The pharmacology of impulsive behaviour in rats II: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and other drugs on fixed consecutive number schedules (FCN 8 and FCN 32)

 The effects of drugs on one aspect of impulsive behaviour were evaluated using a schedule in which rats were trained to complete a fixed consecutive number of responses on one of two levers before pressing the second to obtain a reinforcer (FCN). Terminating the chain before completing the FCN resulted in the omission of the food, and can be considered an impulsive decision. Two groups of food-deprived rats were trained to press either 8 or 32 times on the left lever (FCN lever) of a two lever operant chamber before pressing the right lever (Reinforcement lever) to deliver a food pellet. Responding on the Reinforcement lever before completion of the sequence resulted in a short time-out and the rat had to begin the sequence again. After responding had stabilised, the rats were treated with a range of doses of a number of drugs. Impulsivity was assessed by several measures, including the mean chain length and the proportion of chains terminating in food delivery, and the distribution of chain lengths was analysed. The efficiency of the rats was similar under both FCN 8 and FCN 32, although it was more difficult to maintain a consistent baseline under FCN 32. Under the FCN 8 schedule, significant decreases in chain length were obtained with d-amphetamine (0.8–2.4 mg/kg), haloperidol (0.1 mg/kg), ethanol (1 and 3 g/kg) and chlordiazepoxide (10.0 mg/kg), and there were alterations in other measures consistent with an increase in impulsivity. Imipramine (1–10 mg/kg), citalopram (1–10 mg/kg) and metergoline (0.3–3.0 mg/kg) had no effect on mean chain length, although the first two drugs shifted the chain length distribution to the left. d-Amphetamine (0.4–1.2 mg/kg) and PCPA (100 mg/kg) reduced chain length and had other effects consistent with increased impulsivity under FCN 32 schedule, whereas imipramine had little, and citalopram no, effect. Taken generally, effect of the active drugs was relatively non-specific, including both a reduction in response rate and alterations in choice measures proposed to reflect an increase in impulsivity. Detailed analysis of the effect of amphetamine revealed that three processes were at work: chain shortening, an increased preference for the lever most closely associated with food delivery, and a gradual shift in the control over responding from the response sequence (pattern) to the individual lever press (act). Received: 24 April 1997 / Final version: 14 January 1998     

The pharmacology of impulsive behaviour in rats III: the effects of amphetamine, haloperidol, imipramine, chlordiazepoxide and ethanol on a paced fixed consecutive number schedule

 The behavioural trait of impulsivity may be made up of different components, including rapid decision making, intolerance to the delay of reward and a tendency to terminate chains of responses prematurely. It has been proposed to measure the last of these in rats using fixed consecutive number (FCN) schedules. The present study uses a modified version of the FCN procedure in which responding was paced by retracting the response lever for short periods between presses. In this way, the experimenter could control the maximum rate of responding. The procedure was made up of two components based on an FCN 8 schedule of food reinforcement. In the Fast component, lever presses were spaced by a minimum of 2 s and in the Slow component by a minimum of 5 s. The average chain length was significantly shorter, and the rats were less efficient in the Slow component. Five drugs were tested on this baseline, imipramine (1.0–10.0 mg/kg), ethanol (300–3000 mg/kg administered PO), haloperidol (0.01–0.1 mg/kg), chlordiazepoxide (1.0–10.0 mg/kg) and d-amphetamine (0.2–0.8 mg/kg). All the drugs reduced responding at the highest dose, but imipramine was different from the others in that it increased the average number of responses in the chain and produced a shift in the chain length distribution to the right, possibly reflecting a reduction in impulsivity. The other four drugs reduced chain length at the highest dose, although in the case of ethanol this effect was very small and, unlike the other three drugs, did not result in a shift in the distribution to the left. The paced FCN procedure can differentiate the effects of different drugs on one aspect of impulsivity, and is likely to be a useful procedure for further study of this aspect of behaviour. Received: 24 April 1997 / Final version: 14 January 1998     

Reduction of impulsivity with amphetamine in an appetitive fixed consecutive number schedule with cue for optimal performance in rats

