Long-access Self-administration Research Articles

Assessment of ethanol and nicotine interactions using a reinforcer demand modeling with grouped and individual levels of analyses in a long-access self-administration model using male rats.

Previous reports have indicated the reciprocal effects of nicotine and ethanol on their rewarding and reinforcing properties, but studies using methodological approaches resembling substance use in vulnerable populations are lacking. In our study, rats first self-administered ethanol, and their sensitivity to ethanol's reinforcing effects was assessed using a reinforcer demand modeling approach. Subsequently, rats were equipped with intravenous catheters to self-administer nicotine, and their sensitivity to nicotine's reinforcing effects was evaluated using the same approach. In the final phase, rats were allowed to self-administer ethanol and nicotine concurrently, investigating the influence of one substance on the rate of responding for the other substance. Group analyses revealed notable differences in demand among sucrose, sweetened ethanol, and ethanol-alone, with sucrose demonstrating the highest demand and ethanol-alone exhibiting greater sensitivity to changes in cost. At the individual level, our study finds significant correlations between rats' demand for sucrose and sweetened ethanol, suggesting parallel efforts for both substances. Our individual data also suggest interconnections in the elasticity of demand for sweetened ethanol and ethanol-alone, as well as a potential relationship in price response patterns between ethanol and nicotine. Furthermore, concurrent self-administration of ethanol and nicotine at the group level displayed reciprocal effects, with reduced responding for nicotine in the presence of ethanol and increased responding for ethanol in the presence of nicotine. This study provides valuable insights into modeling the co-use of ethanol and nicotine and assessing their interaction effects using reinforcer demand modeling and concurrent self-administration or noncontingent administration tests. These findings contribute to our understanding of the complex interplay between ethanol and nicotine and have implications for elucidating the underlying mechanisms involved in polydrug use.

Intermittent access training produces greater motivation for a non-drug reinforcer than long access training.

It has recently been proposed that the intermittent access (IntA) drug self-administration procedure better produces behavioral changes relevant to addiction than the long access (LgA) procedure. In this version of the IntA procedure, the drug is made available for a 5-min period during each half hour of a 6-h session. In contrast, on the LgA procedure, the drug is available continuously for 6 h. Previous studies have found that IntA drug self-administration produces greater drug motivation, measured by increased progressive ratio breakpoints, than LgA self-administration. It has been hypothesized that this effect is due to the rapid, "spiking" brain levels of the drug, and consequent neuroadaptations, experienced by rats during IntA sessions. However, no study has compared the effects of IntA versus LgA training on reinforcer motivation when using a non-drug reinforcer. The present study compared motivation for a saccharin reinforcer after IntA or LgA training. In Experiment 1, separate groups of rats lever-pressed for saccharin on the IntA or LgA procedures. In Experiment 2, a within-subjects design was used where rats pressed one lever on the IntA procedure and another lever on the LgA procedure for saccharin. In both experiments, IntA training produced greater breakpoints than LgA training. As no drug was used here, spiking drug levels could not have been responsible for the increased saccharin motivation observed after IntA training. Instead, it is proposed that differences in stimulus-reinforcer associations learned during IntA versus LgA training may be responsible for the effect. Future research is needed to determine the extent to which such learning factors may contribute to the increased motivation observed after IntA training with drug reinforcers.

Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat.

Methamphetamine use disorder is a chronic neuropsychiatric disorder characterized by recurrent binge episodes, intervals of abstinence, and relapses to drug use. Humans addicted to methamphetamine experience various degrees of cognitive deficits and other neurological abnormalities that complicate their activities of daily living and their participation in treatment programs. Importantly, models of methamphetamine addiction in rodents have shown that animals will readily learn to give themselves methamphetamine. Rats also accelerate their intake over time. Microarray studies have also shown that methamphetamine taking is associated with major transcriptional changes in the striatum measured within a short or longer time after cessation of drug taking. After a 2-h withdrawal time, there was increased expression of genes that participate in transcription regulation. These included cyclic AMP response element binding (CREB), ETS domain-containing protein (ELK1), and members of the FOS family of transcription factors. Other genes of interest include brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor, type 2 (TrkB), and synaptophysin. Methamphetamine-induced transcription was found to be regulated via phosphorylated CREB-dependent events. After a 30-day withdrawal from methamphetamine self-administration, however, there was mostly decreased expression of transcription factors including junD. There was also downregulation of genes whose protein products are constituents of chromatin-remodeling complexes. Altogether, these genome-wide results show that methamphetamine abuse might be associated with altered regulation of a diversity of gene networks that impact cellular and synaptic functions. These transcriptional changes might serve as triggers for the neuropsychiatric presentations of humans who abuse this drug. Better understanding of the way that gene products interact to cause methamphetamine addiction will help to develop better pharmacological treatment of methamphetamine addicts.

