Strain differences in delay discounting between Lewis and Fischer 344 rats at baseline and following acute and chronic administration of d-amphetamine

Stimulant drugs have been shown either to increase or decrease rates of delay discounting (impulsive choice). These mixed findings may result from genetic, neurochemical, or environmental factors. Lewis (LEW) and Fischer 344 (F344) rats have neurochemical and behavioral differences that may be relevant to delay discounting and were used to examine effects of acute and chronic administration of d-amphetamine (d-AMP) on impulsive choice using a within-session delay-discounting procedure. Male LEW (n = 8) and F344 (n = 8) rats chose between one food pellet delivered immediately and three food pellets delivered after an increasing delay. Saline and d-AMP (0.1, 0.3, 1.0, and 1.7 mg/kg) were tested acutely and during chronic d-AMP exposure. Choice for the larger reinforcer decreased as the delay to its presentation increased for both strains at baseline. LEW rats made more impulsive choices than F344 rats as indicated by shorter indifference points, and this is consistent with previous research. Acute administration of d-AMP dose dependently increased larger-reinforcer choice and area under the curve (AUC) for LEW, but not F344 rats. During chronic exposure to d-AMP, larger-reinforcer choice and AUC increased relative to acute administration for F344 rats responding in shorter delay series, but not for F344 rats responding in longer delay series or for LEW rats. Differential effects of acute and chronic administration of d-AMP on impulsive choice in LEW and F344 rats may be a result of various factors, including genetic, neurochemical, and environmental variables. Future research should attempt to tease apart the relative contribution of each of these factors on impulsive choice.     

High impulsivity in rats predicts amphetamine conditioned place preference

Stimulants such as d-amphetamine (AMPH) are used commonly to treat attention-deficit hyperactivity disorder (ADHD), but concerns have been raised regarding the use of AMPH due to its reinforcing and potentially addictive properties. The current study examined if individual differences in impulsive choice predict AMPH-induced hyperactivity and conditioned place preference (CPP). Rats were first tested in delay discounting using an adjusting delay procedure to measure impulsive choice and then were subsequently tested for AMPH CPP. High impulsive (HiI) and low impulsive (LoI) rats were conditioned across four sessions with 0.1, 0.5, or 1.5 mg/kg of AMPH. AMPH increased locomotor activity for HiI and LoI rats following 0.5 mg/kg but failed to increase activity following 0.1 and 1.5 mg/kg. CPP was established for HiI rats with both 0.5 and 1.5 mg/kg of AMPH, whereas LoI rats did not develop CPP following any dose of AMPH; HiI and LoI groups differed significantly following 0.5 mg/kg of AMPH. These results indicate that HiI rats are more sensitive to the rewarding effects of AMPH compared to LoI rats, which is consistent with research showing that high impulsive individuals may be more vulnerable to stimulant abuse.     

Intermittent methylphenidate during adolescent development produces locomotor hyperactivity and an enhanced response to cocaine compared to continuous treatment in rats

The consequences of chronic methylphenidate (MPH) administration in adolescents for the treatment of attention-deficit/hyperactivity disorder (ADHD) remain to be fully understood. Studies in rats indicate that the pharmacokinetics of psychostimulant administration can powerfully influence the behavioral and neural consequences of chronic treatment. The purpose of the present study was to assess the effects of intermittent (0.8 or 1.6 mg/kg, s.c., twice daily) versus continuous (1.6 or 3.2 mg/kg/day via osmotic minipump) MP administration across four weeks of adolescent development in rats. Results indicate that intermittent treatment produced hyperactivity in a novel open field and increased sensitivity to both the reinforcing and locomotor-activating effects of cocaine. In contrast, continuous MPH resulted in a hypoactive response to the novel open field and a reduced sensitivity to both operant and non-contingent cocaine. To the extent that the continuous release condition models the sustained-release formulations utilized in human ADHD treatment, we interpret these data to indicate that sustained-release formulations are less likely to advance a risk of subsequent substance abuse.     

