Sucrose Pellets Research Articles

Sign tracking predicts cue-induced but not drug-primed reinstatement to methamphetamine seeking in rats: Effects of oxytocin treatment.

The incentive sensitisation theory of addiction posits that drug-associated stimuli become imbued with incentive motivational properties, driving pathological drug seeking. However, pre-existing variability in the incentive salience to non-drug reward cues ('sign trackers' (STs); 'goal trackers' (GTs)) is also predictive of the desire for and relapse to cocaine and opioids. Here, we asked whether variation in propensity to attribute incentive salience to a food cue is predictive of reinstatement to the highly addictive psychostimulant methamphetamine (METH), and whether treatment with the promising anti-addiction therapy oxytocin differentially reduces METH behaviour between STs and GTs. Rats were trained to associate a Pavlovian cue with delivery of a sucrose pellet over 8 days. They then received jugular vein catheters for intravenous METH self-administration, followed by behavioural extinction, and cue-induced and METH-primed reinstatement to METH-seeking behaviours. Oxytocin was administered prior to self-administration and reinstatement tests. Despite the self-administration of similar amounts of METH, STs reinstated more to METH cues than did GTs, yet METH-priming reinstated STs and GTs similarly. Furthermore, oxytocin attenuated cue-induced reinstatement more so in STs than in GTs, and reduced METH-primed reinstatement to a greater extent in the top quartile of reinstaters, indicating that oxytocin treatment may be most effective for those at highest risk of addiction. This pre-existing bias towards reward cues presents a possible tool to screen for METH addiction susceptibility and may be useful for understanding the neurobiology of addiction and for pharmacotherapeutic discovery.

Divergent projections of the prelimbic cortex bidirectionally regulate active avoidance.

The prefrontal cortex (PFC) integrates incoming information to guide our actions. When motivation for food-seeking competes with avoidance of danger, the PFC likely plays a role in selecting the optimal choice. In platform-mediated active avoidance, rats avoid a tone-signaled footshock by stepping onto a nearby platform, delaying access to sucrose pellets. This avoidance requires prelimbic (PL) PFC, basolateral amygdala (BLA), and ventral striatum (VS). We previously showed that inhibitory tone responses of PL neurons correlate with avoidability of shock (Diehl et al., 2018). Here, we optogenetically modulated PL terminals in VS and BLA to identify PL outputs regulating avoidance. Photoactivating PL-VS projections reduced avoidance, whereas photoactivating PL-BLA projections increased avoidance. Moreover, photosilencing PL-BLA or BLA-VS projections reduced avoidance, suggesting that VS receives opposing inputs from PL and BLA. Bidirectional modulation of avoidance by PL projections to VS and BLA enables the animal to make appropriate decisions when faced with competing drives.

Non-symmetrical effects in the temporal bisection after selective food devaluation in rats

The present study investigated the effects of selective food devaluation on performance in the temporal bisection procedure with rats. Differential outcomes (sucrose vs. grain pellets) were associated with correct responding for a short and a long duration in order to analyze the effects of a selective duration-specific food devaluation on the temporal bisection function. Selective prefeeding produced differential changes in proportion of responding, the p(long) function, and PSE. A more consistent impact was observed when the food associated with the long anchor duration was devalued than when the short anchor duration food was devalued. The results are discussed in relation to the bias as well as a choose-short effect.

Evidence that haloperidol impairs learning and motivation scores in a probabilistic task by reducing the reward expectation

Activation of midbrain dopamine neurons in response to positive prediction errors and reward predictive cues is proposed to “energize” reward seeking behaviors and approach responses to places where the reward is expected. In the present study, we tested the effect of the D2-dopamine receptor antagonist haloperidol on response latencies to enter two arms of a Y-maze with different reward probabilities. Adult male Wistar rats were trained to explore the Y-maze with sucrose pellets placed 30% of times at the end of one arm and 70% of times at the opposite arm. Therefore, the reward expectation was different among arms, and was updated in the trials when the reward was omitted. After training, rats received 0.05, 0.10, 0.15 mg/kg haloperidol, or saline 30 min before the test session. In the last, but not in the first trials, haloperidol caused a dose-dependent increase in arm choice latency and response latency. Saline, but not haloperidol, treated rats presented significantly longer response latencies for the 30% compared to the 70% reward probability arm. Haloperidol also caused a dose-dependent decrease in the number of entries in the 70% reward probability arm, increased the number of non-responses, and caused a dose-dependent increase in the number of re-entries in the 30% reward probability arm after non-rewarded trials. Control experiments suggested that haloperidol did not cause motor impairment or satiation, but rather impaired learning and motivation scores by reducing the reward expectation.

