Dopamine-D1 and δ-opioid receptors co-exist in rat striatal neurons

Cocaine’s enhancement of dopaminergic neurotransmission in the mesolimbic pathway plays a critical role in the initial reinforcing properties of this drug. However, other neurotransmitter systems are also integral to the addiction process. A large body of data indicates that opioids and dopamine together mediate emotional and reinforced behaviors. In support of this, cocaine-mediated increases in activation of dopamine D1 receptors (D1R) results in a desensitization of δ-opioid receptor (DOR) signaling through adenylyl cyclase (AC) in striatal neurons. To further define cellular mechanisms underlying this effect, the subcellular distribution of DOR and D1R was examined in the rat dorsolateral striatum. Dual immunoperoxidase/gold-silver detection combined with electron microscopy was used to identify DOR and D1R immunoreactivities in the same section of tissue. Semi-quantitative analysis revealed that a subset of dendritic cellular profiles exhibited both DOR and D1R immunoreactivities. Of 165 randomly sampled D1R immunoreactive profiles, 43% contained DOR. Similarly of 198 DOR-labeled cellular profiles, 52% contained D1R. The present data provide ultrastructural evidence for co-existence between DOR and D1R in striatal neurons, suggesting a possible mechanism whereby D1R modulation may alter DOR function

Poly-substance use and antisocial personality traits at admission predict cumulative retention in a buprenorphine programme with mandatory work and high compliance profile

Background: Continuous abstinence and retention in treatment for alcohol and drug use disorders are central challenges for the treatment providers. The literature has failed to show consistent, strong predictors of retention. Predictors and treatment structure may differ across treatment modalities. In this study the structure was reinforced by the addition of supervised urine samples three times a week and mandatory daily work/structured education activities as a prerequisite of inclusion in the program. Methods: Of 128 patients consecutively admitted to buprenorphine maintenance treatment five patients dropped out within the first week. Of the remaining 123 demographic data and psychiatric assessment were used to predict involuntary discharge from treatment and corresponding cumulative abstinence probability. All subjects were administered the Structured Clinical Interview for DSM-IV-TR, and the Symptom Checklist 90 (SCL-90), the Alcohol Use Disorder Identification Test (AUDIT), the Swedish universities Scales of Personality (SSP) and the Sense of Coherence Scale (SOC), all self-report measures. Some measures were repeated every third month in addition to interviews. Results: Of 123 patients admitted, 86 (70%) remained in treatment after six months and 61 (50%) remained in treatment after 12 months. Of those discharged involuntarily, 34/62 individuals were readmitted after a suspension period of three months. Younger age at intake, poly-substance abuse at intake (number of drugs in urine), and number of conduct disorder criteria on the SCID Screen were independently associated with an increased risk of involuntary discharge. There were no significant differences between dropouts and completers on SCL-90, SSP, SOC or AUDIT. Conclusion: Of the patients admitted to the programme 50% stayed for the first 12 months with continuous abstinence and daily work. Poly-substance use before intake into treatment, high levels of conduct disorder on SCID screen and younger age at intake had a negative impact on retention and abstinence

Influence of opioid and estrogen systems on cocaine withdrawal in females

Recent interest has focused on elucidating sex differences in cocaine addiction, a major public health concern worldwide. Anxiety, a hallmark of cocaine withdrawal, is mediated by both estrogen and δ-opioid receptor (DOR) systems. The overall aim of this thesis project was to evaluate the contribution of circulating estrogen and the DOR system on cocaine withdrawal-induced anxiety in females. In humans, retrospective analysis of treatment-seeking females supports a potential link between menstrual cycle, anxiety, intake urinalysis and treatment outcome. Preclinical studies were conducted using ovariectomized (OVX) and intact female rats to directly test the role of estrogen on cocaine-withdrawal induced anxiety using the elevated-plus and elevated-zero mazes. A direct correlation between blood estrogen level and anxiety-like behavior was not evident; however, these data point to the potential role of circulating hormones on all phases of addiction and warrant further analysis. Moreover, the DOR agonist SNC-80 was shown to be anxiolytic in females highlighting a potential role for DOR in the modulation of cocaine withdrawal-induced anxiety. Electron microscopic (EM) analysis in the nucleus accumbens (NAcb), a major target of cocaine\u27s action, revealed cocaine-induced sex-dependent DOR trafficking and co-existence of DOR and Dopamine-D1 Receptor (D1R) providing an anatomical substrate for dopamine-opioid receptor interaction. Finally, preliminary evidence using immunofluorescence microscopy supports the co-existence of estrogen receptor β (ERβ) and DOR which may facilitate potential co-mediation of anxiety by these systems. In summary, our results demonstrate cocaine withdrawal-induced changes in DOR and the anxioytic properties of DOR agonists in female rodent models. Future studies are needed to gain a greater understanding of how circulating hormones contribute to sex differences in cocaine addiction. This project corroborates the need for development of individualized treatment and implementation of pharmacotherapy targeting opioid and estrogen systems to improve current cocaine addiction treatments

Cocaine withdrawal-induced anxiety in females: Impact of circulating estrogen and potential use of delta-opioid receptor agonists for treatment

Sex differences in cocaine addiction warrants further research focused on examining the growing population of female cocaine addicts. As demonstrated in both clinical and preclinical research, females are more susceptible to drug relapse with anxiety being a contributing factor. In support of this, a recent clinical study from our laboratory highlights the importance of menstrual cycle phase and anxiety at treatment admission for cocaine addiction on treatment retention. In support of these trends in the clinical population, the purpose of the present study was to design an animal model to directly test the role of circulating hormone levels during cocaine withdrawal. To directly measure the influence of estrogen on anxiety-like behavior during early stages of withdrawal, both ovariectomized and intact female rodent models were employed. The elevated-plus maze and elevated-zero maze were used to assess anxiety-like behavior. Recent evidence in male rodents highlights a potential role for the delta opioid-receptor (DOR) system in the modulation of cocaine withdrawal-induced anxiety. In addition to the evaluation of hormonal effects, a potential anxiolytic specific for DOR was tested for its efficacy in females withdrawn from cocaine. Our results support the use of DOR agonists as a potential anxiolytic in females and highlight the importance of estrogen and other circulating hormones during all phases of cocaine addiction

Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European-American females.

Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. Although these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors have a role in determining treatment outcome. This study analyses the pharmacogenetic association of six polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone (Suboxone) over the course of a 24-week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid-positive urine drug screens over the 24 weeks. In the total sample, no single-nucleotide polymorphisms (SNPs) in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed two intronic SNPs (rs581111 and rs529520) that predicted treatment outcome in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine (P=0.03, relative risk (RR)=1.67, 95% confidence interval (CI) 1.06-2.1). For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype when (P=0.006, RR=2.15, 95% CI 1.3-2.29). No significant associations were detected in males. These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts, however, confirmation in an independent sample is warranted