Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Inactivation of phosphodiesterase-4B gene in rat nucleus accumbens shell by CRISPR/Cas9 or positive allosteric modulation of the protein affects the motivation to chronically self-administer nicotine.

Large scale human genome wide association studies (GWAS) have identified a growing pool of genes associated with cigarette smoking. One of the most prominent, phosphodiesterase-4B (PDE4B), has been associated with multiple smoking phenotypes. Although PDE4B modulates the half-life of neuronal cAMP, its precise role in smoking behaviors is unknown. To address this knowledge gap, we used a reverse translational approach. We inactivated PDE4B in bilateral medial nucleus accumbens shell (NAcs) neurons by injecting AAV containing a specific gRNA in female transgenic Cas9+ Long Evans rats. These rats then were given 23-h chronic access to nicotine intravenous self-administration (IVSA) under a schedule of increasing fixed ratios (FR). With the increased effort required at FR7, nicotine SA (i.e. active presses and drug infusions) declined significantly in controls, whereas it was maintained in the mutagenized group. A progressive ratio (PR) study also showed significantly greater cumulative nicotine infusions in the PDE4B-edited group. Hence, we hypothesized that enhanced PDE4B protein activity would reduce nicotine IVSA. A positive allosteric modulator, 2-(3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl)-N-(3,5-dichlorobenzyl)acetamide (MR-L2), was microinfused into NAcs bilaterally at FR3 or FR5; in both cohorts, MR-L2 acutely reduced nicotine IVSA. In summary, these studies show that the activity of PDE4B regulates the capacity of NAcs to maintain nicotine IVSA in face of the cost of increasing work. This finding and the results of the PR study indicate that PDE4B affects the motivation to obtain nicotine. These reverse translational studies in rats provide insight into the motivational effects of NAcs PDE4B that advance our understanding of the smoking behaviors mapped in human GWAS.

Restoration of a paraventricular thalamo-accumbal behavioral suppression circuit prevents reinstatement of heroin seeking.

Lack of behavioral suppression typifies substance use disorders, yet the neural circuit underpinnings of drug-induced behavioral disinhibition remain unclear. Here, we employ deep-brain two-photon calcium imaging in heroin self-administering mice, longitudinally tracking adaptations within a paraventricular thalamus to nucleus accumbens behavioral inhibition circuit from the onset of heroin use to reinstatement. We find that select thalamo-accumbal neuronal ensembles become profoundly hypoactive across the development of heroin seeking and use. Electrophysiological experiments further reveal persistent adaptations at thalamo-accumbal parvalbumin interneuronal synapses, whereas functional rescue of these synapses prevents multiple triggers from initiating reinstatement of heroin seeking. Finally, we find an enrichment of µ-opioid receptors in output- and cell-type-specific paraventricular thalamic neurons, which provide a mechanism for heroin-induced synaptic plasticity and behavioral disinhibition. These findings reveal key circuit adaptations that underlie behavioral disinhibition in opioid dependence and further suggest that recovery of this system would reduce relapse susceptibility.

Rats have low motivation to self-administer oral methamphetamine across increasing response requirements.

Methamphetamine (METH) is a psychostimulant drug that has become increasingly popular in recent years, with overdose deaths more than doubling during the second half of the 2010s. As methamphetamine use disorder rates continue to increase, finding effective treatment strategies to decrease METH dependence is important. Animal studies are well-suited for studying the neurobiological mechanisms underlying addiction-like behaviors. Although individuals can ingest METH orally, few studies have examined oral METH self-administration in animals. Mice show decreased responding for oral METH as the response requirement increases across sessions. The purpose of the current study was to determine if rats show a similar decrease in motivation to earn oral METH across increasing response requirements. Sixteen Sprague Dawley rats were trained to emit a response in an aperture to receive a 0.1-ml METH solution (40 mg/l) according to an FR 1 schedule. The FR requirement increased across sessions to a terminal FR 10. Responses for METH decreased significantly when an FR 10 schedule was used. These results suggest that rats, similarly to mice, have low motivation to self-administer oral METH.

Nicotine modifies cocaine responding in a concurrent self-administration model.

BACKGROUND: Preclinical models of cocaine use disorder (CUD) have not yielded any FDA-approved pharmacotherapies, potentially due to a focus on cocaine use in isolation, which may not fully translate to real-world drug taking patterns. Cocaine and nicotine are commonly used together, and clinical research suggests that nicotine may increase the potency and reinforcing strength of cocaine. In this study, we sought to determine whether and how the addition of nicotine would alter ongoing intravenous cocaine self-administration and motivation to take cocaine in rats. METHODS: Male Sprague-Dawley rats self-administered cocaine alone on a long access, Fixed Ratio one (FR1) schedule, and then switched to a combination of cocaine and nicotine. Finally, rats responded on a Progressive Ratio (PR) schedule for several doses of cocaine alone and in combination with a single dose of nicotine. RESULTS: Under long access conditions, rats co-self-administering cocaine and nicotine responded less and with decreased response rates than for cocaine alone and did not escalate responding. However, under PR conditions that test motivation to take drugs, the dose response curve for the combination was shifted upwards relative to cocaine alone. CONCLUSIONS: Together, these results suggest that nicotine may enhance the reinforcing strength of cocaine, increasing PR responding for cocaine across the dose response curve.

