Weeks Of Self-administration Research Articles

Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration.

The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naïve, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.

Prelimbic Cortex Activity during a Distress Tolerance Task Predicts Cocaine-Seeking Behavior in Male, But Not Female Rats.

Distress tolerance (DT) is defined as the ability to persist in challenging goal-directed behavior in the face of stress, and individuals with low DT exhibit heightened drug-seeking behavior. However, no preclinical studies have examined the neurobiology underlying this phenomenon. To assess this, in vivo electrophysiology was used in Long Evans male and female rats during a DT task to record neural activity in the prelimbic cortex (PrL), a brain region implicated in drug-seeking. Rats were first assessed for DT, defined as the amount of time elapsed before rats quit seeking reward in an increasingly difficult operant task. Subsequently, rats underwent 2 weeks of self-administration for either water/saline or cocaine for 6 h/day. Animals then began a 1 month period of experimenter-imposed abstinence to induce heightened drug-seeking behavior. On day 28 of abstinence, DT and neural activity were reassessed; and on day 30, cocaine-seeking behavior was examined under extinction. Males had significantly higher DT than females and exhibited significantly more phasic PrL activity during the DT task. Furthermore, in male rats with a history of cocaine, PrL activity shifted to track DT; and this change in activity significantly correlated with the change in DT. Additionally, male (but not female) rats with low DT after 28 d of abstinence had significantly heightened drug-seeking behavior. Finally, PrL activity during the DT task predicted cocaine-seeking behavior. Collectively, these data demonstrate an important role for the PrL in DT in males, and link this neural activity and behavior to drug-seeking, particularly in males.SIGNIFICANCE STATEMENT Distress tolerance (DT) is defined as the ability to persist in challenging goal-directed behavior in the face of stress, and individuals with low DT exhibit heightened drug-seeking. Here, we investigated the role of the prelimbic cortex (PrL) in DT and its relationship to cocaine-seeking in male and female rats. We found that males had significantly higher DT than females and exhibited significantly more PrL activity during the DT task. Furthermore, male (but not female) rats with low DT after 28 d of abstinence had significantly heightened drug-seeking behavior. Finally, PrL activity during the DT task predicted cocaine-seeking. These data demonstrate an important role for the PrL in DT and link this neural activity and behavior to drug-seeking in males.

Hormonal milieu drives economic demand for cocaine in female rats.

There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q0, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q0). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.

Effects of early life stress on cocaine intake in male and female rhesus macaques.

It is critical to identify potential risk factors, such as a history of early life stress (ELS), that may confer specific vulnerabilities to increased drug intake. In this study, we examined whether male and female rhesus monkeys with a history of ELS (infant maltreatment; MALT) demonstrated significantly greater cocaine intake compared with controls. Monkeys were trained to self-administer cocaine during 4-h sessions at a peak dose (0.003-0.1 mg/kg/infusion; extended access, "EA peak") and a dose of 0.1 mg/kg/infusion (EA 0.1) of cocaine. These data were compared with data obtained previously in monkeys trained during 1-h limited access (LA) sessions at the same peak dose of cocaine used here (Wakeford et al. Psychopharmacology, 236:2785-2796, 2019). Monkeys significantly increased total number of infusions earned in EA compared with LA, but total session response rates significantly decreased in EA compared with LA. There was no evidence of escalation in drug intake when we compared response rates to obtain the first 20 cocaine infusions between LA and EA peak conditions. Moreover, there was no evidence of escalation in drug intake during an additional 7 weeks of self-administration at 0.1 mg/kg/injection. The current study expands on previous reports demonstrating that rhesus macaques did not escalate cocaine intake under the experimental conditions employed and extended these findings by using a unique population of nonhuman primates with a history of infant MALT to test the hypothesis that ELS is a risk factor for escalation of cocaine intake in nonhuman primates. There was no clear evidence of escalation in cocaine intake as a consequence of ELS.

Assessment of Self-Administration of Romiplostim after Receipt of Home Administration Training Materials: A Cross-Sectional Study of Patients with Immune Thrombocytopenic Purpura and Caregivers