Rationale Impulsivity is a key feature of many psychopathologies such as mania, personality disorders or attention deficit–hyperactivity disorder (ADHD). Most experimental paradigms assessing impulsive behaviour also require non-specific capacities such as time estimation. This may interact with the measures and mask the beneficial effects of psychostimulants—the most commonly used treatment for ADHD—on impulsivity, given that these drugs speed up the internal clock. Objectives The present experiment investigated the effects of suppressing behaviours non-specific to impulsivity in a fixed consecutive number (FCN) schedule and examined whether amphetamine, previously shown to increase impulsive responses in this task, could have beneficial effects when impulsive responses are promoted. Materials and methods Food-deprived rats were trained to press one lever of a two-lever operant chamber eight times before pressing the other lever to obtain food. Premature ending of responses resulted in absence of food delivery and reset the counter. A cue light indicating the required number of presses was present (FCN8_cue) and removed after training (FCN8). Rats were then trained under an FCN16_cue schedule to be challenged with d-amphetamine (0.125, 0.25 and 0.5 mg/kg). Results The cue improved performances, and similar scores were obtained under FCN16_cue compared to FCN8. Premature responses under these two conditions were unrelated. Amphetamine reduced impulsive responses in FCN16_cue at the lower dose. Conclusions Suppression of capacities non-specific to impulsivity in the FCN schedule, associated with conditions that permit the expression of inhibitory deficits, allows the beneficial effects of psychostimulants observed clinically to be evidenced experimentally.     

The behavior of spontaneously hypertensive and Wistar Kyoto rats under a paced fixed consecutive number schedule of reinforcement.

Spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) were trained under paced FCN schedules of reinforcement to complete a minimum number of consecutive responses on one lever, before responding on a second. The levers were retracted from the test chamber for a short period after each response to control the speed at which the rats could complete the sequence (paced FCN). Changes in the average chain length may reflect the influence of impulsivity on the execution of behavioral patterns. Although they quickly learned to press the levers, SHR rats performed poorly compared to the WKY rats when the chain length requirement was increased to FCN 6 and FCN 8. Eventually stable performance was obtained under paced FCN 6, although the SHR rats continued to have a consistently lower average chain length. Both strains of rats were treated with imipramine (10 mg/kg), chlordiazepoxide (3 and 10 mg/kg), d-amphetamine (0.4 and 0.8 mg/kg), haloperidol (0.05 and 0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), WAY-100635 (0.1 mg/kg), and DOI (0.3 and 1.0 mg/kg). The SHR rats were less sensitive to the effects of d-amphetamine, chlordiazepoxide, and DOI and slightly more sensitive to the effects of haloperidol. All of these drugs reduced the average chain length. There was no difference in the response of the two strains to imipramine and 8-OH-DPAT, both of which increased the average chain length. These results support the suggestion that SHR rats may more impulsive than WKY rats. The data with d-amphetamine and haloperidol support biochemical findings that these rats have a deficit in dopaminergic function, and the strain differences in response to chlordiazepoxide and DOI suggest that that there may be differences in GABAergic and 5-HT2-mediated neurotransmission relevant to regulating impulse control in the rat.     

The pharmacology of impulsive behaviour in rats IV: the effects of selective serotonergic agents on a paced fixed consecutive number schedule

An impulsive cognitive style may affect behaviour in several different ways, including rapid decision making, intolerance of the delay of reward and a tendency to terminate chains of responses prematurely. It has been proposed to measure the last of these in rats using fixed consecutive number (FCN) schedules. The present study uses a modified version of the FCN procedure in which responding was paced by retracting the response lever for short periods between presses. In this way, the experimenter can control the maximum rate of responding. The procedure was made up of two components. In both, the schedule requirement was FCN 8, but in the Fast component lever presses were spaced by a minimum of 2.5?s and in the Slow component by a minimum of 5?s. Alterations in impulsivity were inferred from changes in the mean chain length and the distribution of chain lengths. The 5-HT_1A agonist, 8-OH-DPAT (0.03–0.3?mg/kg), increased chain lengths within a narrow dose range, whereas the 5-HT_1A antagonist, WAY 100 635 (0.03–0.3?mg/kg), reduced chain lengths. The 5-HT₂ agonist, DOI (0.1–1.0?mg/kg), markedly reduced chain lengths, whereas the 5-HT₂ antagonist, ritanserin (0.03–0.3?mg/kg), had no effect. The 5-HT_1A/1b agonist, RU 24969 (0.03–0.3?mg/kg), reduced chain lengths. The 5-HT releaser, p-chloramphetamine (0.1–1.0?mg/kg), had a weak, biphasic effect, slightly reducing the number of short chains at the lowest dose tested and slightly increasing this number at the highest dose. Other drugs tested, citalopram (1.0–10.0?mg/kg), metergoline (0.3–3.0?mg/kg) and MDL-72222 (0.1–3.0?mg/kg), had no significant effects. These results suggest that stimulation of 5-HT_1A receptors reduces impulsivity, whereas stimulation of 5-HT₂ receptors increases it. These data are in agreement with previous results using the DRL-72 schedule, and indicate that there is no simple role for serotonin in the control of impulsivity.     