Sensitized nucleus accumbens dopamine terminal responses to methylphenidate and dopamine transporter releasers after intermittent-access self-administration

Long-access methylphenidate (MPH) self-administration has been shown to produce enhanced amphetamine potency at the dopamine transporter and concomitant changes in reinforcing efficacy, suggesting that MPH abuse may change the dopamine system in a way that promotes future drug abuse. While long-access self-administration paradigms have translational validity for cocaine, it may not be as relevant a model of MPH abuse, as it has been suggested that people often take MPH intermittently. Although previous work outlined the neurochemical and behavioral consequences of long-access MPH self-administration, it was not clear whether intermittent access (6 h session; 5 min access/30 min) would result in similar changes. For cocaine, long-access self-administration resulted in tolerance to cocaine's effects on dopamine and behavior while intermittent-access resulted in sensitization. Here we assessed the neurochemical consequences of intermittent-access MPH self-administration on dopamine terminal function. We found increased maximal rates of uptake, increased stimulated release, and subsensitive D2-like autoreceptors. Consistent with previous work using extended-access MPH paradigms, the potencies of amphetamine and MPH, but not cocaine, were increased, demonstrating that unlike cocaine, MPH effects were not altered by the pattern of intake. Although the potency results suggest that MPH may share properties with releasers, dopamine release was increased following acute application of MPH, similar to cocaine, and in contrast to the release decreasing effects of amphetamine. Taken together, these data demonstrate that MPH exhibits properties of both blockers and releasers, and that the compensatory changes produced by MPH self-administration may increase the abuse liability of amphetamines, independent of the pattern of administration.

Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated by CRF Receptor Type 1 But Not CRF Receptor Type 2

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.

Intrathecal cocaine delivery enables long-access self-administration with binge-like behavior in mice

Long-access intravenous drug self-administration shows diurnal alterations in drug intake, with escalation and binge patterns, in rats. A similar long-access model in mice would allow the use of genetically modified animals to better understand the molecular mechanisms underlying drug addiction and relapse. However, attempts to transfer this model to mice have been less successful, mainly because of technical difficulties with long-term maintenance of the indwelling catheter implanted into small veins. We devised an intrathecal probe implanted in the supracerebellar cistern as an alternative for intravenous drug administration to address this challenge and allow continuous, chronic drug self-administration in mice. We found that mice readily self-administered intrathecal infusions of cocaine as a drug reward, and, under daily 24-h access conditions, animals exhibited a binge-like behavior comparable to rats. This innovation enables a full analysis of long-access drug self-administration behavior in mice not possible with intravenous administration.

Surgical Adrenalectomy with Diurnal Corticosterone Replacement Slows Escalation and Prevents the Augmentation of Cocaine-Induced Reinstatement in Rats Self-Administering Cocaine Under Long-Access Conditions

The loss of control over cocaine use and persistently heightened susceptibility to drug relapse that define human cocaine addiction are consequences of drug-induced neuroplasticity and can be studied in rats self-administering cocaine under conditions of daily long access (LgA) as escalating patterns of drug intake and heightened susceptibility to reinstatement. This study investigated the potential contribution of elevated glucocorticoids at the time of LgA cocaine self-administration (SA) to these behavioral indices of addiction-related neuroplasticity. Rats provided 14 days of 6-h access (LgA) to cocaine showed a progressive escalation of SA and were more susceptible to cocaine-induced reinstatement (10 mg/kg, i.p.) compared to rats self-administering under short-access (ShA; 2 h) conditions. A surgical adrenalectomy and corticosterone replacement (ADX/C) regimen that eliminated SA-induced increases in corticosterone (CORT) while maintaining the diurnal pattern of secretion failed to alter SA or reinstatement in ShA rats but slowed escalation and attenuated later reinstatement in LgA rats when applied before but not after chronic LgA SA testing. Although the contribution of other adrenal hormones cannot be ruled out, these data suggest that elevated glucocorticoids at the time of cocaine exposure may be required for the effects of LgA SA on cocaine intake and later reinstatement. The inability of daily CORT administration before daily ShA SA, at a dose that reproduced the response during LgA SA, to mimic the effects of LgA SA suggests that elevated glucocorticoids during SA may play a permissive role in cocaine-induced neuroplasticity that contributes to addiction.

Continuous exposure to the competitive N-methyl-d-aspartate receptor antagonist, LY235959, facilitates escalation of cocaine consumption in Sprague–Dawley rats

Chronic high dose consumption of cocaine is associated with significant negative effects to individual users and society. Nevertheless, the precise mechanisms that mediate increases in cocaine consumption in a drug-using individual are not fully understood. This study used a long access version of the drug self-administration procedure to determine whether escalation of cocaine consumption is mediated by increased activity through N-methyl-D: -aspartate (NMDA) receptors. Male Sprague-Dawley rats (n = 63) were first trained to self-administer cocaine (0.33 mg/infusion, i.v.) under a fixed-ratio 1 schedule of reinforcement. After training, some rats were implanted with subcutaneous osmotic minipumps filled with vehicle or the competitive NMDA receptor antagonist, LY235959, and subsequently allowed to self-administer cocaine in short (2 h) or long (6 h) access self-administration sessions. Vehicle-treated rats escalated cocaine self-administration across 14 long-access self-administration sessions. Rats treated with LY235959 via osmotic minipump, but not twice daily injections, escalated cocaine self-administration at a greater rate and to a greater degree than vehicle-treated rats. In post-escalation cocaine dose-infusion tests, rats treated continuously with LY235959 self-administered more cocaine (0.08-1.32 mg/infusion) than vehicle-treated rats, regardless of access condition, shifting the dose-infusion curves upward. During extinction sessions, which were conducted after the escalation phase of the study, rats that had long (6 h) access to cocaine stopped responding sooner than rats that had short (2 h) access to cocaine, independent of LY235959 treatment. These data are consistent with hypo-glutamatergic consequences of repeated cocaine exposure.