In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: Involvement of dopamine D1 and alpha 2 adrenergic receptors

Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children. Psychostimulants such as methylphenidate (MPH) are used as first line treatment. The prefrontal cortex (PFC) has a proven role in the expression of ADHD. Previous studies from our laboratory have demonstrated that MPH activates the firing activity of medial PFC neurones in anaesthetised rats. The aim of the present study was to determine the respective contribution and location of the different types of catecholamine receptors in mediating these excitatory effects and to compare these effects with those induced by other selective dopamine or noradrenaline uptake blockers.Single unit activity of presumed pyramidal PFC neurones was recorded in rats anaesthetised with urethane. The activation of firing elicited by an iv administration of MPH (1 or 3 mg/kg) was partially reduced or prevented by the selective D1 receptor antagonist SCH 23390 administered systemically (0.5 mg/kg, iv), or locally by passive diffusion through the recording electrode. On the other hand, administration of the alpha 2 receptor antagonist yohimbine (1 mg/kg, iv) significantly potentiated the excitatory effect of MPH and activated PFC neurones previously treated with a low inactive dose of MPH (0.3 mg/kg, iv). Local administration of MPH (1 mM through the recording electrode) significantly increased the firing of PFC neurones in a D1 receptor-dependent manner. In addition, the response of PFC neurones to MPH, administered at a low dose (0.3 mg/kg, iv), is greatly potentiated by dopamine (1 mM), but not by noradrenaline (1 mM), diffusing passively through the recording electrode, and this effect is reversed by D1 receptor blockade. Finally, the selective dopamine uptake inhibitor GBR 12909 (6 mg/kg, iv) and desipramine (6 mg/kg, iv) only activate a subset of PFC neurones.These results demonstrate the involvement of cortical dopamine D1 and noradrenergic alpha 2 receptors in the in vivo electrophysiological effects of MPH on PFC neurones.     

Impulsive choice, as measured in a delay discounting paradigm, remains stable after chronic heroin administration

Heroin addicts display poorer impulse control than non-addicts, however it is not known if high impulsivity is a function of chronic heroin intake or a pre-disposing vulnerability for heroin addiction. Using animal models, relatively few studies have examined changes in impulsive choice as a function of chronic drug. The objective of this study was to measure alterations in impulsive choice through a delay discounting paradigm, as a function of chronic heroin administration. Animals were trained on a series of delay discounting sessions. Each session contained 5 blocks of trials. Blocks started with 2 forced, followed by 6 free choice trials. Pressing one lever resulted in the delivery of a small immediate (1 food pellet) reward and another lever in a large delayed (5 pellets) reward. Sessions consisted of the 3 ascending delay sequences in seconds. On the terminal sequence (0, 10, 20, 40, and 60 s) animals exhibited a reversal of reward choice pattern of responding that allowed for the calculation of an indifference point (IP). After animals showed stable IPs they were treated with either heroin or saline for 12 days. Three days after the last injection animals were again placed in operant chambers and experienced the terminal delay discounting sequence at which time IPs were reassessed. Heroin-treated animals exhibited significant progressive increases in locomotor activity. Groups did not differ in IPs or performance across delay conditions during either before or after chronic treatment periods. These results indicate that chronic heroin intake does not impact later impulsive responding for natural (food) reward.     

Preference reversals and effects of D-amphetamine on delay discounting in rats

Impulsive choice is correlated with behavioral problems such as attention-deficit/hyperactivity disorder and substance abuse. Effects of stimulant drug administration on impulsive choice are not consistent and may depend on baseline differences in impulsive choice. A within-session delay-discounting procedure in which choice was between one food pellet delivered immediately (impulsive choice) and three food pellets delivered after increasing delays (self-controlled choice) was used to determine effects of adding and subtracting delays common to both reinforcers on impulsive choice in male Sprague-Dawley rats (n=8). Delay discounting was observed and impulsive choice was quantified using area under the curve (AUC). Adding delays common to both reinforcers decreased impulsive choice and subtracting delays common to both reinforcers increased impulsive choice. Before administration of D-amphetamine (0.03-1.80 mg/kg, intraperitoneally), subjects were rank ordered into a low-AUC or a high-AUC group. Select doses of D-amphetamine decreased impulsive choice for subjects in the low-AUC group but not for subjects in the high-AUC group. These results indicate that impulsive choice can be altered by changing the delay common to both reinforcers and suggest that effects of D-amphetamine may depend, in part, on baseline differences in impulsive choice.     