Background: Romiplostim is a subcutaneously administered thrombopoietin-receptor agonist approved for use in the EU for adult patients with chronic immune thrombocytopenia (ITP) refractory to other treatments. Initially approved for administration by healthcare providers (HCP), romiplostim was further approved by the European Medicines Agency in December 2012 for self-administration by select patients/caregivers. Romiplostim-treated chronic ITP patients with stable platelet count ≥ 50 x 109/L for ≥ 4 weeks without dose adjustment eligible for self-administration should be trained in self-administration procedures, and be supervised again after the first 4 weeks of self-administration while reconstituting and injecting romiplostim. To mitigate medication error risk due to self-administration, an additional risk minimisation activity in the form of a Home Administration Training (HAT) pack was designed to support HCPs in selecting patients and training of patients/caregivers. For subcutaneous self-administration of romiplostim, each patient (or caregiver) is supplied with self-administration kit (250/500 mcg romiplostim vial, plunger rod, prefilled sterile water syringe, disposable syringe with Luer-lok, safety needle, vial adapter) and a HAT pack, including placemat to lay out the administration components, checklist, instructions for use, self-administration diary, and instructional video.Aims: To estimate the proportion of adult patients and caregivers who administered romiplostim correctly after being trained with HAT pack.Methods: This multicentre, non-interventional, cross-sectional study was conducted at 12 study centres across 8 countries (Austria, Belgium, France, Germany, Greece, The Netherlands, Spain, and The United Kingdom) from 07 July 2014 to 20 November 2015. Adult (≥ 18 years of age) chronic ITP patients prescribed romiplostim self-administration or caregivers new to administering romiplostim, who provided informed consent at beginning of HAT pack training, received HAT pack training, and were available at first standard-of-care 4-week visit after training, were consecutively enrolled in the study. HCPs directly observed the patient/caregiver in the act of administering romiplostim at the first standard-of-care 4-week visit after HAT pack training, and completed a standardized data collection form. Variables collected included patient demographics, prescribed and administered injection volume per syringe, appropriate alcohol wipe use at injection site, clinically appropriate handling of syringe to avoid contamination, and clinically appropriate subcutaneous injection technique. The primary endpoint, correct administration of romiplostim, was defined as romiplostim dose accuracy within 10% margin of error between prescribed and administered romiplostim dose, and correct romiplostim reconstitution, and successful romiplostim injection, and no HCP intervention during administration to correct patient/caregiver error. All analyses were descriptive and no formal hypothesis was tested.Results: A total of 40 patients/caregivers were enrolled in the study (Table 1). At the first standard-of-care visit, 4 weeks (range: 2 - 8 weeks) after HAT pack training, 35 patients/caregivers (87.5%) administered romiplostim correctly. Romiplostim dose accuracy was within 10% margin of error for all patients. HCP intervention was required in 5 instances (3 patients, 2 caregivers): 1 patient did not ensure all romiplostim was dissolved, 1 patient and 1 caregiver needed verbal encouragement, 1 patient needed nursing intervention to read the correct dose from the vial due to poor eyesight, and 1 caregiver needed guidance with syringe and vial connection. Further follow-up data was available for 2 of these 5 patients/caregivers; they both administered romiplostim correctly at a subsequent visit.Conclusion: Given that this study was conducted on a convenience instead of random sample of patients, generalizability of the results may be limited. Direct observation can be susceptible to observation bias and to the Hawthorne effect with the patients/caregivers acting differently when observed. Nonetheless, the success of most patients and caregivers in correctly administering romiplostim after HAT pack training suggests that self-administration of romiplostim is a feasible option for suitable romiplostim-treated ITP patients. [Display omitted] DisclosuresSchipperus:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Partial sponsorship(50% of costs)ASH 2015. Taylor:Amgen: Consultancy. Wetten:Amgen: Employment, Equity Ownership. Bennett:Amgen: Employment. Kreuzbauer:Amgen: Employment, Equity Ownership. Boshier:Amgen: Employment, Equity Ownership. Seesaghur:Amgen: Employment, Equity Ownership.

Changes in the Influence of Alcohol-Paired Stimuli on Alcohol Seeking across Extended Training.

Previous work has demonstrated that goal-directed control of alcohol-seeking and other drug-related behaviors is reduced following extended self-administration and drug exposure. Here, we examined how the magnitude of stimulus influences on responding changes across similar training and drug exposure. Rats self-administered alcohol or sucrose for 2 or 8 weeks. Previous work has shown that 8 weeks, but not 2 weeks of self-administration produces habitual alcohol seeking. Next, all animals received equivalent Pavlovian conditioning sessions where a discrete stimulus predicted the delivery of alcohol or sucrose. Finally, the impact of the stimuli on ongoing instrumental responding was examined in a Pavlovian–instrumental transfer (PIT) test. While a significant PIT effect was observed following 2 weeks of either alcohol or sucrose self-administration, the magnitude of this effect was greater following 8 weeks of training. The specificity of the PIT effect appeared unchanged by extended training. While it is well established that evaluation of the outcome of responding contributes less to behavioral control following extended training and/or drug exposure, our data indicate that reward–predictive stimuli have a stronger contribution to responding after extended training. Together, these findings provide insight into the factors that control behavior after extended drug use, which will be important for developing effective methods for controlling and ideally reducing these behaviors.