High frequency DBS-like optogenetic stimulation of nucleus accumbens dopamine D2 receptor-containing neurons attenuates cocaine reinstatement in male rats.

Previous work indicated that deep brain stimulation (DBS) of the nucleus accumbens shell in male rats attenuated reinstatement of cocaine seeking, an animal model of craving. However, the potential differential impact of DBS on specific populations of neurons to drive the suppression of cocaine seeking is unknown. Medium spiny neurons in the nucleus accumbens are differentiated by expression of dopamine D1 receptors (D1DRs) or D2DRs, activation of which promotes or inhibits cocaine-related behaviors, respectively. The advent of transgenic rat lines expressing Cre recombinase selectively in D1DR-containing or D2DR-containing neurons, when coupled with Cre-dependent virally mediated gene transfer of channelrhodopsin (ChR2), enabled mimicry of DBS in a selective subpopulation of neurons during complex tasks. We tested the hypothesis that high frequency DBS-like optogenetic stimulation of D1DR-containing neurons in the accumbens shell would potentiate, whereas stimulation of D2DR-containing neurons in the accumbens shell would attenuate, cocaine-primed reinstatement of cocaine seeking. Results indicated that high frequency, DBS-like optogenetic stimulation of D2DR-containing neurons attenuated reinstatement of cocaine seeking in male rats, whereas DBS-like stimulation of D1DR-containing neurons did not alter cocaine-primed reinstatement. Surprisingly, DBS-like optogenetic stimulation did not alter reinstatement of cocaine seeking in female rats. In rats which only expressed eYFP, intra-accumbens optogenetic stimulation did not alter cocaine reinstatement, indicating that the effect of DBS-like stimulation to attenuate cocaine reinstatement is mediated specifically by ChR2 rather than by prolonged light delivery. These results suggest that DBS of the accumbens may attenuate cocaine-primed reinstatement in male rats through the selective manipulation of D2DR-containing neurons.

Adolescent and Youth Experiences With Contraceptive Self-Injection in Uganda: Results From the Uganda Self-Injection Best Practices Project.

PURPOSE: We used qualitative and quantitative data to evaluate the differing experiences of adolescents and adult women in the contraceptive self-injection program in primary care settings in Uganda. From these results, we assessed barriers to adolescent DMPA-SC self-injection access and continuation and provide recommendations to address them. METHODS: The Self-Injection Best Practices (2017-2019) project in four districts trained clinic-based providers and Village Health Teams to provide self-injection training in clinics, community settings, and small group meetings for adolescent girls and young women. More than 12,000 women of reproductive age received self-injection services through the program, including 2,215 under 20 years. Structured surveys (n = 1,060) and in-depth interviews (n = 36) were conducted with randomly selected adolescent participants between July and November 2018. Mixed-effects logistic regression was used to assess quantitative differences in outcomes of interest between age groups. RESULTS: The study found no significant difference in self-injection proficiency or continuation between adolescents and adult women; 86.1% of adolescents self-injected independently when due for reinjection. Adolescents were significantly less likely than adults to report first hearing about self-injection from a community health worker. More adolescents expressed concern over discovery when seeking contraception at a clinic and fear of their DMPA-SC units being discovered at home. Adolescents were significantly less likely than adult women to mention convenience as a rationale for self-injecting, and more likely to mention wanting to learn a new skill and/or that friends recommended self-injection. DISCUSSION: Self-injection is a promising method of contraception for adolescents in Uganda, given comparable proficiency and continuation relative to adult women. Policies and programs should ensure rights-based access to a range of methods, including self-injection for this age group.

Differential effects of acute and chronic antagonist and an irreversible antagonist treatment on cocaine self-administration behavior in rats.

According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D1-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.

Testosterone Therapy With Subcutaneous Injections: A Safe, Practical, and Reasonable Option.

CONTEXT: Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route. EVIDENCE ACQUISITION: Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration. EVIDENCE SYNTHESIS: Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route. CONCLUSION: Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.

Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats.

