motor effect in female rats. Mirtazapine may be considered an effective therapeutic option for the treatment of CUD in women, even in those who are on hormonal treatment or antidepressant therapy with estradiol.

Characterization and optimization of fluorescein isothiocyanate labeling of humanized h2E2 anti-cocaine mAb

Fluorescein isothiocyanate (FITC) is widely used to fluorescently label reactive lysine residues on proteins, including antibodies. The rate and extent of labeling varies with reaction conditions, concentration of label, and the concentration and nature of the protein. Fluorescently labeled proteins are very useful, and one use for FITC labeled mAbs is development of assays to measure anti-mAb antibodies produced in vivo during treatment with antibody therapeutics. Our laboratory has developed a humanized anti-cocaine mAb (h2E2) intended for the treatment of cocaine use disorders. Thus, a well characterized FITC labeled h2E2 mAb is needed to quantitate possible anti-mAb antibodies. The time course of labeling and the relative incorporation of FITC into the heavy and light chains, as well as into the Fab and Fc portions of the mAb, was assessed. A novel use of differential scanning fluorimetry in the absence of any extrinsic fluorophore was developed and demonstrated to be capable of measuring antigen (cocaine) binding. In addition, the effect of increasing degrees of labeling by FITC on the thermodynamic parameters driving the binding of cocaine to the mAb was assessed via isothermal titration calorimetry (ITC). This binding technique, unlike others developed recently to measure cocaine binding, is not dependent on, or subject to interference by, the absorbance or fluorescence of the incorporated FITC label. The methods and results reported herein guide the optimization of FITC labeling needed for anti-mAb assays and other assays important for the development of therapeutic mAbs, which are some of the most specific and clinically useful drugs available.

Dopamine Transporter Knockout Rats Display Epigenetic Alterations in Response to Cocaine Exposure.

(1) Background: There is an urgent need for effective treatments for cocaine use disorder (CUD), and new pharmacological approaches targeting epigenetic mechanisms appear to be promising options for the treatment of this disease. Dopamine Transporter (DAT) transgenic rats recently have been proposed as a new animal model for studying susceptibility to CUD. (2) Methods: DAT transgenic rats were treated chronically with cocaine (10 mg/kg) for 8 days, and the expression of epigenetic modulators, Lysine Demethylase 6B (KDM6B) and Bromodomain-containing protein 4 (BRD4), was examined in the prefrontal cortex (PFC). (3) Results: We show that only full knockout (KO) of DAT impacts basal levels of KDM6B in females. Additionally, cocaine altered the expression of both epigenetic markers in a sex- and genotype-dependent manner. In response to chronic cocaine, KDM6B expression was decreased in male rats with partial DAT mutation (HET), while no changes were observed in wild-type (WT) or KO rats. Indeed, while HET male rats have reduced KDM6B and BRD4 expression, HET female rats showed increased KDM6B and BRD4 expression levels, highlighting the impact of sex on epigenetic mechanisms in response to cocaine. Finally, both male and female KO rats showed increased expression of BRD4, but only KO females exhibited significantly increased KDM6B expression in response to cocaine. Additionally, the magnitude of these effects was bigger in females when compared to males for both epigenetic enzymes. (4) Conclusions: This preliminary study provides additional support that targeting KDM6B and/or BRD4 may potentially be therapeutic in treating addiction-related behaviors in a sex-dependent manner.

Cocaine Regulates NLRP3 Inflammasome Activity and CRF Signaling in a Region- and Sex-Dependent Manner in Rat Brain.

Cocaine, one of the most abused drugs worldwide, is capable of activating microglia in vitro and in vivo. Several neuroimmune pathways have been suggested to play roles in cocaine-mediated microglial activation. Previous work showed that cocaine activates microglia in a region-specific manner in the brains of self-administered mice. To further characterize the effects of cocaine on microglia and neuroimmune signaling in vivo, we utilized the brains from both sexes of outbred rats with cocaine self-administration to explore the activation status of microglia, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activity, corticotropin-releasing factor (CRF) signaling, and NF-κB levels in the striatum and hippocampus (HP). Age-matched rats of the same sex (drug naïve) served as controls. Our results showed that cocaine increased neuroinflammation in the striatum and HP of both sexes with a relatively higher increases in male brains. In the striatum, cocaine upregulated NLRP3 inflammasome activity and CRF levels in males but not in females. In contrast, cocaine increased NLRP3 inflammasome activity in the HP of females but not in males, and no effects on CRF signaling were observed in this region of either sex. Interestingly, cocaine increased NF-κB levels in the striatum and HP with no sex difference. Taken together, our results provide evidence that cocaine can exert region- and sex-specific differences in neuroimmune signaling in the brain. Targeting neuroimmune signaling has been suggested as possible treatment for cocaine use disorders (CUDs). Our current results indicate that sex should be taken into consideration when determining the efficacy of these new therapeutic approaches.

