Progressive Ratio Schedule Research Articles

Lack of evidence for positive reinforcing and prosocial effects of MDMA in pair-housed male and female rats

3,4-Methylenedioxymethamphetamine (MDMA) is classified as an entactogen, producing feelings of emotional openness and relatedness. One unique feature of MDMA is that people tend to selectively take this drug in social and/or intimate situations. Although MDMA is recognized as having abuse liability, preclinical studies report that it has weak reinforcing effects in animals. The objective of this study was to characterize the positive reinforcing and prosocial effects of MDMA in a translational model of the social environment in which two rats have simultaneous and contingent access to MDMA in close physical proximity. To this end, MDMA self-administration was examined on both fixed and progressive ratio schedules of reinforcement in six groups of rats: (1) isolated males, (2) isolated females, (3) male-male dyads, (4) female-female dyads, (5) male-female dyads, and (6) female-male dyads. For pair-housed rats, data from both rats were analyzed. Next, social preferences were examined in a partner preference test. MDMA failed to produce positive reinforcing effects under all conditions examined. Across a 30-fold dose range (0.01–1.0 mg/kg/infusion), MDMA did not maintain higher responding than saline on both schedules of reinforcement and in all groups tested. In partner preference tests, a history of shared exposure to MDMA did not establish a social preference, and acute administration of MDMA failed to establish a preference for another MDMA-treated rat. These data suggest that social contact does not increase the positive reinforcing effects of MDMA in rats, and that neither contingent nor noncontingent MDMA administration establishes a social preference in rats.

The effect of visually evoked innate fear on reward-associated conditional response and reversal learning in mice

The response to visually evoked innate fear is essential for survival and impacts the cognition and behavior of animals to threats in the environment. However, contradictory findings of the interaction of fear and executive behaviors were reported by previous studies. To address this question, the present study investigated the effect of looming stimuli-driven visually innate fear on reward-associated conditioned response and reversal learning in mice with low or high motivation for sucrose. The mice with low motivation exposed to looming stimuli displayed reduced efficiency in the test of conditional response in the fixed ratio 1 schedule and impaired executive motivation as tested in the progressive ratio schedule of reinforcement. However, the high motivated mice exposed to looming stimuli showed an unaffected conditional response but an increased executive motivation. In the reversal learning program, looming stimuli at the middle stage caused deficits in cognitive flexibility in the mice with low and high motivation. Therefore, these results illuminate the impact of visually evoked innate fear on conditional response and reversal learning and further show that the impacts are relevant to internal motivation and external fear stimuli.

Disruption of the PDZ domain–binding motif of the dopamine transporter uniquely alters nanoscale distribution, dopamine homeostasis, and reward motivation

The dopamine (DA) transporter (DAT) is part of a presynaptic multiprotein network involving interactions with scaffold proteins via its C-terminal PDZ domain–binding sequence. Using a mouse model expressing DAT with mutated PDZ-binding sequence (DAT-AAA), we previously demonstrated the importance of this binding sequence for striatal expression of DAT. Here, we show by application of direct stochastic reconstruction microscopy not only that the striatal level of transporter is reduced in DAT-AAA mice but also that the nanoscale distribution of this transporter is altered with a higher propensity of DAT-AAA to localize to irregular nanodomains in dopaminergic terminals. In parallel, we observe mesostriatal DA adaptations and changes in DA-related behaviors distinct from those seen in other genetic DAT mouse models. DA levels in the striatum are reduced to ∼45% of that of WT, accompanied by elevated DA turnover. Nonetheless, fast-scan cyclic voltammetry recordings on striatal slices reveal a larger amplitude and prolonged clearance rate of evoked DA release in DAT-AAA mice compared with WT mice. Autoradiography and radioligand binding show reduced DA D2 receptor levels, whereas immunohistochemistry and autoradiography show unchanged DA D1 receptor levels. In behavioral experiments, we observe enhanced self-administration of liquid food under both a fixed ratio of one and progressive ratio schedule of reinforcement but a reduction compared with WT when using cocaine as reinforcer. In summary, our data demonstrate how disruption of PDZ domain interactions causes changes in DAT expression and its nanoscopic distribution that in turn alter DA clearance dynamics and related behaviors.