The Roles of Dopamine and α1-Adrenergic Receptors in Cocaine Preferences in Female and Male Rats.

Cocaine dependence is characterized by compulsive drug taking and reduced involvement in social, occupational, or recreational activities. Unraveling the diverse mechanisms contributing to the loss-of-interest in these 'non-drug' pursuits is essential for understanding the neurobiology of addiction and could provide additional targets for treating addiction. The study objectives were to examine changes in cocaine-induced dopamine (DA) overflow in the nucleus accumbens (NAc) over the course of self-administration and determine the roles of α1- and β-adrenergic receptors (AR) in the loss-of-interest in food rewards following the development of an addicted phenotype in male and female rats. Subjects were given access to cocaine and palatable food pellets in a choice self-administration paradigm to identify 'addicted' cocaine-preferring (CP) individuals and resistant pellet-preferring (PP) individuals based on their patterns of self-administration over 7 weeks. Cocaine-induced DA overflow in the NAc was examined with microdialysis early and late during self-administration (weeks 2 and 7). Subjects were treated in counter-balanced order with propranolol (β-AR antagonist), terazosin (α1-AR antagonist), or vehicle for an additional 3 weeks of self-administration. CP rats displayed increased motivation for cocaine and attenuated motivation for pellets following the development of cocaine preferences. In females, the estrous cycle affected pellet, but not cocaine, self-administration. CP rats displayed attenuated cocaine-induced DA overflow in the NAc. Propranolol enhanced cocaine reinforcement and reduced pellet intake, whereas terazosin enhanced motivation for pellets and reversed preferences in a subset of CP rats. The implications of these results for the treatment of addiction are discussed.

Association between initial morphine intake and body weight change, acoustic startle reflex and drug seeking in rats.

Although chronic use of opiates can induce physical dependence and addiction, individual differences contributing to these symptoms are largely unknown. Using intravenous morphine self-administration (MSA), we investigated whether individual differences in drug intake are associated with weight change, acoustic startle reflex (ASR), pre-pulse inhibition (PPI), and drug seeking during spontaneous withdrawal. Male Sprague-Dawley rats self-administered morphine (0.5 mg/kg/infusion) or saline for 3 weeks (4-6 h/day, 5 days/week) and drug intake and body weight were monitored daily. The ASR and the PPI (baseline, 1 day and 1 week) and drug seeking (1 week) were measured during spontaneous withdrawal. Morphine animals did not gain weight (101 % ± 0.69), while the control animals did (115 % ± 1.06) after 3 weeks of self-administration. The ASR and the PPI were not significantly different between morphine and saline animals in 1-day or 1-week withdrawal. However, individual differences in initial (first 10 min), but not total (4-6 h), morphine intake of the daily sessions were positively correlated with weight change (r = 0.437, p = 0.037) and drug seeking (r = 0.424, p = 0.035) while inversely correlated with the ASR (r = -0.544, p = 0.005) in 1-week withdrawal from chronic morphine. A subgroup of animals that self-administered a larger amount of morphine at the beginning of the daily sessions exhibited subsequent weight gain, reduced ASR, and enhanced drug seeking in morphine withdrawal. Thus, individual differences in initial morphine intake may reveal a novel behavioral phenotype in opioid addiction.

Methamphetamine Self-Administration Produces Attentional Set-Shifting Deficits and Alters Prefrontal Cortical Neurophysiology in Rats

Chronic methamphetamine abusers exhibit deficits in tasks requiring intact prefrontal cortex function, and prefrontal cortex dysfunction has been implicated in the loss of control over drug use. This study used a combination of behavioral and electrophysiologic assessments in rats with a history of long access methamphetamine self-administration to determine methamphetamine-induced changes in prefrontal cortex-dependent attentional set-shifting performance, drug-seeking, and prefrontal cortex neuronal activity. Male Long-Evans rats self-administered methamphetamine (.02 mg/infusion, intravenous) or received yoked saline infusions for 6 hours a day for 14 days. Cognitive flexibility was assessed using an attentional set-shifting task before 2 weeks of self-administration and 1 day after self-administration. Animals then underwent 11 days of abstinence, followed by three subsequent tests for context-induced drug seeking. Finally, animals were anesthetized, and single-unit in vivo extracellular recordings were performed in the dorsomedial prefrontal cortex. Methamphetamine-experienced rats showed escalated drug intake and context-induced drug-seeking following abstinence. During the extradimensional set-shift component, meth-experienced rats showed selective impairments that were identical to deficits produced by excitotoxic lesions of the prefrontal cortex. Rats with a history of chronic methamphetamine intake also exhibited higher basal firing frequency and a significantly greater proportion of burst-firing cells in the prefrontal cortex compared with yoked-saline controls. Prefrontal cortex-specific alterations in neuronal function may play a key role in methamphetamine-induced attentional deficits and drug-seeking. These data support the possibility that targeting prefrontal cortex pathology may improve treatment outcome in methamphetamine addiction.