BACKGROUND: Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies strongly suggest that deep brain stimulation of the nucleus accumbens (NAcc) is a viable target for the treatment of cocaine use disorder (CUD). OBJECTIVE: Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated. METHODS: Rats were made cocaine dependent by allowing them to self-administer cocaine in extended access conditions (6 h/day, 0.5 mg/kg/infusion). The effects of monophasic bilateral high-frequency DBS (60 µs pulse width and 130 Hz frequency) stimulation with a constant current of 150 µA of the NAcc shell on cocaine intake was then evaluated. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence, and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated. RESULTS: Contrary to our expectations, DBS of the NAcc shell induced a slight increase in cocaine self-administration, and increased cocaine-induced locomotion after extended access of cocaine self-administration. In addition, DBS decreased irritability-like behavior 18 h into cocaine withdrawal. Finally, DBS increased both cytosolic and synaptosomal levels of GluR1, but not GluR2, in the central nucleus of the amygdala but not in other brain regions. CONCLUSIONS: These preclinical results with cocaine-dependent animals support the use of high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of the negative emotional state that emerges during cocaine abstinence, but also demonstrate that DBS does not decrease cocaine intake in active, long-term cocaine users. These data, together with the existing evidence that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, suggest that NAcc shell DBS may be beneficial for the treatment of the negative emotional states and craving during abstinence, although it may worsen cocaine use if individuals continue drug use.

Extinction blunts paraventricular thalamic contributions to heroin relapse.

Here, we use optogenetics and chemogenetics to investigate the contribution of the paraventricular thalamus (PVT) to nucleus accumbens (NAc) pathway in aversion and heroin relapse in two different heroin self-administration models in rats. In one model, rats undergo forced abstinence in the home cage prior to relapse testing, and in the other, they undergo extinction training, a procedure that is likened to cognitive behavioral therapy. We find that the PVT→NAc pathway is both sufficient and necessary to drive aversion and heroin seeking after abstinence, but not extinction. The ability of extinction to reduce this pathway's contribution to heroin relapse is accompanied by a loss of synaptic plasticity in PVT inputs onto a specific subset of NAc neurons. Thus, extinction may exert therapeutic reductions in opioid seeking by altering synaptic plasticity within the PVT→NAc pathway, resulting in reduced aversion during opioid withdrawal as well as reduced relapse propensity.

Practice on Metered Dose Inhaler Techniques and Its Associated Factors among Asthmatic Patients at Debre Markos Comprehensive Specialized Hospital, East Gojjam, Ethiopia: A Prospective Study.

BACKGROUND: Asthma stands 16th among the leading causes of years lived with disability and 28th among the leading causes of disease in the world. A metered-dose inhaler remains the principal route for drug administration, and it has greater advantages over systemic treatment. In routine use, however, a majority of patients make inhalation errors. Suboptimal inhaler technique worsens health outcomes, with poor disease control, and increases the risk of hospitalization. This study aimed to assess practice metered-dose inhalation techniques and associated factors among asthmatic patients at Debre Markos Comprehensive Specialized Hospital, East Gojjam, Amhara region, Ethiopia. METHODS: Prospective cross-sectional study was conducted from July 15 to August 30, 2020. Data were collected through a semistructured questionnaire. The data were analyzed using SPSS version 25. Associations between dependent and independent variables were assessed by using binary and multiple logistic regressions. P values less than 0.05 were considered to be statistically significant in all cases. Results are presented in tables, figures, numbers, and percentages. RESULT: A total of 166 patients had involved in the study, of which 52.4% were females. One hundred and eleven (66.9%) participants had good knowledge of asthma and inhalational techniques, while the rest of them had poor knowledge. One hundred and eight (65.1%) patients had effective practice on metered-dose inhaler use techniques. Participant's knowledge regarding asthma and meter dose inhaler and marital status has a significant association with their practice of metered-dose inhaler techniques with P value 0.001 and 0.006, respectively. CONCLUSION: In this study, most participants are suffering from asthma for a long duration and they have repeated exacerbation. Around two-thirds of patients had good knowledge regarding asthma and metered-dose inhaler and practice on metered-dose inhaler techniques. Participants with poor knowledge had poor practice on metered-dose inhaler techniques, and single patients were less likely to have poor practice on metered-dose inhaler techniques. Health education and counseling services should be consistently provided to the clients regarding the proper steps of inhalers use.

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

Flavor additives facilitate oral self-administration of nicotine solution in mice.

