Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task

Rationale

Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward.

Objectives

To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward.

Materials and methods

Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays.

Results

Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine.

Conclusions

The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity.     

Delay discounting of food and remifentanil in rhesus monkeys

Rationale

Drug abuse can be conceptualized as choice between drug and nondrug reinforcers in which drug choice is excessive; factors impacting drug taking can be examined using procedures in which subjects choose between drug and an alternative reinforcer.

Objective

This experiment examined the effects of delayed reinforcement on choice between food and the mu-opioid receptor agonist remifentanil.

Methods

Rhesus monkeys responded under a concurrent fixed-ratio 5, fixed-ratio 5 schedule in which responding on one lever delivered one food pellet and responding on another lever delivered an i.v. infusion.

Results

With no delay, monkeys responded predominantly for food rather than saline or small doses of remifentanil; as the dose of remifentanil increased (0.1–1.0 μg/kg/infusion), monkeys responded more for drug. Delaying delivery (30–240 s) of 0.32 and not 1.0 μg/kg/infusion of remifentanil (food delivered immediately) decreased responding for drug and increased responding for food, resulting in a rightward shift in the remifentanil dose–effect curve. Delaying delivery of food (60–240 s) when doses of remifentanil smaller than 0.32 μg/kg/infusion (but not saline) were available decreased responding for food and increased responding for drug, resulting in a leftward shift in the remifentanil dose–effect curve.

Conclusion

These results provide evidence that delaying the delivery of a mu-opioid receptor agonist reduces its potency as a positive reinforcer; more importantly, delaying the delivery of an alternative nondrug reinforcer (e.g., food) enhances the reinforcing potency of the agonist. Thus, understanding the factors that control substance abuse requires examination of contingencies for both drug and nondrug reinforcers.     

Effects of acute administration of nicotinic and muscarinic cholinergic agonists and antagonists on performance in different cost–benefit decision making tasks in rats

Rationale

Alterations in cost?Cbenefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost?Cbenefit decision making.

Objectives

The goal of these experiments was to determine how cholinergic signaling is involved in cost?Cbenefit decision making, using a behavioral pharmacological approach.

Methods

Male Long-Evans rats were trained in either ??probability discounting?? or ??delay discounting?? tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task.

Results

In the probability discounting task, acute nicotine administration (1.0?mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3?mg/kg) and atropine (0.3?mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks.

Conclusions

These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes.     

Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase

Background

In previous studies with male and female rhesus monkeys, withdrawal of access to oral phencyclidine (PCP) self-administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females, and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer impulsive choice for SACC increased during PCP withdrawal more in males than females.

Objectives

The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle.

Materials and methods

In component 1, PCP and water were available from two drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In component 2, a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or six delayed SACC deliveries, and the delay was increased by 1 s after a response on the delayed lever and decreased by 1 s after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP withdrawal, that occurred during the mid-follicular phase (days 7–11) or the late luteal phase (days 24–28) of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases.

Results

PCP deliveries were higher during the luteal (vs follicular) phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration.

Conclusions

PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys.     

Delay Discounting of Oral Morphine and Sweetened Juice Rewards in Dependent and Non-Dependent Rats

Rationale

Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats

Methods

We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose.

Results

Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly.

Conclusions

These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.     

Drugs of abuse as memory modulators: a study of cocaine in rats

Rationale

It has been proposed that drugs of abuse reinforce behavior partly, or wholly, because they facilitate learning by enhancing memory consolidation. Cocaine can clearly serve as a reinforcer, but its effect on learning has not been fully characterized.

Objectives

To explore the effects of different regimens of pre- and post-training cocaine administration on win-stay and object learning.

Methods

Cocaine naïve and cocaine pre-exposed (30 mg/kg/day, ×5 days followed by 7 days drug-free) male Sprague-Dawley rats received cocaine (0, 1, 2.5, 7.5, or 20 mg/kg, i.p.) immediately following training on a win-stay task in a radial maze or following the sample phase of an object learning task. Win-stay performance was also assessed in tests of extinction and after a set shift.

Results

Post-training cocaine did not improve accuracy on the win-stay task and produced performance deficits at 20 mg/kg. These deficits were attenuated by prior cocaine exposure. There was indirect evidence of facilitated learning in extinction and set shift tests, but the effective dosage was different (2.5 and 7.5 mg/kg, respectively). Post-training cocaine produced dose-dependent improvements in object learning.