The Novel Positive Allosteric Modulator of the GABAB Receptor, KK-92A, Suppresses Alcohol Self-Administration and Cue-Induced Reinstatement of Alcohol Seeking in Rats.

Positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) are of interest in the addiction field due to their ability to suppress several behaviors motivated by drugs of abuse. KK-92A is a novel GABAB PAM found to attenuate intravenous self-administration of nicotine and reinstatement of nicotine seeking in rats. This present study was aimed at extending to alcohol the anti-addictive properties of KK-92A. To this end, Sardinian alcohol-preferring rats were trained to lever-respond for oral alcohol (15% v/v) or sucrose (0.7% w/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding behavior had stabilized, rats were exposed to tests with acutely administered KK-92A under FR5 and progressive ratio schedules of reinforcement and cue-induced reinstatement of previously extinguished alcohol seeking. KK-92A effect on spontaneous locomotor activity was also evaluated. Treatment with 10 and 20 mg/kg KK-92A suppressed lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol. Treatment with 20 mg/kg KK-92A reduced sucrose self-administration. Combination of per se ineffective doses of KK-92A (2.5 mg/kg) and the GABAB receptor agonist, baclofen (1 mg/kg), reduced alcohol self-administration. Treatment with 5, 10, and 20 mg/kg KK-92A suppressed reinstatement of alcohol seeking. Only treatment with 80 mg/kg KK-92A affected spontaneous locomotor activity. These results demonstrate the ability of KK-92A to inhibit alcohol-motivated behaviors in rodents and confirm that these effects are common to the entire class of GABAB PAMs. The remarkable efficacy of KK-92A is discussed in terms of its ago-allosteric properties.

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.

Individual Differences in Frustrative Nonreward Behavior for Sucrose in Rats Predict Motivation for Fentanyl under Progressive Ratio.

Frustrative nonreward (FN) is a construct in the Negative Valence Systems domain of the Research Domain Criteria (RDoC) from the National Institute of Mental Health. An organism’s response to frustrating situations (e.g., inability to obtain an expected reward) has broad implications for a variety of neuropsychiatric conditions, including substance use disorders. The current project developed a first of its kind rat operant behavioral model of FN based loosely on the human Point Subtraction Aggression Paradigm (PSAP). The current study shows that individual differences in FN for sucrose pellets are consistent across sessions at baseline and that the task is sensitive to reward size in male rats. More importantly, high FN behavior for sucrose predicts early “breaking” for intravenous fentanyl self-administration under a progressive ratio (PR) schedule. These results solidify frustration/ FN as an important factor for substance use disorders in addition to craving, impulsivity, and habit.

Effects of β-Phenylethylamine on Psychomotor, Rewarding, and Reinforcing Behaviors and Affective State: The Role of Dopamine D1 Receptors.

Beta-phenylethylamine (β-PEA) is a well-known and widespread endogenous neuroactive trace amine found throughout the central nervous system in humans. In this study, we demonstrated the effects of β-PEA on psychomotor, rewarding, and reinforcing behaviors and affective state using the open-field test, conditioned place preference (CPP), self-administration, and ultrasonic vocalizations (USVs) paradigms. We also investigated the role of the dopamine (DA) D1 receptor in the behavioral effects of β-PEA in rodents. Using enzyme-linked immunosorbent assay (ELISA) and Western immunoblotting, we also determined the DA concentration and the DA-related protein levels in the dorsal striatum of mice administered with acute β-PEA. The results showed that acute β-PEA increased stereotypic behaviors such as circling and head-twitching responses in mice. In the CPP experiment, β-PEA increased place preference in mice. In the self-administration test, β-PEA significantly enhanced self-administration during a 2 h session under fixed ratio (FR) schedules (FR1 and FR3) and produced a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement in rats. In addition, acute β-PEA increased 50-kHz USV calls in rats. Furthermore, acute β-PEA administration increased DA concentration and p-DAT and TH expression in the dorsal striatum of mice. Finally, pretreatment with SCH23390, a DA D1 receptor antagonist, attenuated β-PEA-induced circling behavior and β-PEA-taking behavior in rodents. Taken together, these findings suggest that β-PEA has rewarding and reinforcing effects and psychoactive properties, which induce psychomotor behaviors and a positive affective state by activating the DA D1 receptor in the dorsal striatum.