RATIONALE: Tobacco products are very addictive, partly because they contain nicotine which is reinforcing, but also because they include appealing aromas and tastes. Flavor additives are such sensory stimuli which enhance attractiveness, as well as use and abuse of tobacco and vaping products. Yet, the interaction between these flavor additives and nicotine remains poorly understood. OBJECTIVES: We want to understand how flavors may reduce nicotine' aversive taste and how it may enhance its voluntary oral self-administration in mice. METHODS: We first studied the effect of flavor additives on nicotine solution palatability in a free bottle choice paradigm. Second, we investigated the effect of vanilla flavoring on the different stages of nicotine (40 µg/ml) oral self-administration in mice. RESULTS: We show that adding flavors increase nicotine palatability and facilitate acquisition and maintenance of oral self-administration when compared to nicotine-alone group. Mice adapt their operant behavior depending on changes in nicotine concentration. All mice reinstate nicotine seeking upon presentation of associated cues. Nevertheless, vanilla-flavored nicotine was not more reinforcing than vanilla-flavored water which was reinforcing enough to drive similar operant response rates. CONCLUSIONS: Flavor additives increase nicotine oral consumption and help maintaining operant behavior in mice. Moreover, flavors can be very attractive and can have high reinforcing value by themselves. Thus, it is crucial that the investigation on how taste signals play an important role in modulating oral nicotine intake in rodent models remains explored.

Enhancement of cue-induced reinstatement of alcohol seeking by acute total sleep restriction in male Wistar rats.

Clinical studies suggest that sleep impairment is a barrier to successful treatment in alcohol use disorder (AUD) patients, with sleep disruption associated with relapse to alcohol taking. To date, no preclinical study has evaluated the relationship between impaired sleep and alcohol relapse. In the present study, we used a self-administration model to investigate the effects of sleep restriction on reinstatement induced by alcohol-paired environmental cues. Using a sucrose fading protocol, male Wistar rats (N = 8) were trained to self-administer alcohol under a fixed-ratio 2 schedule of alcohol delivery such that completion of every second response resulted in the delivery of the alcohol solution and activation of the alcohol-paired cue light. Once self-administration was stable, behavior was extinguished by omitting delivery of the alcohol solution and the alcohol-paired cues. When responding reached low, stable levels, alcohol seeking was induced by re-presentation of the alcohol-paired cues but with no alcohol solution available for self-administration. To evaluate the effects of sleep restriction on cue-induced alcohol seeking, reinstatement tests were conducted after 6-h of total (slow wave + rapid eye movement [REM]) sleep restriction using the gentle handling method or after 6-h of REM sleep-only restriction using the flower pot method. Relevant control conditions also were evaluated. The results showed that acute restriction of total sleep, but not REM sleep primarily, significantly augmented cue-induced reinstatement of alcohol seeking. This increase was specific to total sleep restriction conditions and cannot be attributed to differences in alcohol intake, responding, or days to extinction. Our findings imply that acute slow wave sleep restriction is necessary and/or sufficient for the enhancement of cue-induced alcohol seeking and, further, suggest that decreased slow wave sleep in AUD patients places individuals at a unique risk for relapse.

Threshold dose for intravenous nicotine self-administration in young adult non-dependent smokers.

RATIONALE: Reducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies. OBJECTIVES: The current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure. METHODS: Young adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo. RESULTS: Mixed effect models revealed a significant effect of nicotine dose for positive (i.e., "stimulatory" and "pleasurable"; p < .0001) effects, but not "aversive" effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p = .03-.05). CONCLUSIONS: Using our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target.

Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats.

RATIONALE AND OBJECTIVE: Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food. METHODS: In Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund's Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food. RESULTS: In Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice. CONCLUSIONS: Results extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.

Samidorphan, an opioid receptor antagonist, attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in male Wistar rats.

Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (µ), kappa- (κ), and delta- (δ) opioid receptors and functions as a µ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DAext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DAext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DAext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.

The NMDA Receptor Subunit (GluN1 and GluN2A) Modulation Following Different Conditions of Cocaine Abstinence in Rat Brain Structures.

Different neuronal alterations within glutamatergic system seem to be crucial for developing of cocaine-seeking behavior. Cocaine exposure provokes a modulation of the NMDA receptor subunit expression in rodents, which probably contributes to cocaine-induced behavioral alterations. The aim of this study was to examine the composition of the NMDA receptor subunits in the brain structures in rats with the history of cocaine self-administration after cocaine abstinence (i) in an enriched environment, (ii) in an isolated condition, (iii) with extinction training, or (iv) without instrumental task, as well as the Grin1 (encoding GluN1) and Grin2A (encoding GluN2A) gene expression were evaluated after 10-day extinction training in rat brain structures. In the present study, we observed changes only following cocaine abstinence with extinction training, when the increased GluN2A subunit levels were seen in the postsynaptic density fraction but not in the whole homogenate of the prelimbic cortex (PLC) and dorsal hippocampus (dHIP) in rats previously self-administered cocaine. At the same time, extinction training did not change the Grin1 and Grin2A gene expression in these structures. In conclusion, NMDA receptor subunit modulation observed following cocaine abstinence with extinction training may represent a potential target in cocaine-seeking behavior.