Conclusion

Post-training cocaine administration can facilitate learning, but this effect is highly dependent on the dose and the type of task employed.     

Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice

Introduction

Prior research indicates methylphenidate (MPH) and alcohol (ethanol, EtOH) interact to significantly affect responses humans and mice. The present studies tested the hypothesis that MPH and EtOH interact to potentiate ethanol-related behaviors in mice.

Methods

We used several behavioral tasks including: drug discrimination in MPH-trained and EtOH-trained mice, conditioned place preference (CPP), rota-rod and the parallel rod apparatus. We also used gas chromatographic methods to measure brain tissue levels of EtOH and the d- and l-isomers of MPH and the metabolite, ethylphenidate (EPH).

Results

In discrimination, EtOH (1 g/kg) produced a significant leftward shift in the MPH generalization curve (1–2 mg/kg) for MPH-trained mice, but no effects of MPH (0.625–1.25 mg/kg) on EtOH discrimination in EtOH-trained mice (0–2.5 g/kg) were observed. In CPP, the MPH (1.25 mg/kg) and EtOH (1.75 g/kg) combination significantly increased time on the drug paired side compared to vehicle (30.7 %), but this was similar to MPH (28.8 %) and EtOH (33.6 %). Footslip errors measured in a parallel rod apparatus indicated that the drug combination was very ataxic, with footslips increasing 29.5 % compared to EtOH. Finally, brain EtOH concentrations were not altered by 1.75 g/kg EtOH combined with 1.25 mg/kg MPH. However, EtOH significantly increased d-MPH and l-EPH without changing l-MPH brain concentrations.

Conclusions

The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain d-MPH concentrations. These studies are consistent with observations in humans of increased interoceptive awareness of the drug combination and provide new clinical perspectives regarding enhanced ataxic effects of this drug combination.     

Impulsivity and cigarette smoking: discounting of monetary and consumable outcomes in current and non-smokers

Rationale

In delay discounting, temporally remote rewards have less value. Cigarette smoking is associated with steeper discounting of delayed money. The generality of this to nonmonetary outcomes, however, is unknown.

Objectives

We sought to determine whether cigarette smokers also show steep discounting of other delayed outcomes.

Methods

Sixty-five participants (32 smokers and 33 non-smokers) completed four delay-discounting tasks, each involving different hypothetical outcomes. In the monetary task, participants indicated their preference for a smaller amount of money available immediately (titrated across trials) and $100 awarded at delays ranging from 1 week to 25 years (tested in blocks). In the three other discounting tasks the larger-later reward was $100 worth of a favorite food, alcoholic drink, or a favorite form of entertainment. All other aspects of these discounting tasks were identical to the monetary discounting task.

Results

As previously shown, smokers discounted delayed money more steeply than non-smokers did. In addition, smokers discounted delayed food and entertainment rewards more steeply than did nonsmokers. A person’s discounting of one outcome was correlated with discounting of other outcomes. Non-smokers discounted money less steeply than all other outcomes; smokers discounted money significantly less than food.

Conclusions

When compared to nonsmokers, cigarette smokers more steeply discount several types of delayed outcomes. This result, together with the finding that cross-commodity discounting rates were correlated within subjects, suggests that delay discounting is a trait that extends across domains.     

Trait differences in response to chronic nicotine and nicotine withdrawal in rats

Introduction

Understanding an individual’s vulnerability to drug addiction has important implications for the development of effective personal treatment plans. Although theories acknowledge impulsive behaviour as a key component of drug addiction, little is known about the influence of trait impulsivity on an individual’s susceptibility to the effects of psychostimulants on impulsivity at critical phases of the addiction cycle.

Methods

This study investigated the short and longer-term effects of chronic nicotine administration on impulsive choice in rats selected for high (HI) and low impulsivity (LI) on a delay discounting task. Rats prepared with subcutaneously osmotic mini-pumps received either nicotine (3.16 mg/kg/day [freebase]) or saline for 7 days. Performance was assessed during chronic treatment, early and late withdrawal, and in response to acute nicotine challenges following prolonged abstinence.