Methocinnamox (MCAM) antagonizes the behavioral suppressant effects of morphine without impairing delayed matching-to-sample accuracy in rhesus monkeys.

Opioid abuse remains a serious public health problem. The pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) might be useful for treating opioid abuse and overdose. Because endogenous opioid systems can modulate cognition and decision-making, it is important to evaluate whether long-term blockade of mu opioid receptors by MCAM adversely impacts complex operant behavior involving memory. This study tested the effects of MCAM in rhesus monkeys responding under a delayed matching-to-sample task, with correct responses reinforced by sucrose pellets. Because MCAM did not alter performance, antagonism of the rate-decreasing effects of morphine was used to confirm that an effective dose of MCAM was administered. Moreover, the muscarinic receptor antagonist scopolamine and the N-methyl-D-aspartate antagonist phencyclidine were studied as positive controls to demonstrate sensitivity of this procedure to memory disruption. Neither MCAM (0.32mg/kg) nor morphine (1-5.6mg/kg) impaired delayed matching-to-sample accuracy. Morphine dose-dependently decreased the number of trials completed before MCAM administration, and a single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7days. Scopolamine (0.01-0.056mg/kg) and phencyclidine (0.1-0.56mg/kg) dose-dependently decreased delayed matching-to-sample accuracy and the number of trials completed. MCAM did not impair memory (as measured by accuracy in a delayed matching-to-sample task) and did not decrease responding for or consumption of sucrose pellets. This dose of MCAM attenuates self-administration of opioids and reverses as well as prevents opioid-induced respiratory depression. These results provide further support for a favorable adverse effect profile for MCAM.

Pro-social preference in an automated operant two-choice reward task under different housing conditions: Exploratory studies on pro-social decision making

In this study, we aimed to develop a behavioral task that measures pro-social decision making in rats. A fully automated, operant pro-social two-choice task is introduced that quantifies pro-social preferences for a mutual food reward in a set-up with tightly controlled task contingencies. Pairs of same-sex adult Wistar rats were placed in an operant chamber divided into two compartments (one rat per compartment), separated by a transparent barrier with holes that allowed the rats to see, hear, smell, but not touch each other. Test rats could earn a sucrose pellet either for themselves (own reward) or for themselves and the partner (both reward) by means of lever pressing. On average, male rats showed a 60 % preference for the lever that yielded a food reward for both themselves and their partner. In contrast, females did not show lever preference, regardless of the estrous cycle phase. Next, the impact of juvenile environmental factors on male rat social decision making was studied. Males were group-housed from postnatal day 26 onwards in complex housing Marlau™ cages that provided social and physical enrichment and stimulation in the form of novelty. Complex housed males did not show a preference for the pro-social lever.

Reward and punisher experience alter rodent decision-making in a judgement bias task

The influence of affective states on decision-making is likely to be complex. Negative states resulting from experience of punishing events have been hypothesised to generate enhanced expectations of future punishment and ‘pessimistic’/risk-averse decisions. However, they may also influence how decision-outcomes are valued. Such influences may further depend on whether decisions at hand are germane to the rewards or punishers that induced the affective state in the first place. Here we attempt to dissect these influences by presenting either many or few rewards or punishers of different types (sucrose vs air-puff; 50 kHz vs 22 kHz ultrasonic vocalisations) to rats, and investigating their subsequent decisions in a judgement bias task that employed sucrose and air-puff as decision outcomes. Rats that received many sucrose pellets prior to testing were more risk-averse than those receiving many air-puffs. Ultrasonic vocalisations did not alter decision-making. Computational analysis revealed a higher weighting of punishers relative to rewards (in agreement with findings from a separate behavioural task) and a bias towards the risk-averse response following pre-test sucrose compared to pre-test air-puff. Thus, in this study reward and punisher manipulation of affective state appeared to alter decision-making by influencing both expectation and valuation of decision-outcomes in a domain-specific way.