Methylphenidate reduces impulsive behaviour in juvenile Wistar rats, but not in adult Wistar, SHR and WKY rats

Rationale Impulsivity is a core symptom of attention deficit/hyperactivity disorder (ADHD). The spontaneously hypertensive rats (SHR) is a strain commonly used as an animal model of ADHD. However, there is no clear evidence that psychostimulants, which are used for treatment of ADHD, reduce impulsivity in SHR. Because ADHD mainly affects children, it may be relevant to study psychostimulants on juvenile animals. Objectives Using tolerance to delay of reward as index of impulsivity, the effects of methylphenidate were assessed in adult SHR, Wistar Kyoto (WKY) and Wistar rats and in juvenile Wistar rats. Materials and methods Animals were trained in a T-maze to choose between a small-but-immediate and a large-but-delayed reward. Adult SHR, WKY and Wistar rats were compared for their ability to tolerate a 15-s delay. The effect of methylphenidate on the tolerance to a 30-s delay was studied in adult rats of the three strains and in juvenile (4.5 to 6.5-week-old) Wistar rats. Results In adult rats, the waiting ability was lower in SHR than in control strains. Waiting ability was improved by methylphenidate (3 and 5 mg/kg) in juveniles, but not by methylphenidate (3 mg/kg) in adults. Conclusions These data support the idea that SHR are more impulsive than control strains. However, at the dose studied, methylphenidate fails to improve tolerance to delay in adult rats whatever the strain used. The reduction of impulsivity induced by methylphenidate in juvenile Wistar rats indicates that juvenile animals may be suitable for testing the therapeutic potential of drugs intended to the treatment of ADHD in children.     

Effect of methylphenidate on attention in children with attention deficit hyperactivity disorder (ADHD): ERP evidence.

Methylphenidate is the most common treatment for attention deficit hyperactivity disorder (ADHD) and has been shown to improve attention and behaviour. However, the precise nature of methylphenidate on specific aspects of attention at different dose levels remains unclear. We studied methylphenidate effects in ADHD from a neurophysiological perspective, recording event-related potentials (ERPs) during attention task performance in normal controls and children with ADHD under different dose conditions. Twenty children with ADHD and 20 age matched controls were assessed with a continuous performance task requiring subjects to identify repeating alphabetic characters. ERPs and behavioural measures were recorded and analyzed for trials where a correct response was made. The ADHD group was assessed off drug (baseline) and on placebo, low (0.28 mg/kg) and high (0.56 mg/kg) dose levels of methylphenidate. The results showed that the ADHD group at baseline was more impulsive and inattentive than controls and had shorter P2 and N2 latencies and longer P3 latencies. Low dose methylphenidate was associated with reduced impulsivity (fewer false alarms) and decreased P3 latencies, whereas the higher dose level was associated with reduced impulsivity and less inattention (more hits), as well as increased P2 and N2 latencies and decreased P3 latencies. Amplitudes were unaffected and there were no adverse effects of the higher dose for any of the children. These results suggest differential dosage effects and a dissociation between dose levels and aspects of processing.     

Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder

The validity of the Spontaneously Hypertensive rat (SHR) as a model for Attention Deficit Hyperactivity Disorder (ADHD) is explored by comparing the SHR with Wistar-Kyoto (WKY) and Wistar rats in a number of different tests. In the open field, SHR are hyperactive compared to both Wistar and WKY, but only at specific ages. At those ages, methylphenidate (1mg/kg) did not attenuate hyperactivity. Subsequently, a dose response study of methylphenidate (0.1-10mg/kg) was conducted in the Differential Reinforcement of Low-rate responding (DRL)-72s and five-choice serial reaction time tests (5-CSRTT). Compared to WKY but not Wistar rats, SHR performed worse on the DRL-72s. Performance was not improved by methylphenidate (0.1-1.0mg/kg). In the 5-CSRTT, attentional performance was similar for all rat strains, but Wistar rats made more impulsive responses than both the SHR and the WKY. Methylphenidate only attenuated impulsivity in Wistar rats. Because SHR do not consistently display symptoms of ADHD across the different tests, and methylphenidate effects were observed in both WKY and Wistar rats, but not in SHR, we conclude that SHR is not a representative animal model for ADHD.     

The neuropharmacology of impulsive behaviour

Impulsivity is a heterogenous phenomenon encompassing several behavioural phenomena that can be dissociated neuroanatomically as well as pharmacologically. Impulsivity is pathological in several psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), drug addiction and personality disorders. Pharmacological agents alleviating impulsivity therefore might substantially aid the treatment of these disorders. The availability of preclinical models that measure various forms of impulsivity has greatly increased our understanding of its neuropharmacological substrates. Historically, deficits in central serotonin neurotransmission are thought to underlie impulsivity. Accumulating evidence also points towards an important role of brain dopamine and noradrenaline systems in impulsive behaviour, consistent with the therapeutic efficacy of amphetamine, methylphenidate and atomoxetine in ADHD. However, recent findings also implicate glutamate and cannabinoid neurotransmission in impulsivity. In this review, we will discuss some of the recent developments in the neuropharmacological manipulation of impulsive behaviour.     

Pharmacological characterization of performance on a concurrent lever pressing/feeding choice procedure: effects of dopamine antagonist,cholinomimetic, sedative and stimulant drugs

This experiment was undertaken to provide a pharmacological characterization of performance on a task involving food-related instrumental and consummatory behavior. Rats were tested in an operant chamber in which there was a choice between pressing a lever to receive a preferred food (Bioserve pellets) or approaching and consuming a less-preferred food (Lab Chow). The lever pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the lever pressing schedule. Previous work has shown that injection of dopamine (DA) antagonists, or depletion of DA in the nucleus accumbens, caused a substantial shift in behavior such that lever pressing was reduced but chow consumption increased. In the present study it was shown that the DA antagonist haloperidol decreased lever pressing and increased chow consumption at doses of 0.1 and 0.15 mg/kg. The D1 antagonist SCH 23390 (0.05, 0.1 and 0.15 mg/kg) and the non-selective DA antagonistcis-flupenthixol (0.3 and 0.45 mg/kg) decreased lever pressing and produced substantial increases in chow consumption. The D2 antagonist sulpiride decreased lever pressing, but produced only slight increases in chow intake at the highest dose. Pentobarbital reduced lever pressing and increased chow consumption at 10.0 mg/kg. The muscarinic agonist pilocarpine produced dose-related decreases in lever pressing, but failed to increase chow consumption. Amphetamine produced dose-related decreases in both lever pressing and chow consumption. These results indicate that low/moderate doses of the DA antagonists haloperidol,cis-flupenthixol and SCH 23390 can suppress lever pressing in doses that leave the animal directed towards food acquisition and consumption.     