A within-subject analysis of d-amphetamine exposure on delay discounting in rats

Studies concerning the relation between stimulant drug exposure and subsequent delay discounting (impulsive choice) have resulted in mixed findings that could be related to the type of stimulant drug exposure or the use of between-subject comparisons. The purpose of the present study was to examine effects of prior d-amphetamine exposure on subsequent delay discounting using a within-subject assessment. Two groups of rats were trained under a discrete-trials choice procedure until delay discounting was stable. One group of rats then received repeated administration of 3.0 mg/kg d-amphetamine in their home cage for 14 consecutive days, while the other group received saline. After a three-week drug-free period, delay discounting was reassessed. No significant differences in area under the curve within (before or after drug exposure) or between (saline or d-amphetamine) groups were found. Thus, delay discounting was not systematically affected following termination of repeated 3.0 mg/kg d-amphetamine exposure in the present experimental arrangement. The current results, coupled with past research, indicate that there may be a distinction between cocaine exposure and d-amphetamine exposure on subsequent delay discounting; however, within-subject comparisons of cocaine exposure on delay discounting are warranted.     

Safety evaluation of longan seed extract: Acute and repeated oral administration

Longan seed extract (LSE) contains high levels of beneficial polyphenolic compounds. The present study evaluated acute and repeated dose (4 and 13 weeks) toxicological effects of aqueous extract of longan seed to ensure the safety of utilization of this extract. Our study revealed that all treated animals survived through the whole experimental periods without adverse effects observed in either sex of animals after acute and repeated dose (4 and 13 weeks) oral administration of LSE. Likewise, growth pattern (body weights, food consumption, and relative organ weights), hematology analysis, and clinical biochemistry analysis in all LSE-treated animals were in normal physiological ranges. Moreover, histopathological finding of LSE-treated animals in repeated dose studies demonstrated no obvious alterations. Although the significant increment in food consumption of female rats (100 mg/kg, Week 4) and % eosinophil of male rats (400 mg/kg), and decrement in food consumption of male rats (250 mg/kg, Week 3 and 9) were observed, these alterations were not dose- and time-response relationships. Therefore, we concluded that acute and repeated dose (4 and 13 weeks) oral administration of LSE has no significant toxicological effects;hence it may be safe to use with caution pending its chronic toxicity study and/or clinical trial.     

The effects of chronic methylphenidate administration on operant test battery performance in juvenile rhesus monkeys

Methylphenidate (MPH) is an amphetamine derivative widely prescribed for the treatment of attention deficit–hyperactivity disorder. Recent concern over its genotoxic potential in children [11] spurred a study on the effects of chronic MPH treatment in a nonhuman primate population and the studies reported here were conducted in conjunction with that study in the same animals. Here, the focus was on the ability of juvenile rhesus monkeys to learn how to perform a battery of operant behavioral tasks while being treated chronically with MPH. Performance of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB) was used to quantify the learning of tasks thought to model specific aspects of cognitive function including learning, motivation, color and position discrimination, and short-term memory. The OTB tasks designed to assess these specific behaviors included Incremental Repeated Acquisition (IRA), Progressive Ratio (PR), Conditioned Position Responding (CPR), and Delayed Matching-to-Sample (DMTS), respectively. Juvenile males (n = 10/group) pressed levers and press-plates for banana-flavored food pellets. Subjects were treated orally, twice a day, five days per week (M–F) for 66 weeks with escalating doses (0.15 mg/kg initially, increased to 2.5 mg/kg for the low dose group and to 12.5 mg/kg for the high dose group) and tested in OTB tasks 30 to 60 min after the morning dose. The findings indicate that MPH at doses up to 2.5 mg/kg twice per day were well tolerated (performance was no different than controls) but at doses of 12.5 mg/kg twice per day there was a significant decrement in OTB performance, characterized by decreases in both percent task completed and response rates for all tasks. These effects of MPH seem primarily due to decreases in motivation to perform for food, which is not surprising given the well known appetite suppressing effects of amphetamine-like stimulants. Thus, the current data do not strongly suggest cognitive impairments following chronic MPH administration.     