Hippocampal gamma oscillations by sucrose instrumental memory retrieval in rats across sleep/wake cycle

Memory reconsolidation is a process allowing previously consolidated memories to be updated. In order for memory reconsolidation to occur, a memory first needs to be reactivated. It has been shown recently that memory retrieval during awake/sleep phases may affect susceptibility to memory reactivation. Given the importance of hippocampal gamma frequencies in memory processes, the purpose of the present research was to study changes in gamma bands power during retrieval of instrumental appetitive memories. Local field potentials were recorded in the CA1 area of dorsal hippocampus of Sprague Dawley rats during retrieval of instrumental appetitive memory performed either during light or dark phases of the circadian cycle. Appetitive memory retrieval was performed by using a protocol of sucrose self-administration in operant chambers equipped with levers (Piva et al., 2018): rats were first trained to self-administer sucrose pellets and, after a 14-days forced abstinence stage, memory retrieval stage consisted in training context exposure. At the retrival stage performed during the light phase, a decreased low-gamma power was observed in CA1 when rats were not lever pressing compared to when they were lever pressing (actual instrumental memory retrieval). Moreover, results showed an inverse correlation between gamma power and rate of responding when retrieval was performed in the dark phase.Our findings suggest that hippocampal gamma power is differently modulated when retrieval is performed during the light phase compared to the dark phase. Further investigations should explore the role of gamma oscillations as potential markers of instrumental appetitive memory reactivation in both light and dark conditions.

The role of NMDA receptors in rat propofol self-administration

BackgroundPropofol is among the most frequently used anesthetic agents, and it has the potential for abuse. The N-methyl-D-aspartate (NMDA) receptors are key mediators neural plasticity, neuronal development, addiction, and neurodegeneration. In the present study, we explored the role of these receptors in the context of rat propofol self-administration.MethodsSprague-Dawley Rats were trained to self-administer propofol (1.7 mg/kg/infusion) using a fixed-ratio (FR) schedule over the course of 14 sessions (3 h/day). After training, rats were intraperitoneally administered the non-competitive NDMA receptor antagonist MK-801, followed 10 min later by a propofol self-administration session.ResultsAfter training, rats successfully underwent acquisition of propofol self-administration, as evidenced by a significant and stable rise in the number of active nose-pokes resulting in propofol administration relative to the number of control inactive nose-pokes (P < 0.01). As compared to control rats, rats that had been injected with 0.2 mg/kg MK-801 exhibited a significantly greater number of propofol infusions (F (3, 28) = 4.372, P < 0.01), whereas infusions were comparable in the groups administered 0.1 mg/kg and 0.4 mg/kg of this compound. In addition, MK-801 failed to alter the numbers of active (F (3, 28) = 1.353, P > 0.05) or inactive (F (3, 28) = 0.047, P > 0.05) responses in these study groups. Animals administered 0.4 mg/kg MK-801 exhibited significantly fewer infusions than animals administered 0.2 mg/kg MK-801 (P = 0.006, P < 0.01). In contrast, however, animals in the 0.4 mg/kg MK-801 group displayed a significant reduction in the number of active nose-poke responses (F (3, 20) = 20.8673, P < 0.01) and the number of sucrose pellets (F (3, 20) = 23.77, P < 0.01), while their locomotor activity was increased (F (3, 20) = 22.812, P < 0.01).ConclusionThese findings indicate that NMDA receptors may play a role in regulating rat self-administration of propofol.

Chemogenetic Modulation and Single-Photon Calcium Imaging in Anterior Cingulate Cortex Reveal a Mechanism for Effort-Based Decisions.