Symmetrical effects of amphetamine and alpha-flupenthixol on conditioned punishment and conditioned reinforcement: contrasts with midazolam

 In a test of conditioned punishment, saline-treated controls showed a moderate bias in responding away from a lever producing a response-contingent auditory conditioned stimulus (CS) that had been paired with mild footshock during training and towards a lever producing a neutral auditory CS. Systemic treatment with the indirect dopamine (DA) agonist amphetamine (0.25–1.0 mg/kg) produced a dose-dependent increase in the punishing effect of the aversive CS, whilst responding on the neutral CS lever was unchanged. Treatment with the dopamine-receptor antagonist α-flupenthixol (0.125, 0.25 mg/kg) decreased the efficacy of the punishing CS, but again left responding on the neutral lever unchanged. The benzodiazepine midazolam (0.1, 0.3 mg/kg) had a similar effect to α-flupenthixol, but treated animals showed a preference for the aversive CS. Parallel results were observed with amphetamine (0.25 mg/kg) and α-flupenthixol (0.125, 0.25 mg/kg) in a matched test of positive conditioned reinforcement, with amphetamine enhancing, and α-flupenthixol reducing, the efficacy of the CS paired with food. Midazolam treatment (0.1–1.0 mg/kg) had no effect on the reinforcing impact of an appetitive CS. Thus dopaminergic agents modulate the behavioural impact of both appetitively and aversively motivated conditioned stimuli on instrumental performance, whilst the benzodiazepine midazolam has a selective impact on aversively-motivated stimuli that is qualitatively distinct from that of the dopaminergic antagonist α-flupenthixol. Received: 27 March 1996 / Final version: 6 August 1996     

Role of dopamine D3 receptors in the expression of conditioned fear in rats

There has been considerable interest in the role of dopamine D(3) receptors in appetitive conditioning but few studies have examined their role in aversive conditioning. The present study examined the effect of the dopamine D(3) receptor-preferring partial agonist BP 897 (1-(4-(2-naphthoyl-amino)butyl)-4-(2-methoxyhenyl)-1A-piperazine hydrochloride) and the selective dopamine D(3) receptor antagonist SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]syclohexyl]4-quinolininecarboxamide]) on the expression and acquisition of fear conditioning. Rats (N=143) received 3 conditioned stimulus-shock pairings and then received 15 conditioned stimulus-alone presentations (3 per day) while lever pressing for food. Response suppression was taken as the behavioral measure of fear. Rats showed strong suppression to the conditioned stimulus after it had been paired with shock and suppression progressively weakened over conditioned stimulus-alone presentations. In experiment 1, rats that received BP 897 (1.0, 2.0 mg/kg i.p.) or SB-277011A (10.0 mg/kg i.p.) prior to conditioned stimulus-alone presentation sessions showed reduced suppression to the conditioned stimulus as compared to rats that received vehicle or lower doses of drug (0, 0.1 mg/kg BP 897; 0, 0.5, 5.0 mg/kg SB-277011A). Injections of BP 897 (1.0, 2.0 mg/kg) or SB-277011A (10.0 mg/kg) prior to conditioned stimulus-shock pairings did not significantly affect subsequent response suppression. Thus, BP 897 and SB-277011A dose-dependently attenuated the expression but not the acquisition of conditioned fear. These findings suggest that BP 897 and SB-277011A reduce the control of responding by aversively conditioned stimuli.     

Inhibition of apomorphine-, bromocriptine- and lergotrile-induced circling behaviour in rats by subsequent haloperidol administration

Circling behaviour produced in unilateral nigro-strlatal lesloned rats by apomorphine (0.5 mg/kg) Is markedly Inhibited by haloperidol (0.5 or 1.0 mg/kg) when given either 10 minutes before or 10 minutes after the apomorphine.Haloperidol (0.5 or 1.0 mg/kg) given 10 minutes before either bromocriptine (3 mg/kg) or lergotrile (3 mg/kg) totally inhibited circling induced by these ergots. When haloperidol (0.5 or 1.0 mg/kg) was given 90 minutes after Initiation, by these ergots,of circling behaviour,it also rapidly inhibited the turning.This contrasts with the observation that the vasodilator effects of bromocrlptine in the femoral vasculature of the dog are not reversed by subsequent haloperidol administration and also with an earlier report on the failure of haloperidol to inhibit lergotrile Induced circling behaviour.Possible reasons are discussed.     