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.

BackgroundCannabis 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.MethodsWe 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.ResultsTHC 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).ConclusionsAdolescent 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.

The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.

Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists. The aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone. In the self-administration study, male Sprague-Dawley (SD) rats (n = 6) self-administered intravenous (i.v.) oxycodone alone (0.056mg/kg/inj) or combined with U50,488h (0.032-0.32mg/kg/inj), nalfurafine (0.00032-0.0032mg/kg/inj), or triazole 1.1 (0.32-1.8mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n = 6) received i.v. injections of oxycodone (1.0-5.6mg/kg), U50,488h (1.0-18.0mg/kg), nalfurafine (0.01-1.0mg/kg), or triazole 1.1 (3.2-32.0mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation. All KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures. This study demonstrates that triazole 1.1 reduces oxycodone's reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1's mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability.

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

BackgroundEstradiol 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.MethodsGonad-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.ResultsActivation 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.ConclusionsThese results support the conclusion that activation of GPER1 in the DLS enhances cocaine-seeking behaviors for female, but not male rats.

Conditioned enhancement of the nicotine reinforcer.

This study was designed to assess whether nicotine can acquire additional reinforcing properties through associations with other rewards. To this end, rats self-administered nicotine-alone (0.01 mg/kg) or nicotine paired with access to sucrose during the conditioning phase. In the subsequent challenge phase, we tested the effect of nicotine-sucrose pairings on the reinforcing effects of nicotine using a progressive ratio schedule of reinforcement. Using this approach, we show that (a) rats in both paired and nicotine-alone conditions self-administered similar amounts of nicotine in the initial conditioning phase of the study when intake was limited to 10 infusions per session, (b) nicotine rapidly acquired control over goal-tracking behavior in the paired condition, (c) rats that had a history of nicotine and sucrose pairings worked harder and took more nicotine as measured on a progressive ratio using a distinct response form, and (d) conditioned goal-tracking evoked by nicotine did not show extinction when sucrose was no longer paired with nicotine over the 11 days of nicotine self-administration on a progressive ratio schedule of reinforcement. Overall, our results demonstrate that in addition to the multifaceted nature of nicotine stimulus that includes primary reinforcing effects, conditioned reinforcing effects, and reward enhancing effects, nicotine can also acquire additional reinforcing properties through associations with other rewards. This ability to acquire additional reinforcing properties through associative learning may contribute to the development and perpetuation of tobacco use disorder. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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.

Binge eating behavior and incentive motivation with a cafeteria diet

Binge-like eating behavior (BLE) has been characterized as an eating disorder in which subjects have an enhanced intake of food, mainly fats. However, intake of fats and carbohydrates may have differential effects on motivation. Previously it was shown that BLE produces an increase in operant responding for vegetable shortening, but others were unable to replicate the finding using sucrose as the reinforcer. Our aim was to determine if BLE behavior induced with a cafeteria-like diet (CaLD) with several options with fat content would produce an increment in performance. Male Wistar rats were trained under an exponential progressive ratio schedule of sucrose reinforcement; thereafter, the limited access model was used to induce BLE using CaLD options. Finally, subjects were tested for increments in break points (BPs) in the progressive ratio schedule. Rats with intermittent access to CaLD options showed a clear BLE with an escalation in their intake; however they showed compensatory decrements of chow intake that rendered a similar body weight gain to a continuous access group. Although we were unable to observe an increase in BPs after BLE we were able to observe a protection against the decrements of BP previously observed with sugar. Different mechanisms for processing high fat and high carbohydrate reinforcers are variables worth exploring to gain a better understanding of BLE behavior in rodent models.