The ACC is implicated in effort exertion and choices based on effort cost, but it is still unclear how it mediates this cost-benefit evaluation. Here, male rats were trained to exert effort for a high-value reward (sucrose pellets) in a progressive ratio lever-pressing task. Trained rats were then tested in two conditions: a no-choice condition where lever-pressing for sucrose was the only available food option, and a choice condition where a low-value reward (lab chow) was freely available as an alternative to pressing for sucrose. Disruption of ACC, via either chemogenetic inhibition or excitation, reduced lever-pressing in the choice, but not in the no-choice, condition. We next looked for value coding cells in ACC during effortful behavior and reward consumption phases during choice and no-choice conditions. For this, we used in vivo miniaturized fluorescence microscopy to reliably track responses of the same cells and compare how ACC neurons respond during the same effortful behavior where there was a choice versus when there was no-choice. We found that lever-press and sucrose-evoked responses were significantly weaker during choice compared with no-choice sessions, which may have rendered them more susceptible to chemogenetic disruption. Together, findings from our interference experiments and neural recordings suggest that a mechanism by which ACC mediates effortful decisions is in the discrimination of the utility of available options. ACC regulates these choices by providing a stable population code for the relative value of different options.SIGNIFICANCE STATEMENT The ACC is implicated in effort-based decision-making. Here, we used chemogenetics and in vivo calcium imaging to explore its mechanism. Rats were trained to lever press for a high-value reward and tested in two conditions: a no-choice condition where lever-pressing for the high-value reward was the only option, and a choice condition where a low-value reward was also available. Inhibition or excitation of ACC reduced effort toward the high-value option, but only in the choice condition. Neural responses in ACC were weaker in the choice compared with the no-choice condition. A mechanism by which ACC regulates effortful decisions is in providing a stable population code for the discrimination of the utility of available options.

Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System.

BackgroundThe prevalence of eating disorders, including binge eating disorder, is significantly higher in women. These findings are mirrored by preclinical studies, which indicate that female rats have a higher preference for palatable food and show greater binge-like eating compared with male rats.MethodsHere, we describe a novel within-session behavioral-economic paradigm that allows for the simultaneous measurement of the intake at null cost (Q0) and normalized demand elasticity (α) of 3 types of palatable food (low fat, high fat, and chocolate sucrose pellets) via demand curve analysis. In light of evidence that the orexin (hypocretin) system is critically involved in reward and feeding behaviors, we also examined the role of orexin function in sex differences of economic demand for palatable foods.ResultsThe novel within-session behavioral-economic approach revealed that female rats have higher intake (demand) than males for all palatable foods at low cost (normalized to body weight) but no difference in intake at higher prices, indicating sex-dependent differences in the hedonic, but not motivational, aspects of palatable food. Immediately following behavioral-economic testing, we observed more orexin-expressing neurons and Fos expression (measure of recent neural activation) in these neurons in female rats compared with male rats. Moreover, the orexin-1 receptor antagonist SB334867 reduced both low- and high-cost intake for palatable food in both male and female rats.ConclusionsThese findings provide evidence of higher demand at low prices for palatable food in females and indicate that these behavioral differences may be associated with sexual dimorphism in orexin system function.

0224 Optogenetic Manipulation of Basal Forebrain Parvalbumin Neurons Modulates Vigilant Attention and Rescues Sleep Deprivation Induced Impairments

Abstract Introduction Sleep disruption leads to attention impairments, excessive daytime sleepiness, and is a major contributor to accident rates and decreased workplace productivity. The basal forebrain (BF) region has long been associated with promoting cortical arousal and wakefulness. Recently, selective excitation of BF parvalbumin (PV) GABAergic neurons has been shown to produce high frequency cortical activation and brief periods of wakefulness. Here we test the hypothesis that BF PV neurons are involved in vigilant attention using bidirectional optogenetic manipulations in a signaled reaction time task. Methods Brief optogenetic excitation (ChR2) and inhibition (ArchT) of BF PV neurons was applied during a lever release version of the rodent psychomotor vigilance task (rPVT). Mice were trained to hold a lever down to initiate a trial and after a random delay, a 200ms cue light signaled the mouse to quickly release the lever within 1s to receive a sucrose pellet reward. The reaction time between cue light onset and lever release was the primary measure of attentional performance. Sleep deprivation (8h) produced by gentle handling was also investigated. Laser parameters: brief (1s) of continuous (non-pulsatile) laser stimulation was delivered beginning 500ms prior to cue light onset (5mW 473nm blue light for ChR2-mediated excitation; 10mW 530nm green light for ArchT-mediated inhibition). Results BF PV excitation led to faster reactions times (N=6, 14% faster, p&amp;lt;.001), interpreted as an enhancement of attention. Sleep deprivation slowed reaction times (20% slower, p&amp;lt;.01) and BF PV excitation rescued the sleep deprivation induced impairments. BF PV inhibition significantly slowed reaction times (25% slower, p&amp;lt;.02), an effect that resembled the effects of sleep deprivation. Conclusion This is the first demonstration of a role for BF PV neurons in attention and in the attention deficits produced by sleep deprivation. Support T32 HL007901, I01 BX002774, P01 HL095491, R01 MH039683, I01 BX004500, IK2 BX002130, Stonehill College SURE program, I01 BX001356