Modulation of cholinergic activity and the aversive threshold in the rat

The analgesic potency of atropine sulfate (5.0, 10.0, 20.0, 40.0 mg/kg), eserine sulfate (0.5, 1.0, 1.5 mg/kg), pilocarpine nitrate (5.0, 10.0, 20.0 mg/kg), scopolamine methylbromide (0.5, 1.0 mg/kg) and scopolamine hydrobromide (1.0 mg/kg) was measured in the rat using the spatial preference technique. Enhanced cholinergic tone via the administration of eserine or pilocarpine in conjunction with scopolamine methylbromide produced significant increments in the aversive threshold. These increments could not be accounted for solely by changes in motor activity or the debilitating effects of enhanced peripheral cholinergic stimulation. None of the anticholinergics tested affected the aversive threshold. Scopolamine hydrobromide (1.0 mg/kg), however, was able to fully block the increments in the aversive threshold noted after the administration of pilocarpine (10.0 mg/kg). These results were interpreted to suggest that agents which enhance cholinergic tone can produce significant analgesia in the rat. While no firm conclusions can be made without further evidence, especially with regard to the antianalgesic effects of the anticholinergics, it is possible that central cholinergic mechanisms may mediate the aversive qualities of electric shock in the rat.     

Effects of acute and chronic methylphenidate on delay discounting

Methylphenidate (MPH) is one of the most common therapeutics used for the treatment of attention-deficit/hyperactivity disorder (ADHD), which consists of symptoms of inattention, and/or impulsivity and hyperactivity. Acute administration of MPH has been found to decrease impulsive choice in both humans and nonhuman animals, however, little is known about potential long-term changes in impulsive choice due to chronic administration of MPH. In the present experiment, effects of acute and chronic MPH (1.0-10.0 mg/kg) were assessed on impulsive choice in the adult male Spontaneously Hypertensive Rat (SHR) to determine the extent of behavioral changes after chronic MPH exposure. Subjects chose between an immediate single food pellet and three food pellets delivered after a delay that increased within session (0 to 16 s). At relatively higher doses during acute and chronic administration, choice maintained by the larger reinforcer was disrupted when there was no delay to either outcome, suggesting that MPH may be affecting stimulus control under the current delay-discounting task. When this disruption was not observed, however, MPH effects were selective in that only one intermediate dose (3.0 mg/kg) decreased mean impulsive choice at one delay (8 s) following acute administration. The same effect was observed following chronic MPH administration except that the dose was higher (5.6 mg/kg) and the delay was shorter (4 s). Chronic administration of MPH did not show any negative indicators (e.g., an increase in impulsive choice) when administration was discontinued.     

A Simple Behavioral Paradigm to Measure Impulsive Behavior in an Animal Model of Attention Deficit Hyperactivity Disorder (ADHD) of the Spontaneously Hypertensive Rats

Impulsiveness is an important component of many psychiatric disorders including Attention-deficit/hyperactivity disorder (ADHD). Although the neurobiological basis of ADHD is unresolved, behavioral tests in animal models have become indispensable tools for improving our understanding of this disorder. In the punishment/extinction paradigm, impulsivity is shown by subjects that persevere with responding despite punishment or unrewarded responses. Exploiting this principle, we developed a new behavioral test that would evaluate impulsivity in the most validated animal model of ADHD of the Spontaneously Hypertensive rat (SHR) as compared with the normotensive “control” strain, the Wistar Kyoto rat (WKY). In this paradigm we call the Electro-Foot Shock aversive water Drinking test (EFSDT), water-deprived rats should pass over an electrified quadrant of the EFSDT apparatus to drink water. We reasoned that impulsive animals show increased frequency to drink water even with the presentation of an aversive consequence (electro-shock). Through this assay, we showed that the SHR was more impulsive than the WKY as it demonstrated more “drinking attempts” and drinking frequency. Methylphenidate, the most widely used ADHD medication, significantly reduced drinking frequency of both SHR and WKY in the EFSDT. Thus, the present assay may be considered as another behavioral tool to measure impulsivity in animal disease models, especially in the context of ADHD.     

Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro

In previous studies we have demonstrated that the γ-aminobutryic acid-A (GABA-A) receptor antagonist oroxylin A has an awakening effect and it also represses ADHD-like behaviors (hyperactivity, impulsivity and inattention) in the spontaneously hypertensive rat (SHR) model of attention-deficit hyperactivity disorder (ADHD). We hypothesized that the effects of oroxylin A were exerted via the GABA-A receptor given the important role of the GABAergic system in ADHD. However, it is possible that aside from the GABAergic system, oroxylin A may influence other systems especially those implicated in ADHD (e.g. DAergic, etc.). To test this hypothesis, we evaluated the effects of GABA agonist, or dopamine (DA) antagonist in oroxylin A-induced alleviation of ADHD-like behaviors in SHR. SHR showed inattention and impulsivity as measured by the Y-maze and the electro-foot shock aversive water drinking tests, respectively. Oroxylin A significantly improved these behaviors, furthermore, its effect on SHR impulsivity was attenuated by haloperidol, a DA antagonist, but not by baicalein, an agonist of the GABA-A receptor. In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor. Collectively, the present findings suggest that oroxylin A improves ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not modulation of GABA pathway as previously reported. Importantly, the present study indicates the potential therapeutic value of oroxylin A in the treatment of ADHD.     

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists

Rationale

Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.

Objective

The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).

Methods

We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ??HI?? and low impulsive ??LI??, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.

Results

Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.

Conclusions

These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.     

Discriminative stimulus properties of cocaine, alone and in combination with buprenorphine, morphine and naltrexone

Rats were trained to discriminate a dose of 10.0 mg/kg cocaine from saline. During substitution tests, both cocaine (5.6–10.0 mg/kg) and d-amphetamine (1.0–3.0 mg/kg) produced greater than 80% responding on the cocaine-appropriate lever. In contrast, buprenorphine (0.03–0.56 mg/kg), morphine (0.3–10.0 mg/kg) and naltrexone (1.0–10.0 mg/kg) failed to substitute for the cocaine stimulus, up to doses that substantially decreased rate of responding. When the cocaine dose-effect curve was redetermined in the presence of selected doses of buprenorphine, the amount of cocaine-appropriate responding following a low dose of cocaine (1.0 mg/kg) was increased slightly whereas cocaine-appropriate responding following higher doses of cocaine (3.0 and 5.6 mg/kg) was reduced slightly. Responding following the training dose of cocaine (10.0 mg/kg) was not changed. These results indicate that buprenorphine produced only small alterations in cocaine's discriminative stimulus effects and that the nature of these alterations differed depending on the dose of cocaine examined.     

Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders.

Forebrain serotonergic lesions attenuate the ability of d-amphetamine to decrease impulsivity in a delay-discounting paradigm, potentially through interactions between the serotonin (5-HT) and dopamine (DA) systems. Nucleus accumbens (NAC) lesions increase impulsivity, but the extent to which accumbal DA is involved in regulating impulsive choice is unknown. In the current study, the effects of intra-accumbal infusions of 6-hydroxydopamine (6-OHDA) on impulsive choice were evaluated, in combination with d-amphetamine and serotonergic drugs, in order to investigate the importance of 5-HT : DA interactions in the control of impulsive behavior. Following training on a delay-discounting task, animals received intra-NAC 6-OHDA or sham surgery. Postoperatively, subjects received systemic injections of d-amphetamine (0, 0.3, 1.0, 1.5 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0, 0.1, 0.3, 1.0 mg/kg). Intra-NAC 6-OHDA, which reduced local DA and NA levels by 70-75%, had no effect on delay-discounting, but transiently potentiated the d-amphetamine-induced decrease in impulsive choice. 8-OH-DPAT (1.0 mg/kg) increased impulsivity in sham-operated controls, an effect which was blocked by the 5-HT(1A) receptor antagonist WAY 100635. However, 8-OH-DPAT had no effect on impulsivity in 6-OHDA NAC lesioned rats. 8-OH-DPAT (0.3 mg/kg), which did not itself alter task performance, blocked the effect of d-amphetamine in sham-operated controls, while WAY 100635 augmented the effect of amphetamine in all subjects. In an additional experiment, intracerebroventricular administration of the selective serotonergic toxin 5,7-dihydroxytryptamine, which decreased forebrain 5-HT levels by 85-90%, did not block 8-OH-DPAT's ability to increase impulsive choice. These data suggest a significant role for 5-HT : DA interactions within the NAC in the control of impulsivity, and in the mechanism by which amphetamine decreases impulsive choice.