Reciprocal effects of response contingent and noncontingent intravenous heroin on in vivo nucleus accumbens shell versus core dopamine in the rat: a repeated sampling microdialysis study

Although passive administration of heroin to drug-naive rats increases extracellular dopamine (DA) in the nucleus accumbens (NAc), its ability to do so also after active drug exposure (self-administration) is debated. This study investigated by repeated microdialysis sampling the inter- and intrasession changes in the responsiveness of the NAc shell and core DA and the behavioral effects of active and passive heroin exposure in the intravenous self-administration/yoked paradigm. Rats were implanted with jugular catheters and bilateral intracerebral chronic guide cannulae. Nose poking in the active hole by master rats resulted in heroin administration to the same subjects and to their yoked mates. Concentric microdialysis probes were inserted daily in the guide cannulae, and changes in dialysate DA in response to heroin exposure (0.05 mg/kg) were monitored in the same subject for 90 min for 4 weeks. Behavior associated with heroin exposure, distinguished into nonstereotyped and stereotyped, was also recorded. Dialysate DA increased preferentially in the shell of master rats from the first session (+112%) and throughout the 4 weeks of self-administration (+130-140%). In yoked rats, a preferential but lesser increase in DA in the shell was observed only on the first session (+60%), as the DA response in the NAc core increased progressively (+25-118%), so that within a week, the shell/core ratio was reversed, and this pattern was maintained for the following 2 weeks. Yoked rats showed a progressive and larger increase in stereotyped behaviors than master rats. Chronic heroin self-administration increases extracellular DA preferentially in the NAc shell. Response-noncontingent heroin administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.

PET Imaging of Dopamine D2 Receptor and Transporter Availability During Acquisition of Cocaine Self-administration in Rhesus Monkeys

Previous studies have demonstrated that cocaine use alters availability of brain dopamine D2 receptors (D2R) and transporters (DAT). The present study examined the effects of low doses of cocaine on this neuroadaptation. Using positron emission tomography (PET), D2R and DAT availability in the caudate nucleus (Cd), putamen (Pt), anterior cingulate cortex (ACC), and amygdala (AMY) were assessed before and after monkeys acquired cocaine self-administration. Twelve rhesus monkeys were trained to self-administer intravenous cocaine (0.03 mg/kg per injection) under conditions that resulted in low drug intakes. PET scans using radiotracers targeting D2R ([F]fluoroclebopride, FCP) or DAT ([F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane, FCT) were performed when monkeys were cocaine naive and after 9 weeks of self-administration. Before self-administration, D2R availability was significantly higher only in left vs. right Cd, whereas DAT availability was higher in left vs. right Cd, Pt, and ACC. Nonetheless, after cocaine exposure, left-right differences in D2R were apparent in 3 of 4 regions, but only in the ACC for DAT availability. Self-administration of this dose of cocaine did not significantly affect DAT availability in any region and only decreased D2R availability in the ACC. These results demonstrate lateralization of D2R and DAT availability in brain areas that mediate cocaine self-administration, even under conditions in which cocaine does not affect overall receptor availability.

Dopaminergic responses to self‐administered cocaine in Rhesus monkeys do not sensitize following high cumulative intake

Sensitization of mesolimbic dopamine (DA) systems by administration of psychostimulants has been observed repeatedly in rodents. This phenomenon has been incorporated into theories of neurobiological adaptation underlying addiction, and is believed to be a mechanism whereby drug-associated cues acquire the ability to control behaviour via a conditioned release of DA. However, we have previously demonstrated in nonhuman primates that drug cues that cause cocaine seeking do not promote a conditioned increase in DA release of sufficient endurance to be measured in 2-min samples. In addition, imaging studies in humans and nonhuman primates that have been chronically exposed to psychostimulants have not demonstrated an increase in DA release upon psychostimulant challenge. Here we report that following 32 weeks of self-administration by rhesus monkeys, no increase over time in the DA response to self-administered cocaine was observed in any striatal subregion or individual animal. These results are consistent with clinical imaging studies showing a lack of DA sensitization, and might provide a mechanism to explain our previous observation that the rodent and primate differ in neurochemical response to drug-associated cues.