Cebranopadol reduces cocaine self-administration in male rats: Dose, treatment and safety consideration

As a novel first-in-class potent analgesic acting as an agonist of multiple opioid receptors, cebranopadol showed high efficacy and good tolerability in a broad range of preclinical models and clinical trials related to pain. In the present study, to evaluate the efficacy and safety of cebranopadol as a potential treatment of cocaine dependence, we tested the effects of cebranopadol with single and repeated doses (25, 50, 75, or 100 μg/kg, oral gavage) using rat models of cocaine fixed-ratio (FR) self-administration (SA), cocaine progressive-ratio (PR) SA, and sucrose pellet SA. In single-dosing treatment paradigm, cebranopadol significantly and dose-dependently reduced cocaine SA under FR and PR schedules and suppressed food intake under FR schedule without causing apparent side effects. In repeated-dosing treatment scheme, i.e. daily administration of 25, 50, 75, or 100 μg/kg cebranopadol for a week, the similar reduction in cocaine intake was detected, while non-negligible complications/side effects were observed at repeated high doses (75 and 100 μg/kg). The observed side effects were similar to the common toxic signs elicited by heroin at high doses, although cebranopadol did not fully substitute heroin's discriminative stimulant effects in our drug discriminative tests. These results demonstrated that the most appropriate oral dose of cebranopadol to balance the efficacy and safety is 50 μg/kg. Collectively, although cebranopadol may serve as a new treatment for cocaine dependence, more consideration, cautiousness, and a clear optimal dose window to dissociate its therapeutic effects from opioid side effects/complications in male and female subjects will be necessary to increase its practical clinical utility.

Distinct projections from the prelimbic cortex modulate active avoidance

Avoiding threatening stimuli is a survival mechanism that can become maladaptive when avoidance interferes with other goal‐directed behaviors. For example, when an individual is seeking food, a threatening stimulus may be encountered, leading to an avoidance response, which comes at a cost of obtaining food. To model this behavior, we used an active avoidance task in which food‐restricted rats learn to step onto a platform to avoid a tone‐signaled shock, at the cost of obtaining a sucrose pellet. Activity in prelimbic cortex (PL), basolateral amygdala (BLA), and ventral striatum (VS) are necessary for the expression of platform‐mediated active avoidance (PMA) (Bravo‐Rivera, et. al., 2014), suggesting that these structures form a neural circuit to regulate PMA. We recently reported that inhibitory tone responses in PL signal the avoidability of shock, and opposing these responses using 4Hz photoactivation impaired avoidance (Diehl, et. al., 2018). Here, we want to know if PL inhibition signals downstream structures that are necessary for avoidance (i.e. VS and BLA), using an optogenetic approach. Photoactivating PL‐VS projections using Channelrhodopsin (ChR2) impaired avoidance (eYFP 88% (n=12) vs. ChR2 22% (n=8), p&lt;0.0001), whereas photosilencing PL‐VS projections using Archaerhodopsin (ArchT) had no effect, suggesting that inhibition of this pathway promotes avoidance. Additionally, photoactivating PL‐BLA projections accelerated avoidance (eYFP 75% (n=9) vs. ChR2 88% (n=8), p=0.017), and photosilencing PL‐BLA projections impaired avoidance (eYFP 77% (n=9) vs. ArchT 40% (n=7), p=0.026), suggesting that excitation of this pathway promotes avoidance. Overall, these findings suggest that distinct PL projections have opposing roles in controlling avoidance by driving or suppressing avoidance.Support or Funding InformationThis work was supported by NIH grants R37‐MH058883 and P50‐MH086400 (Conte Center) to GJQ; F32‐MH105185 to MMD; 5T34‐GM00782140 to GRB, 5R25‐GM097635 to JIG and VVV; 5R25‐GM061151 to GRB, FDG and JMS.