Chronic levetiracetam (Keppra®) treatment increases the reinforcing strength of cocaine in rhesus monkeys

BackgroundDrugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders. ObjectiveThe present study assessed the ability of chronically administered levetiracetam (Keppra®), a clinically available anticonvulsant drug that increases GABA by binding to synaptic vesicle glycoprotein 2A, to modulate the reinforcing strength of cocaine in monkeys. MethodsThree adult male rhesus monkeys (Macaca mulatta) self-administered cocaine intravenously each day under a progressive-ratio (PR) schedule of reinforcement. Two monkeys also responded to receive food pellets under a 50-response fixed-ratio schedule (FR 50) each morning. After determining a cocaine dose-response curve (0.001–0.3 mg/kg per injection, i.v.) in the evening, levetiracetam (5–75 mg/kg, p.o., b.i.d.) was administered for 12–16 days per dose. To model a treatment setting, cocaine self-administration sessions were conducted using the PR schedule every 4 days during levetiracetam treatment. After tapering the dose of levetiracetam over two weeks in the absence of cocaine sessions, cocaine dose-effect curves were re-determined. ResultsLower doses of levetiracetam produced non-systematic fluctuations in numbers of cocaine injections received in each subject, whereas the highest tested dose significantly increased the reinforcing strength of cocaine; no effects on food-maintained responding were observed. After termination of levetiracetam treatment, dose-effect curves for cocaine self-administration were shifted to the left in two monkeys. ConclusionThese data suggest that levetiracetam is not likely to be an efficacious pharmacotherapy for cocaine dependence. Rather, sensitivity to cocaine may be increased during and after levetiracetam treatment.

Impact of Morphine Dependence and Withdrawal on the Reinforcing Effectiveness of Fentanyl, Cocaine, and Methamphetamine in Rats.

Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10–40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.

Korean Red Ginseng inhibits methamphetamine addictive behaviors by regulating dopaminergic and NMDAergic system in rodents

BackgroundMethamphetamine (METH) is the most widely used psychostimulant and has been known to exhibit reinforcing effects even after long abstinence. We showed the inhibitory effect of Korean Red Ginseng extract (RGE) on METH-induced addictive behaviors in animal models mimicking the human drug-use pattern. MethodsWe first investigated the effect of RGE on the acquisition of METH-induced dependence using self-administration and conditioned place preference (CPP) tests. Additionally, further experiments such as METH-induced motivational behavior and seeking behavior were conducted. To study the underlying mechanism, dopamine receptor, dopamine transporter, and N-methyl-D-aspartate receptor were assessed through Western blot analysis. ResultsTreatment with RGE significantly reduced METH-induced self-administration on a fixed-ratio 1 schedule of reinforcement. It could be also decreased a progressive ratio schedule, and inhibited METH-primed reinstatement. In CPP, RGE significantly prevented the development of METH-induced CPP. Moreover, RGE not only shortened the withdrawal period clearly, but also prevented the reinstatement of CPP. RGE treatment also reversed METH-induced overexpression of dopamine transporter, dopamine receptor D1, and NMDA receptor in the nucleus accumbens. ConclusionOur findings reflect that RGE has therapeutic potential to suppress METH-induced addictive behaviors by regulating dopaminergic and NMDAergic system.

Effects of Maternal Sucrose Consumption on Inflammation and Steroids in the Placenta and Fetal Brain

