Transcranial direct current stimulation (tDCS) reduces motivation to drink ethanol and reacquisition of ethanol self-administration in female mice

Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on “liking” (hedonic aspect; no effect in the CPP) and “wanting” (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.

Addictive Games: Case Study on Multi-Armed Bandit Game

The attraction of games comes from the player being able to have fun in games. Gambling games that are based on the Variable-Ratio schedule in Skinner’s experiment are the most typical addictive games. It is necessary to clarify the reason why typical gambling games are simple but addictive. Also, the Multiarmed Bandit game is a typical test for Skinner Box design and is most popular in the gambling house, which is a good example to analyze. This article mainly focuses on expanding on the idea of the motion in mind model in the scene of Multiarmed Bandit games, quantifying the player’s psychological inclination by simulation experimental data. By relating with the quantification of player satisfaction and play comfort, the expectation’s feeling is discussed from the energy perspective. Two different energies are proposed: player-side (Er) and game-side energy (Ei). This provides the difference of player-side (Er) and game-side energy (Ei), denoted as Ed to show the player’s psychological gap. Ten settings of mass bandit were simulated. It was found that the setting of the best player confidence (Er) and entry difficulty (Ei) can balance player expectation. The simulation results show that when m=0.3,0.7, the player has the biggest psychological gap, which expresses that player will be motivated by not being reconciled. Moreover, addiction is likely to occur when m∈[0.5,0.7]. Such an approach can also help the developers and educators increase edutainment games’ efficiency and make the game more attractive.

D-amphetamine maintenance therapy reduces cocaine use in female rats

Currently, there are no approved medications to treat cocaine addiction. In this context, d-amphetamine maintenance therapy is a promising pharmacological strategy to reduce cocaine use. In both male rats and human cocaine users, d-amphetamine treatment reduces cocaine taking and seeking. However, this has not been examined systematically in female animals, even though cocaine addiction afflicts both women and men, and the sexes can differ in their response to cocaine. Here, we determined how d-amphetamine maintenance therapy during cocaine self-administration influences cocaine use in female rats. In experiment 1, two groups of female rats received 14 intermittent access (IntA) cocaine self-administration sessions. One group received concomitant d-amphetamine maintenance treatment (COC + A rats; 5 mg/kg/day, via minipump), the other group did not (COC rats) After discontinuing d-amphetamine treatment, we measured responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. In experiment 2, we assessed the effects of d-amphetamine maintenance on these measures in already cocaine-experienced rats. To this end, rats first received 14 IntA cocaine self-administration sessions without d-amphetamine. They then received 14 more sessions now either with (COC/COC + A rats) or without (COC/COC rats) concomitant d-amphetamine treatment. In both experiments, d-amphetamine-treated rats showed reduced motivation to take and seek cocaine, responding less for cocaine both under progressive ratio and extinction conditions. In contrast, d-amphetamine treatment did not influence cocaine-primed reinstatement of cocaine seeking. Thus, d-amphetamine treatment reduces both the development and expression of addiction-relevant patterns of cocaine use in female animals.

Maintained goal-directed control with overtraining on ratio schedules

It is thought that goal-directed control of actions weakens or becomes masked by habits over time. We tested the opposing hypothesis that goal-directed control becomes stronger over time, and that this growth is modulated by the overall action–outcome contiguity. Despite group differences in action–outcome contiguity early in training, rats trained under random and fixed ratio schedules showed equivalent goal-directed control of lever pressing that appeared to grow over time. We confirmed that goal-directed control was maintained after extended training under another type of ratio schedule—continuous reinforcement—using specific satiety and taste aversion devaluation methods. These results add to the growing literature showing that extensive training does not reliably weaken goal-directed control and that it may strengthen it, or at least maintain it.