Oleoylethanolamide attenuates cocaine-primed reinstatement and alters dopaminergic gene expression in the striatum

The lipid oleoylethanolamide (OEA) has been shown to affect reward-related behavior. However, there is limited experimental evidence about the specific neurotransmission systems OEA may be affecting to exert this modulatory effect. The aim of this study was to evaluate the effects of OEA on the rewarding properties of cocaine and relapse-related gene expression in the striatum and hippocampus. For this purpose, we evaluated male OF1 mice on a cocaine-induced CPP procedure (10 mg/kg) and after the corresponding extinction sessions, we tested drug-induced reinstatement. The effects of OEA (10 mg/kg, i.p.) were evaluated at three different timepoints: (1) Before each cocaine conditioning session (OEA-C), (2) Before extinction sessions (OEA-EXT) and (3) Before the reinstatement test (OEA-REINST). Furthermore, gene expression changes in dopamine receptor D1 gene, dopamine receptor D2 gene, opioid receptor µ, cannabinoid receptor 1, in the striatum and hippocampus were analyzed by qRT-PCR. The results obtained in the study showed that OEA administration did not affect cocaine CPP acquisition. However, mice receiving different OEA treatment schedules (OEA-C, OEA-EXT and OEA-REINST) failed to display drug-induced reinstatement. Interestingly, the administration of OEA blocked the increase of dopamine receptor gene D1 in the striatum and hippocampus caused by cocaine exposure. In addition, OEA-treated mice exhibited reduced striatal dopamine receptor gene D2 and cannabinoid receptor 1. Together, these findings suggest that OEA may be a promising pharmacological agent in the treatment of cocaine use disorder.

Low doses of pharmaceutical formulations loaded with UFMG-V4N2 immunogen induce the production of IgG anti-cocaine antibodies and provide evidence of cerebral protection in the preclinical model

Anti-cocaine vaccines are a promising therapeutic strategy for treating cocaine use disorders. Here we hypothesize that nanoemulsions (NE) or suspensions (SS) loaded with the calix [4]arene-based immunogen UFMG-V4N2 can induce the production of anti-cocaine antibodies and decrease the passage of radiolabeled cocaine analog [99mTc]Trodat-1 through of the brain barrier. UFMG-V4N2 was characterized (solubility, morphology, DSC, XRD) and loaded into NEs and SSs using excipients approved for human use. Immunogenic efficacy was assessed by quantifying the titers and determining the specificity of anti-cocaine IgG antibodies, and by assessing the inhibition of [99mTc]Trodat-1 trafficking across the mice brain-barrier. UFMG-V4N2 is an amorphous, thermally stable molecule with very low hydrophilicity. The immunogenicity of NE or SS was similar, but aluminum phosphate and the lower dose of UFMG-V4N2 induced higher anti-cocaine IgG antibody titers, minimizing [99mTc]Trodat-1 uptake in the brain. Therefore, the UFMG-V4N2 may represent an alternative for the treatment of cocaine use disorder.

Prolonged exposure to cocaine self-administration results in a continued progression of alterations in functional activity in a nonhuman primate model

BackgroundStudies of nonhuman primates with exposures of up to 100 days of cocaine self-administration (SA) have provided evidence that the central effects of cocaine progress over time. These durations of cocaine exposure, however, may be insufficient to capture the extent of the neurobiological alterations observed in cocaine users, many of whom use the drug for years. The goal of the present study was to determine whether 1.5 years of cocaine SA would result in further progression of alterations in functional brain activity. MethodsAdult male rhesus monkeys were exposed to 300 sessions of high-dose cocaine SA over 1.5 years. Following the final session rates of local cerebral glucose utilization (LCGU) were assessed with the 2-[14C]-deoxyglucose method and compared to rates of LCGU in control monkeys who responded for food reinforcement. In addition, LCGU in these animals was compared to a previously published group of monkeys that had self-administered cocaine or food for 100 sessions over a 4–5 month period. ResultsCompared to 100 days of exposure, 300 days of cocaine SA further reduced LCGU in the post-commissural striatum and produced reductions in areas unaffected by the shorter duration of exposure, such as the hypothalamus, all of the amygdala, and large expanses of cortex. ConclusionsThese findings demonstrate a clear progression of the impact of cocaine on functional activity with increasing durations of drug experience and have important implications for the development of potential strategies for the treatment of cocaine use disorder.