Methylphenidate alters monoaminergic and metabolic pathways in the cerebellum of adolescent rats

Abnormalities in the cerebellar circuitry have been suggested to contribute to some of the symptoms associated with attention deficit hyperactivity disorder (ADHD). The psychostimulant methylphenidate (MPH) is the major drug for treating this condition. Here, the effects of acute (2.0?mg/kg and 5.0?mg/kg) and chronic (2.0?mg/kg, twice daily for 15 days) MPH treatments were investigated in adolescent (35–40 days old) rats on monoaminergic and metabolic markers in the cerebellum. Data acquired indicates that acute MPH treatment (2.0?mg/kg) decreased cerebellar vesicular monoamine transporter (VMAT2) density, while chronic treatment caused an increase. In contrast, protein levels of tyrosine hydroxylase (TH) and the dopamine D1 receptor were not significantly altered by neither acute nor chronic MPH treatment. In addition, while chronic but not acute MPH treatment significantly enhanced dopamine turnover (DOPAC/dopamine) in the cerebellum, levels of dopamine and homovanillic acid (HVA) were not altered. Acute MPH (5.0?mg/kg) significantly modified levels of a range of cerebellar metabolites with similar trends also detected for the lower dose (2.0?mg/kg). In this regard, acute MPH tended to decrease cerebellar metabolites associated with energy consumption and excitatory neurotransmission including glutamate, glutamine, N-acetyl aspartate, and inosine. Conversely, levels of some metabolites associated with inhibitory neurotransmission, including GABA and glycine were reduced by acute (5.0?mg/kg) MPH, together with acetate, aspartate and hypoxanthine. In conclusion, this study demonstrated that MPH alters cerebellar biochemistry, and that this effect depends on both dose and duration of treatment. The therapeutic significance of these results requires further investigation.     

Effects of olanzapine on extracellular concentrations and tissue content of neurotensin in rat brain regions

We have previously shown that both the psychostimulant d-amphetamine and the antipsychotics haloperidol and risperidone affect extracellular concentrations and tissue content of neurotensin (NT) in distinct brain regions. This study investigated the effects of acute olanzapine (1, 5 mg/kg, s.c.) on extracellular NT-like immunoreactivity (− LI) concentrations in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC), and the effects of acute d-amphetamine (1.5 mg/kg, s.c.) on extracellular NT-LI in these brain regions after a 30-day olanzapine (15 mg/kg, p.o.) administration in rats. The effects of a 30-day olanzapine (3, 15 mg/kg, p.o.) administration and d-amphetamine (1.5 mg/kg, s.c.) coadministration during either the last day (acute) or the last 8 days (chronic) on NT-LI tissue content in distinct rat brain regions were also studied. Acute olanzapine increased extracellular NT-LI, in both the vSTR and the mPFC. Chronic olanzapine increased and decreased basal extracellular NT-LI in the vSTR and the mPFC, respectively, and abolished the stimulatory effects of acute d-amphetamine on extracellular NT-LI in these brain regions. Chronic olanzapine as well as acute and chronic d-amphetamine affected NT-LI tissue content in a brain region-dependent manner. Chronic olanzapine prevented the effects of acute and chronic d-amphetamine on NT-LI tissue content in certain brain regions. The fact that olanzapine and d-amphetamine affected extracellular NT-LI in the vSTR and mPFC as well as NT-LI tissue content in distinct brain regions further supports the notion that NT plays a role in the therapeutic actions of antipsychotic drugs and possibly also in the pathophysiology of schizophrenia.     