Consumption of sucrose (table sugar) is high in much of the world. The effects of a maternal diet high in sucrose on the placenta and fetal brain remain unknown. In rats, maternal consumption of sucrose at a human-relevant level has effects on the mother’s physiology and steroids, as well as long-lasting and sex-specific effects on the adult offspring’s brain and behavior. In the mothers, there are metabolic effects of sucrose intake, such as impaired glucose tolerance, increased liver lipids, and increased adipose inflammation. In rat dams, sucrose intake also decreases corticosterone levels in the blood but not in the brain. In the adult male offspring, preference for a high-sucrose diet and a high-fat diet increases due to maternal sucrose intake. In addition, maternal sucrose intake increases motivation for sugar rewards in a progressive ratio schedule of reinforcement in adult male offspring. In adult female offspring, corticosterone levels increase in the blood and brain as a result of maternal sucrose intake. In this study, we investigated the underlying mechanisms of the observed behavioral and endocrine effects in the adult offspring. Here, we examined cytokines and anti-inflammatory steroids in the placenta, amniotic fluid, and fetal blood and brain. In our model, we feed rat dams either a high-sucrose diet (26% of kCal) or an isocaloric, matched, control diet (1% sucrose) 10 weeks prior to and during gestation. At embryonic day 19 (E19), we collected maternal blood, placenta, amniotic fluid, fetal blood, and fetal brain. We use Palkovits punch to microdissect the placenta and fetal brain. Next, we use a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, which is highly precise and specific, to measure multiple steroids (e.g. corticosterone, progesterone, estradiol, allopregnanolone). The method is highly sensitive, and we can measure neurosteroids in multiple regions of the fetal brain (e.g. prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus). Moreover, we will examine steroidogenic enzymes and cytokines in the fetal brain and placenta. Preliminary data show distinct steroid patterns in amniotic fluid and fetal blood, as well as in different parts of the placenta.

Behavioural evaluation of mouse models of type 2 diabetes

Motivation for food reinforcers in mouse models of type 2 diabetes was examined in three experiments. In all experiments, physiological measures indicated the presence of type 2 diabetes. In Experiment 1, high-fat fed Swiss TO mice and lean controls showed a preference for high-fat corn oil reinforcers over high-sugar syrup reinforcers in a T-Maze task, but there were no differences between the two groups. In Experiment 2, high-fat fed Swiss TO mice and lean controls responded for corn oil or food pellet reinforcers on progressive ratio schedules. While break point numbers were higher for corn oil than food pellets, and satiation or extinction reduced break points, there were no differences between the groups. In Experiment 3, streptozotocin treatment was used to induce type 2 diabetes in C57Bl/6 j mice that were compared with controls while responding for corn oil or food pellet reinforcers on progressive ratio schedules. While break point numbers were higher for corn oil than food pellets before and after streptozotocin treatment, and satiation or extinction reduced break points, there were no differences between the groups. Parameters for a more complex method of assessment of progressive ratio behaviour derived from Killeen’s Mathematical Principles of Reinforcement were also computed. While the parameter associated with incentive value was higher for corn oil than for food pellets, parameters were not significantly affected by streptozotocin treatment. Overall, a range of behavioural measures of food motivation failed to reveal effects of changes relative to controls in mice that showed physiological evidence of type 2 diabetes.

Rate of Onset as a Determinant of Abuse Potential Assessment Using Intracranial Self‐Stimulation in Rats