Results

Chronic nicotine increased impulsive choice in LI but not HI animals. Spontaneous withdrawal was associated with a nicotine abstinence syndrome, the early stages of which were characterised by opposing effects on impulsive choice in HI and LI animals. A transient decrease in impulsivity was observed in HI animals whilst the LI group remained more impulsive for up to 1 week following drug termination. Following normalisation of behaviour, acute nicotine challenges (0.125, 0.25, 0.5 mg/kg, SC) markedly increased impulsive choice regardless of trait impulsivity and drug history.

Conclusion

The results indicate that only LI individuals are vulnerable to chronic drug- and withdrawal-induced impairments in self-control which may increase the likelihood of the transition to, and maintenance of, nicotine dependence.     

The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration

Rationale

Previous studies have demonstrated that several N-substituted 4′, 4″-diF-benztropine (BZT) analogs with high dopamine transporter affinity selectively decreased cocaine self-administration without affecting food-maintained behavior in rats.

Objectives

The present study examined if the decreases in cocaine self-administration are due to competition from excess behavioral activity (hyperlocomotion or stereotypy) induced by the BZT analogs alone or in combination with cocaine.

Results

Pretreatments with the typical dopamine uptake inhibitor methylphenidate [1.0, 3.2, and 10 mg/kg, intraperitoneally (i.p.)] dose-dependently shifted the cocaine self-administration dose–effect curve (0, 0.032, 0.1, 0.32, and 1.0 mg/kg/injection) leftward. The shift in the dose–effect curve was obtained at doses of methylphenidate that, when administered alone, also decreased food-maintained behavior and increased locomotor activity and stereotypy. In contrast, the N-substituted BZT analogs, JHW 007 (1.0, 3.2, and 10 mg/kg, i.p.), AHN 1-055 (10 mg/kg), and, AHN 2-005 (10 mg/kg), as previously reported, decreased the maximum for the cocaine self-administration dose–effect curve, and did so at doses that were virtually without effects on food-maintained behavior. Further, the BZT analogs alone had minimal effects on locomotor activity and stereotypies and did not appreciably change the effects of cocaine on these measures when administered in combination with cocaine.

Conclusions

The present results suggest that the decrease in cocaine self-administration produced by the N-substituted BZT analogs is due to an antagonism of the reinforcing effects of cocaine rather than due to interference from competing behavioral overstimulation, and further supports the development of N-substituted BZT analogs as medications to treat cocaine abuse.     

Genetic influences on delay discounting in smokers: examination of a priori candidates and exploration of dopamine-related haplotypes

Rationale

Delay discounting is a behavioral economic index of impulsivity that reflects a person’s relative preference for small immediate rewards versus larger delayed rewards. Elevated delay discounting is robustly linked to addictive disorders and has been increasingly investigated as a viable endophenotype for genetic influences on addiction.

Objective

The aim of this study is to examine associations between delay discounting and two a priori loci, rs4680 in COMT and rs1800497 in ANKK1, and three exploratory haplotypes proximal to rs1800497 in a sample of daily smokers.

Methods

Participants were 713 (60.2 % male) daily smokers of European ancestry who completed a delay discounting assessment and provided a DNA sample.

Results

Significant associations were detected between greater discounting of medium magnitude rewards (~$55) and the G allele of rs4680, as well as the T allele of rs1800497. Exploratory haplotype analyses identified two haplotypes (rs1160467/rs1800497; rs6277/rs1079597) significantly associated with delay discounting rates. However, the rs1160467/rs1800497 haplotype associations appeared to be entirely attributable to variation in rs1800497, suggesting that the association of rs1800497 with discounting is best understood at the individual SNP level. Similarly, the rs6277/rs1079597 haplotype findings suggested that the association was specific to rs1079597.

Conclusions

This study provides further evidence that rs4680 and rs1800497 genotypes are significantly associated with delay discounting preferences and does so among smokers for the first time. The study also provides evidence of specificity for the rs1800497 association and identifies a novel locus, rs1079597, as a genetic contributor to higher delay discounting rates.

     

Impaired flexibility in decision making in rats after administration of the pharmacological stressor yohimbine

Rationale

Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized.

Objective

To characterize changes in decision making caused by acute pharmacological stress, the effects of yohimbine (an α2-adrenergic antagonist) were examined in a delay discounting task. Noradrenergic contributions to decision making were further characterized by examining the effects of propranolol (a β antagonist), prazosin (an α1 antagonist), and guanfacine (an α2 agonist).