Effects of acute and chronic nicotine on impulsive choice in rats

Impulsive choice, or preference for small immediate reinforcers over large delayed reinforcers, has been associated with cigarette smoking. The direct effects of nicotine on impulsive choice in laboratory animals are unknown. We examined the effects of acute and chronic nicotine injections, and the termination of injections, on impulsive choice in rats. Five rats made choices between a one- and a three-pellet reinforcer in a discrete trials procedure. The delay to the smaller reinforcer was always 1 s. A computer adjusted the delay to the larger reinforcer until the pattern of choices reflected indifference between the two alternatives. We assessed the effects of acute and chronic nicotine (vehicle, 0.03, 0.1, 0.3 and 1.0 mg/kg nicotine). The latency to make the first response of the session increased under the acute 1.0 mg/kg dose. There were no consistent differences in the effects of acute and chronic nicotine on response latency and lever pressing during the delays between choices. Acute injections of nicotine dose-dependently increased impulsive responding. After chronic injections, impulsive responding was increased equivalently regardless of dose, and it was increased even in the absence of nicotine. After drug injections were terminated, behavior remained impulsive for about 30 drug-free sessions, and then responding gradually returned to baseline levels. The results suggest that increases in impulsive choice were not due to anorectic effects, response biases or changes in conditioned reinforcement. Nicotine may have decreased the value of delayed reinforcers. Chronic nicotine exposure produced long-lasting but reversible increases in impulsive choice.     

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.     

Acetyl-l-carnitine reduces impulsive behaviour in adolescent rats

The attention deficit/hyperactivity disorder (ADHD) can affect human infants and adolescents. One important feature of this disorder is behavioural impulsivity. This study assessed the ability of chronic acetyl-l-carnitine (ALC, saline or 100 mg/kg SC, plus 50 mg/kg orally) to reduce impulsivity in a validated animal model for ADHD. Food-restricted rats were tested during adolescence (postnatal days, pnd, 30–45) in operant chambers with two nose-poking holes, one delivering one food pellet immediately, and the other five pellets after a delay. Delay length was increased over days (from 0 to 80 s). Individual differences in the preference-delay curve emerged, with the identification of two distinct subpopulations, i.e. one with a nearly horizontal curve and another with a very steep (impulsive) slope. The impulsivity profile was slightly but consistently reduced by chronic ALC administration. Consistent results were also obtained with methylphenidate (MPH, saline or 3 mg/kg IP twice daily). Impulsive rats exhibited a lower metabolite/serotonin (5HIAA/5HT) ratio in the medial frontal cortex (MFC) and lower noradrenaline (NA) levels in the MFC and cingulate cortex (CC) when compared with the other subgroup. The ALC treatment increased NA levels in the CC and the 5HIAA/5HT ratio in both CC and MFC. Present data suggest that ALC, a drug devoid of psychostimulant properties, may have some beneficial effects in the treatment of ADHD children.     

Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex

Rationale Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT_1A agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats.Objectives Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT_1A antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats.Methods In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex.Results Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT_1A receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition.Conclusions These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT_1A receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.     

Differential effects of acute and chronic treatment with the α2-adrenergic agonist,lofexidine, on cocaine self-administration in rhesus monkeys

Background

Lofexidine, an α₂-adrenergic agonist, is being investigated as a treatment for reducing opioid withdrawal symptoms and blocking stress-induced relapse to cocaine taking. Opioid abusers are often polydrug abusers and cocaine is one frequent drug of choice. However, relatively little is known about lofexidine interactions with cocaine. The present study investigated the effects of acute and chronic treatment with lofexidine in a pre-clinical model of cocaine self-administration.

Methods

Male rhesus monkeys were trained to respond for food (1 g) and cocaine (0.01 mg/kg/injection) under a fixed ratio 30 (FR30) or a second order FR2 (VR16:S) schedule of reinforcement. Systematic observations of behavior were conducted during and after chronic treatment with lofexidine.