Dramatic increase in lever-pressing activity in rats after training on the progressive ratio schedule of cocaine self-administration

Transition from the highest rate of lever-pressing activity during the unloading (extinction) phase of a cocaine self-administration session to an extremely low activity rate during the remission phase is in many cases gradual. This makes it difficult to assess the duration of the unloading phase after a fixed ratio 1 (FR1) or breakpoint after a progressive-ratio (PR) self-administration session. In addition, 3–5 days of training under the PR schedule results in a dramatic and persistent increase in the rate of presses during PR sessions and in the unloading phase following FR1 self-administration sessions. The goals of this study were to find the definition of the last press demarcating the border between the unloading and remission phases of the session and to determine if this border was also affected by PR training. Rats were trained to self-administer cocaine under the FR1 schedule and then under the PR schedule of drug delivery. Distributions of inter-press intervals (IPIs) during the unloading phase in sessions before and after PR training were compared. It was found that the distribution of cocaine-induced IPIs during the unloading phase was lognormal, bimodal, and independent of previously injected cocaine unit doses. The first mode represented intervals within the short bouts of stereotypic presses and the second mode represented intervals between bouts. The two modes were approximately 0.7 s and 21 s during unloading prior to and 0.6 s and 1.5 s after PR self-administration training. The total number of presses per unloading phase increased eightfold. When the FR1 schedule was restored, the intervals between bouts remained very short for at least 7–10 days and only then started a gradual increase towards baseline levels. The last unloading press was defined as the press followed by the IPI longer than the defined criterion. PR training resulted in a substantial and long-lasting increase in lever-pressing activity during unloading. The duration of the unloading phase did not depend on the rate of lever-pressing activity.

Δ 9-Tetrahydrocannabinol During Adolescence Reprograms the Nucleus Accumbens Transcriptome, Affecting Reward Processing, Impulsivity, and Specific Aspects of Cocaine Addiction-Like Behavior in a Sex-Dependent Manner

Background Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown. Methods We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior. Results THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females). Conclusions Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner.

Activation of G protein-coupled estradiol receptor 1 in the dorsolateral striatum enhances motivation for cocaine and drug-induced reinstatement in female but not male rats

Background Estradiol potentiates drug-taking behaviors, including motivation to self-administer cocaine and reinstatement of drug-seeking after extinction in females, but not males. The dorsolateral stratum (DLS) is a region of the brain implicated in mediating drug-seeking behaviors and, more specifically, is a target brain area to study how estradiol regulates these behaviors. The estradiol receptors α, β, and G protein-coupled estradiol receptor 1 (GPER1) are all present in the DLS. In this study, the effects of activating GPER1 in the DLS on drug-seeking are investigated. Methods Gonad-intact male and female rats were trained to self-administer cocaine (0.4 mg/kg/inf) on a fixed-ratio 1 schedule of reinforcement. For 4 weeks, animals underwent testing on a progressive ratio schedule of reinforcement to determine their motivation to attain cocaine. Halfway through progressive ratio testing, a selective agonist targeting GPER1 (G1) was administered intra-DLS to determine the contribution of GPER1 activation on motivation for cocaine. The effects of intra-DLS GPER1 activation on drug-induced reinstatement after extinction were subsequently determined. Results Activation of GPER1, via intra-DLS G1 administration, potentiated females’ motivation to self-administer cocaine. There was no effect of prior G1 treatment on extinction of cocaine-taking in females; however, G1 treatment resulted in greater drug-induced reinstatement (10 mg/kg cocaine, i.p.). There were no effects of intra-DLS GPER1 activation observed on motivation for cocaine or cocaine-induced reinstatement of responding in males. Conclusions These results support the conclusion that activation of GPER1 in the DLS enhances cocaine-seeking behaviors for female, but not male rats.

Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

Maintained goal-directed control with overtraining on ratio schedules

It is thought that goal-directed control of actions weakens or becomes masked by habits over time. We tested the opposing hypothesis that goal-directed control becomes stronger over time, and that this growth is modulated by the overall action-outcome contiguity. Despite group differences in action-outcome contiguity early in training, rats trained under random and fixed ratio schedules showed equivalent goal-directed control of lever pressing that grew over time. We confirmed that goal-directed control was maintained over time under another type of ratio schedule—continuous reinforcement—using both specific satiety and taste aversion devaluation methods. These results add to the growing literature showing that extensive training does not always weaken goal-directed control, and can strengthen its expression.

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Background Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates. Methods The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. Results Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose–response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches). Conclusions In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New