Methods

Sprague–Dawley rats were administered drugs prior to performance on a delay discounting task, in which the delay preceding the large reward increased within each session (ascending delays). To dissociate drug-induced changes in delay sensitivity from behavioral inflexibility, drug effects were subsequently tested in a modified version of the discounting task, in which the delay preceding the large reward decreased within each session (descending delays).

Results

Yohimbine increased choice of the large reward when tested with ascending delays but decreased choice of the same large reward when tested with descending delays, suggesting that drug effects could be attributed to perseverative choice of the lever preferred at the beginning of the session. Propranolol increased choice of the large reward when tested with ascending delays. Prazosin and guanfacine had no effect on reward choice.

Conclusions

The stress-like effects of yohimbine administration may impair decision making by causing inflexible, perseverative behavior.     

Methylphenidate and impulsivity: a comparison of effects of methylphenidate enantiomers on delay discounting in rats

Rationale

Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana^®, a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g., Ritalin^®). One potential limitation of increased l-MPH was indicated in a preclinical study showing l-MPH may attenuate effects of d-MPH.

Objectives

The objective of the study was to investigate the interactive effects of MPH enantiomers by (1) assessing drug effects via a preclinical model of “impulsivity” and (2) performing a quantitative dose equivalence analysis of MPH enantiomer interactions.

Methods

Sprague–Dawley rats were trained to emit either of two responses, one producing an immediate food pellet, the other producing four pellets delivered at increasing delays (0, 8, and 32 s). The percent selection of the larger food amount was graphed as a function of delay with the area under the curve (AUC) assessed. Increases in AUC are consistent with decreases in “impulsivity” (i.e., selection of the smaller, immediate over the larger, delayed reinforcer).

Results

Systemic administration of dl-MPH and d-MPH dose-dependently increased AUC, while l-MPH, morphine, and pentobarbital did not alter AUC. An analysis based upon dose equivalence indicated that dl-MPH produced additive effects that were not different from that predicted from effects of the enantiomers administered alone.

Conclusions

The present results indicate pharmacologically selective effects in that only drugs prescribed for the treatment of ADHD symptoms decreased a measure of “impulsivity” and that l-MPH likely does not attenuate or enhance the effects of d-MPH in the current delay-discounting task.     

Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats

Rationale

Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon.

Methods

Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context-cocaine (15?mg/kg, i.p.) and context-saline (1?ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15?mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2 and 2?mg/kg, Experiment 2), using counterbalanced within-subjects testing designs.

Results

Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose-dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline.

Conclusion

Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention.     

Random-ratio schedules produce greater demand for i.v. drug administration than fixed-ratio schedules in rhesus monkeys

Rationale

Organisms emit more responses when food is provided according to random as compared with fixed schedules of reinforcement. Similarly, many human behaviors deemed compulsive are maintained on variable schedules (e.g., gambling). If greater amounts of behavior are maintained by drugs of abuse when earned according to variably reinforced schedules, this would suggest that excessive drug-taking behavior may be due in part to the nature of drug availability.

Objectives

The aim was to determine whether random schedules of contingent intravenous drug delivery would produce more responding than similarly priced fixed schedules.

Methods

Six rhesus macaque subjects responded to produce cocaine (0.003–0.03 mg/kg/inj), remifentanil (0.01–1.0 μg/kg/inj), or ketamine (0.01–0.1 mg/kg/inj) according to either fixed or random ratio requirements that increased systematically across sessions. Demand curves were generated with the most effective dose of each drug and compared across drug and schedule type.

Results

Cocaine and remifentanil maintained higher levels and rates of responding when earned according to random-ratio schedules as compared with fixed-ratio schedules. This difference was most pronounced when drugs were available at high unit prices. Differences in responding across the schedule types generated by ketamine—a lesser-valued reinforcer—were qualitatively similar but smaller in magnitude.

Conclusions

The current study provides a systematic replication across reinforcer type demonstrating that drugs delivered after a random number of responses generate more behavior than those delivered according to a fixed schedule. The variable nature of the availability of drugs of abuse—particularly those that are scarce or expensive—may be a contributing factor to excessive drug intake by humans. This effect is most likely to be observed when more highly demanded (reinforcing) drugs are being consumed.     

Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance

Rationale

Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects.

Objectives

This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions.

Materials and methods

The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers’ behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer’s attitudes and behavior.

Results

Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers.

Conclusions

When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.     