Background Intracranial self-stimulation (ICSS) is one procedure that has been used to evaluate abuse potential of drugs, and as with more commonly used drug self-administration procedures, ICSS is especially sensitive to drugs that activate the mesolimbic dopamine system. Drug self-administration studies have shown that abuse potential can also be influenced by temporal parameters, and especially rate of onset; however, the degree to which rate of onset influences abuse-potential metrics in ICSS procedures has not been systematically examined. To address this issue, this study evaluated three dopamine transporter (DAT) inhibitors that have different onset rates and were shown previously to maintain different peak break points in rhesus monkeys responding under a progressive-ratio schedule (cocaine > WIN35428 > RTI-31 for both rate of onset and break point). In ICSS, abuse potential is generally indicated when a drug increases low rates of responding maintained by low levels of brain stimulation, a phenomenon called “ICSS facilitation”. We hypothesized that these three DAT inhibitors would facilitate ICSS different time courses, but the degree to which rate of onset might influence peak facilitation was unknown. Methods Adult male and female Sprague-Dawley rats (n = 5-7 per drug) were surgically implanted with permanent stainless-steel electrodes targeting the medial forebrain bundle and trained to respond on a lever to receive electrical brain stimulation. Behavioral sessions were organized in components consisting of ten one-minute frequency trials over a range of brain-stimulation frequencies (56-158 Hz), such that a full curve relating brain-stimulation frequency to response rate could be determined every 10 min. On test days, three baseline ICSS components were followed first by intraperitoneal drug injection and then immediately by 12 consecutive test components (120 min). Additional pairs of test components were initiated at 300 and 1440 minutes post-injection. The drugs and dose ranges tested were as follows: cocaine HCl (1.0 - 10 mg/kg), WIN35428 (0.10 – 0.32 mg/kg), and RTI-31 (0.032 – 0.10 mg/kg). All drugs were tested up to doses that produced peak levels of ICSS facilitation; higher doses disrupted responding and produced stereotypies. Results Under baseline conditions, brain stimulation maintained a frequency-dependent increase in reinforcement rates. All three drugs dose-dependently and robustly facilitated ICSS, shifting ICSS frequency-rate curves to the left and increasing the total number of stimulations per component when data were collapsed across all frequencies. Consistent with previous studies, the rate of onset for ICSS facilitation was fastest for cocaine, slower for WIN35428, and slowest for RTI-31. Cocaine also had the shortest duration of action and the lowest potency, whereas RTI-31 had the longest duration of action and highest potency. However, despite these differences in time course and potency, peak ICSS facilitation was not statistically different across drugs. Conclusions These results suggest that ICSS studies should evaluate rate of onset as well as peak ICSS facilitation in reaching conclusions about overall abuse potential of a test drug.

The Relative Reinforcing Value of Cookies Is Higher Among Head Start Preschoolers With Obesity.

The relative reinforcing value (RRV) of food measures how hard someone will work for a high-energy-dense (HED) food when an alternative reward is concurrently available. Higher RRV for HED food has been linked to obesity, yet this association has not been examined in low-income preschool-age children. Further, the development of individual differences in the RRV of food in early childhood is poorly understood. This cross-sectional study tested the hypothesis that the RRV of HED (cookies) to low-energy-dense (LED; fruit) food would be greater in children with obesity compared to children without obesity in a sample of 130 low-income 3- to 5-year-olds enrolled in Head Start classrooms in Central Pennsylvania. In addition, we examined individual differences in the RRV of food by child characteristics (i.e., age, sex, and reward sensitivity) and food security status. The RRV of food was measured on concurrent progressive-ratio schedules of reinforcement. RRV outcomes included the last schedule reached (breakpoint) for cookies (cookie Pmax) and fruit (fruit Pmax), the breakpoint for cookies in proportion to the total breakpoint for cookies and fruit combined (RRV cookie), and response rates (responses per minute). Parents completed the 18-item food security module to assess household food security status and the Behavioral Activation System scale to assess reward sensitivity. Pearson’s correlations and mixed models assessed associations between continuous and discrete child characteristics with RRV outcomes, respectively. Two-way mixed effects interaction models examined age and sex as moderators of the association between RRV and Body Mass Index z-scores (BMIZ). Statistical significance was defined as p < 0.05. Children with obesity (17%) had a greater cookie Pmax [F (1, 121) = 4.95, p = 0.03], higher RRV cookie [F (1, 121) = 4.28, p = 0.04], and responded at a faster rate for cookies [F (1, 121) = 17.27, p < 0.001] compared to children without obesity. Children with higher cookie response rates had higher BMIZ (r = 0.26, p < 0.01); and RRV cookie was positively associated with BMIZ for older children (5-year-olds: t = 2.40, p = 0.02) and boys (t = 2.55, p = 0.01), but not younger children or girls. The RRV of food did not differ by household food security status. Low-income children with obesity showed greater motivation to work for cookies than fruit compared to their peers without obesity. The RRV of HED food may be an important contributor to increased weight status in boys and future research is needed to better understand developmental trajectories of the RRV of food across childhood.