Results

Acute treatment with lofexidine (0.1 or 0.32 mg/kg, IM) significantly reduced cocaine self-administration but responding for food was less effected. In contrast, chronic treatment (7–10 days) with lofexidine (0.1–0.32 mg/kg/h, IV) produced a leftward shift in the cocaine self-administration dose–effect curve, but had no effect on food-maintained responding. Lofexidine did not produce any observable side effects during or after treatment.

Conclusions

Lofexidine potentiated cocaine's reinforcing effects during chronic treatment. These data suggest that it is unlikely to be effective as a cocaine abuse medication and could enhance risk for cocaine abuse in polydrug abusers.     

The psychopharmacology of impulsive behaviour in rats VIII: effects of amphetamine,methylphenidate, and other drugs on responding maintained by a fixed consecutive number avoidance schedule

Rationale Impulsive behaviour is a component of psychiatric disorders such as bipolar disorder, attention deficit hyperactivity disorder (ADHD), or personality disorders. Most experimental studies on impulsive behaviour punish impulsive choices by loss or delay of reward. In the present study, impulsive behaviour was punished by an explicitly aversive stimulus, using a novel fixed consecutive number (FCN) schedule of electric shock avoidance.Objectives This study was conducted to demonstrate stable performance using the FCN avoidance procedure, and examine the effects of drugs previously shown to affect impulsive behaviour using a conventional FCN schedule.Methods First, rats were trained in the appetitive FCN procedure. Pressing the right lever in an operant conditioning chamber after having pressed the left lever at least six times delivered a food pellet (FCN6). Responses on the right lever before completing this ratio resulted in a time out and restarted the ratio. The rats were then switched to FCN avoidance. Responses on the right lever made before completion of the ratio also resulted in food delivery, but were accompanied by an electric shock.Results Chlordiazepoxide (10.0 mg/kg), ethanol (1.0 g/kg), and haloperidol (0.1 mg/kg) increased impulsive behaviour by reducing the number of left lever responses made before the right lever was pressed. Imipramine (1.0–10.0 mg/kg) and desipramine (1.0–10.0 mg/kg) had no effect on impulsive choice. Amphetamine (0.4 and 0.8 mg/kg) and methylphenidate (6.0 mg/kg) significantly increased the mean chain length, and the proportion of very long chains, indicative of reduced impulsivity, although this did not improve efficiency.Conclusions The increases in impulsivity produced by chlordiazepoxide, ethanol, and haloperidol were similar to those under appetitive FCN schedules. In contrast, amphetamine and methylphenidate, by reducing impulsivity in the FCN avoidance, induced effects opposite to those observed in an appetitive FCN procedure. These results suggest that the therapeutic actions of stimulants, to reduce impulsive behaviour in ADHD, may arise in part by increasing the control of behaviour by aversive stimuli.     

Methylphenidate restores visual memory,but not working memory function in attention deficit-hyperkinetic disorder

Rationale Dysfunction of executive neuropsychological performance, mediated by the prefrontal cortex, has been the central focus of recent attention deficit/hyperkinetic disorder (AD-HKD) research. The role of other potential neuropsychological risk factors, such as recognition memory, remains understudied. Further, the impact of methylphenidate (MPH) on key neuropsychological processes in AD-HKD remains poorly understood.Objectives To compare the performance of boys with AD-HKD on a spatial working memory (SWM) task and on two non-working memory tasks [a simultaneous and delayed matching-to-sample task (DMtS) and a pattern-recognition task] with that of healthy boys, and to investigate the impact of acute and chronic MPH on performance of these tasks.Methods Baseline performance of 75 stimulant-naive boys with AD-HKD was compared with that of 70 healthy boys. The AD-HKD boys were then re-tested following the administration of acute and chronic challenges with MPH (0.3 mg/kg and 0.6 mg/kg) under randomised double-blind placebo controlled conditions.Results Compared with healthy boys, the AD-HKD boys demonstrated performance deficits on all neuropsychological tasks. A single dose of MPH restored performance on the DMtS task but had no impact on the SWM or pattern-recognition tasks. Chronic MPH administration did not alter performance on the SWM task but did improve performance on both the pattern-recognition and DMtS tasks. However, the acute restorative effect of MPH on DMtS diminished with repeated administration.Conclusions Our results suggest that current conceptualisations of the neuropsychological basis of AD-HKD and the proposed therapeutic mechanisms of MPH require broadening.     