Long‐term Antagonism of Mu Opioid Receptors by Methocinnamox (MCAM) without Adverse Effects on Memory

Opioid abuse remains a serious public health problem. Methocinnamox (MCAM) is a mu opioid receptor antagonist that has pharmacological properties (e.g., pseudoirreversible binding to mu opioid receptors) that might make it especially well suited for treating opioid abuse and overdose. The endogenous opioid system is involved in cognition and motivation, and long‐term blockade of mu opioid receptors by MCAM might adversely impact complex operant behavior involving memory. This study characterized the effects of MCAM in five adult rhesus monkeys (n=1 male and n=4 females) responding for sucrose pellets under a delayed matching‐to‐sample task. Ten touches (sampling responses) on a colored rectangle (e.g., blue), displayed on a touch‐sensitive screen, presented two comparison stimuli, one of which matched the original stimulus (e.g., blue rectangle), either immediately or after a delay (1 – 32 sec). Touching the matching stimulus delivered a pellet and visual feedback followed by a 5‐sec inter‐trial interval, whereas touching the non‐matching stimulus terminated the trial and initiated a 35‐sec inter‐trial interval. Sessions comprised up to 100 trials in 90 min. Because MCAM was expected to have long‐term antagonist actions on muopioid receptors, the effects of the mu opioid receptor agonist morphine on delayed matching‐to‐sample accuracy and the number of trials completed were determined before and after MCAM administration to establish the duration of action of MCAM. Neither MCAM (0.32 mg/kg) nor morphine (1 – 5.6 mg/kg) impaired delayed matching‐to‐sample accuracy. Administered alone, morphine dose‐dependently decreased the number of trials completed to fewer than 20. When morphine was re‐tested 1 day after MCAM, monkeys completed all trials, and this single injection of MCAM blocked the behavioral suppressant effects of morphine for at least 7 days (and substantially longer in some subjects). Because morphine and MCAM were without effect on delayed matching‐to‐sample accuracy, the muscarinic receptor antagonist scopolamine (0.01 – 0.056 mg/kg) as well as the N‐methyl‐D‐aspartate antagonist phencyclidine (0.1 – 0.56 mg/kg) were studied to confirm sensitivity of the assay to memory‐impairing drug effects; each drug dose‐dependently decreased delayed matching‐to‐sample accuracy and the number of trials completed. MCAM did not impair memory (as measured by accuracy in a delayed‐matching‐sample task). This dose of MCAM attenuates i.v. self‐administration of mu opioid receptor agonists and reverses as well as protects against mu opioid receptor agonist‐induced respiratory depression, with the duration of these effects lasting approximately one week. These data are consistent with a favorable safety profile of MCAM, as MCAM provides long‐lasting antagonism of mu opioid receptors in the absence of any apparent adverse effects, making it a promising candidate for treating opioid abuse and overdose.Support or Funding InformationSupported by: National Institute on Drug Abuse grants R01DA005018 and R01DA048417.

Weight Loss After Obesity is Associated with Increased Food Motivation and Faster Weight Regainin Mice.

While changes in diet often result in short-term weight loss, weight loss is not typically maintained. It remains unclear why long-term weight loss is so difficult. It was hypothesized that obesity produces persistent changes in behavior that bias animals toward weight regain after weight loss. Mice were induced to gain weight with ahigh-fat diet for 6 weeks and then induced to lose this weight with alow-fat diet for 7 subsequent weeks. A control group was maintained on the low-fat diet for all 13 weeks. Activity was measured continuously with home cage activity monitors for the entire experiment. Motivation for sweetened food pellets was tested following weight loss. A separate group of mice was reexposed to ahigh-fat diet following 2, 4, or 8 weeks of withdrawal to assess the rate of weight regain. Activity levels decreased as animals gained weight and partially recovered following weight loss. Motivation for sucrose pellets was persistently heightened after weight loss. Consistent with these behavioral changes, mice also regained weight at a faster rate when reexposed to a high-fat diet after a period of weight loss. Weight loss after obesity was associated with increased motivation for palatable food and an increased rate of weight regain.

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat.