Effects of the AMPA receptor modulator S 18986 on measures of cognition and oxidative stress in aged rats

Rationale

Development of cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer’s disease would be of great benefit.

Objectives

The aim of this study was to examine the ability of (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986), a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, to improve behavioral performance and alleviate age-related deficits in oxidative stress status in the prelimbic cortex and hippocampus.

Materials and methods

Daily administration of S 18986 (0.1, 0.3, and 1.0 mg/kg) or vehicle was given to separate groups of male rats starting at 12 months of age. Additionally, daily vehicle administration was given to a group of rats starting at 3 months of age. Four months after initiation of drug administration, rats were trained and tested in an operant-delayed alternation task and a reinforcer devaluation task. Upon completion of testing, oxidative stress status was assessed in the prelimbic cortex and hippocampus.

Results

S 18986 dose-dependently altered responses in the reinforcer devaluation task such that aged rats came to resemble young rats. There were no age or drug effects in the operant-delayed alternation task. Levels of the lipid peroxidation product 4-hydroxy-nonenal (HNE) were increased, and Cu/Zn–superoxide dismutase (SOD) levels were decreased in prelimbic cortex in aged rats, changes that were reversed by S 18986. Similarly, age-related increases in hippocampal HNE levels were prevented by S 18986.

Conclusions

Positive modulation of AMPA receptor activity may be a therapeutic approach to halt or slow progression of mild cognitive impairment via improvement in oxidative stress status in the hippocampus and prelimbic cortex.     

Characterization of Highper, an ENU-induced mouse mutant with abnormal psychostimulant and stress responses

Rationale

Chemical mutagenesis in the mouse is a forward genetics approach that introduces random mutations into the genome, thereby providing an opportunity to annotate gene function and characterize phenotypes that have not been previously linked to a given gene.

Objectives

We report on the behavioral characterization of Highper, an N-ethyl-N-nitrosourea (ENU)-induced mutant mouse line.

Methods

Highper and B6 control mice were assessed for locomotor activity in the open field and home cage environments. Basal and acute restraint stress-induced corticosterone levels were measured. Mice were tested for locomotor response to cocaine (5, 20, 30, and 45 mg/kg), methylphenidate (30 mg/kg), and ethanol (0.75, 1.25, and 1.75 g/kg). The rewarding and reinforcing effects of cocaine were assessed using conditioned place preference and self-administration paradigms.

Results

Highper mice are hyperactive during behavioral tests but show normal home cage locomotor behavior. Highper mice also exhibit a twofold increase in locomotor response to cocaine, methylphenidate, and ethanol and prolonged activation of the hypothalamic–pituitary–adrenal axis in response to acute stress. Highper mice are more sensitive to the rewarding and reinforcing effects of cocaine, although place preference in Highper mice appears to be significantly influenced by the environment in which the drug is administered.

Conclusions

Altogether, our findings indicate that Highper mice may provide important insights into the genetic, molecular, and biological mechanisms underlying stress and the drug reward pathway.     

The relationship between cocaine self-administration and actigraphy-based measures of sleep in adult rhesus monkeys

Rationale

Clinical trials show that chronic cocaine users suffer from sleep disturbances and preclinical research has shown that acute sleep deprivation increases the rate of cocaine self-administration in rats.

Objective

This study examined the effect of cocaine self-administration on behavioral indices of sleep and alternatively the effect of sleep disruption on cocaine-maintained responding by rhesus monkeys.

Methods

Seven adult rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a concurrent choice paradigm with food (three 1.0-g pellets) and cocaine (0.003–0.3 mg/kg) or saline presentation. For each monkey, the lowest preferred dose of cocaine (>80 % cocaine choice) was determined. Activity data were analyzed during lights out (2000-0600) to determine sleep efficiency, sleep latency, and total activity counts. Subsequently, the monkeys’ sleep was disrupted (every hour during lights-out period) the night prior to food–cocaine choice sessions.

Results

Self-administration of the preferred dose of cocaine resulted in a significant decrease in sleep efficiency, with a significant increase in total lights-out activity. Sleep disruption significantly altered behavioral indices of sleep, similar to those seen following cocaine self-administration. However, sleep disruption did not affect cocaine self-administration under concurrent choice conditions.

Conclusions

Based on these findings, cocaine self-administration does appear to disrupt behavioral indices of sleep, although it remains to be determined if treatments that improve sleep measures can affect future cocaine taking.