Cognitive impulsivity in animal models: Role of response time and reinforcing rate in delay intolerance with two-choice operant tasks

Impulsivity, a key symptom of ADHD (attention-deficit hyperactivity disorder), is also common in obsessive-compulsive and addictive disorders. There is rising interest in animal models of inhibitory-control impairment. Adolescent rats were tested daily in the intolerance-to-delay (ID) task (session 25 min, timeout 20 s), involving choice between either immediate small amount of food (SS), or larger amount of food after a delay (LL). The mixed 5-HT(1A/7) agonist (8-OH-DPAT, 0 or 0.060 mg/kg i.p.) was administered acutely just before the last three sessions at highest delays. In addition to the classical choice parameter (percent LL preference), the spontaneous waiting (termed response time, RT) occurring between end of a timeout (TO) and next nose-poke was calculated. The pace between consecutive reinforcer deliveries is given by the mean inter-trial interval (mITI, i.e. TO + RT). Hence, the impact of any given delay may be proportional to this pace and be expressed as delay-equivalent odds, i.e. the extent by which delays are multiples of the mITI. Data revealed that RT/mITI increased sharply from around 15 s/35 s to around 30 s/50 s when imposed delay changed from 30 s to 45 s (i.e. odds from 0.91 to 1.06). This suggests that rats adopted a strategy allowing them to keep in pace with perceived reinforcing rate. The increasing delay constraint directly influenced the length of rats' spontaneous waiting (RT) before next decision. For higher delays, with odds >1, rats shifted to a clear-cut SS preference, which is devoid of any exogenous temporal constraint. A challenge with 8-OH-DPAT (0 or 0.060 mg/kg i.p.) decreased impulsive choice but also increased RT. Thus, tapping onto 5-HT(1A/7) receptors slightly enhanced RT/mITI values, possibly reflecting ability of rats to cope with slower reinforcing rates and/or with delay-cancelled reward paces. In summary, delay-induced states of aversion may arise from the innate tendency to rely on a regular rate of reinforcement. Conversely, a drug-enhanced capacity to cope with delay may involve an internal ability to adjust expectancy about such a reinforcing rate.     

The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice

The concomitant use of alcohol (EtOH) and the psychotherapeutic agent dl-methylphenidate (MPH) has risen as a consequence of an increase in ADHD diagnoses within the drinking age population. It was recently found that the combination of MPH and EtOH increases the self-report of pleasurable feelings relative to MPH alone. This finding raises concerns regarding the combined abuse liability for these two widely used drugs. The present behavioral study reports on the development of an adult male C57BL/6J (B6) mouse model to further characterize this MPH-EtOH interaction. We examined the effects of MPH on EtOH consumption in a limited access paradigm and EtOH stimulation of locomotor activity. B6 mice consumed about 2 g/kg EtOH daily and MPH dose-dependently reduced drinking. The most effective dose of MPH was 1.25 mg/kg, which produced a 41% decrease in drinking and had no effect on locomotor activity. However, when the 1.25 mg/kg dose of MPH was combined with a stimulatory dose of ethanol (1.75 g/kg) by intraperitoneal injection, there was a significantly enhanced stimulation of locomotor activity. The drug combination increased activity compared to the vehicle or MPH injections by 45% and increased the activity relative to EtOH alone by an additional 25%. The results of the EtOH and MPH interactions observed with the mouse model appear to be behaviorally relevant and suggest several converging mechanisms that may underlie MPH-EtOH interactions.