Tetrodotoxin (TTX) was identified as a latent neurotoxin that has a significant analgesia effect. It was rapidly absorbed and excreted in rat after intramuscular (i.m.) injection. To maintain the effect, frequent injections were required. The enteric sustained-release TTX pellets with sucrose pellets as a drug carrier was prepared by fluidized bed spray irrigation, coated in sequence with Eudragit NE30D as a sustained-release layer, hydroxypropyl methylcellulose (HPMC) as a barrier layer and Eudragit L30D-55 as an enteric coating. TTX in the pellets could be sustained released for 12 h in dissolution test. In vivo, TTX pellets reached Cmax at 5 h, and t1/2 was 14.52 ± 2.37 h after intragastrically (i.g.) administration in rat. In acetic acid induced writhing test in rat, the pellets at the dosages of 20, 40, 60 and 80 μg·kg−1 produced analgesic effect at about 1.5 h to 9 h and the strongest effect was at about 3 h to 6 h. Simultaneously, the LD50 of the enteric sustained-release TTX pellets was 840.13 μg·kg−1, and the ED50 was about 30 μg·kg−1. Thus, the therapeutic index was about 25. The enteric sustained-release TTX pellets with absolute analgesia effect and greatly enhanced safety was prepared.

Diminished food-related motivation in adult rats treated with methamphetamine during adolescence.

Drug use among adolescents continues to be an area of concern because of the possibility of long-lasting physical and mental changes. The aim of this study was to determine whether methamphetamine exposure during adolescence results in long-lasting neurobehavioral alterations in adulthood. Sprague–Dawley rats were injected with methamphetamine (4 mg/kg/day) during postnatal days 28–37. Once rats reached postnatal days 150, they were placed in standard operant chambers, where they were trained to respond to a lever for sucrose pellets, the experimental reinforcement. Methamphetamine exposure during adolescence did not result in a noteworthy impairment in the development of the correct lever touch response in the autoshaped learning test with 4 seconds delayed reinforcement. These rats were also tested for the motivation to obtain sucrose pellets under a progressive ratio schedule of the reinforcement on postnatal days 170. Decreased lever-pressing response was noted in male rats exposed to methamphetamine during adolescence, but not in female rats. These results indicate that methamphetamine exposure during adolescence results in a decrease in the motivation for a natural reinforcer later in adulthood, particularly in male rats. From our data, we suggest that male brains are less capable of facilitating recovery than female brains after methamphetamine-induced perturbation of brain function during the adolescent period.

A behavioral economic analysis of the effects of rimcazole on reinforcing effects of cocaine injection and food presentation in rats.

Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects. Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q0) and sensitivity to price (essential value, EV), derived. Rimcazole dose-dependently decreased Q0 and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q0 at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. Though the drug combinations only replicated rimcazole's effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.

Different periods of forced abstinence after instrumental learning for food reward of different macronutrient value on responding for conditioned cues and AMPAr subunit levels

Food craving can be viewed as an intense desire for a specific food that propagates seeking and consuming behavior. Prolonged forced abstinence from rewarding foods can result in escalated food-seeking behavior as measured via elevated responding for food-paired cues in the absence of the primary reward. Palatable food consumption and food-seeking is associated with changes in the abundance and composition of AMPA receptors in the nucleus accumbens (NAc) but differing results have been reported. The present study examined whether different food types could produce escalated food-seeking behavior after various abstinence periods and whether this was associated with changes in AMPA receptor protein levels. Rats were trained for 10 days to bar press for purified, sucrose, or chocolate-flavored sucrose pellets. Rats were tested at 24 hrs, 7 d or 14 d whereby bar pressing resulted in presentation of cues paired with food but no food reward was delivered. Western blotting was used to determine protein levels of GluR1, GluR1pSer845, and GluR2 in the NAc. Three separate groups were assessed: 1) a group that was trained on the operant task and tested for conditioned responding (tested group); 2) a group that was trained on the operant task but not tested (non-tested group); 3) a group that was neither trained nor tested (control). The purified food group showed a time-dependent elevation in conditioned bar pressing over the 3 abstinence periods. GluR1 AMPAr subunit levels were higher in the purified and sucrose groups tested at 24 hours compared to the non-tested and control values. GluR1 levels subsequently declined at the 7- and 14-day abstinence periods in the purified and sucrose tested and non-tested groups compared to control values. GluR2 and pSer845 Glur1 levels were similar across all groups and abstinence periods. These results show that food-seeking behavior associated with forced abstinence from different food rewards may depend on the macronutrient composition of the food reward or the food type given during the abstinence period. A clear link with AMPAr subunit levels in this model was not established.