The role of dopamine D1 receptors in MDMA-induced memory impairments.

(±) 3,4-Methylenedioxymethamphetamine (MDMA) is a recreationally abused psychostimulant that impairs memory performance. This effect is often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may indirectly impair memory performance through overstimulation of dopamine (DA) D1 receptors, which increases perseverative responding during memory tasks. This hypothesis was explored using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional D1 receptors. Adult male Wistar DAD1-/- rats and wild type controls were trained over 25 sessions on a spatial working memory T-maze delayed non-matching to position (DNMTP) task. Once trained, the rats were administered MDMA (1.5, 2.25 and 3 mg/kg) or saline fifteen minutes prior to testing on DNMTP with all subjects experiencing all drug doses and saline three times. We predicted that controls would demonstrate decreased task accuracy following MDMA, driven by an increase in perseverative errors. In contrast, we predicted that DAD1-/- rats would be protected from MDMA-induced perseverative errors due to their reduced D1 receptor function. As predicted, during the third block of MDMA administration, control rats demonstrated decreased task accuracy following 2.25 and 3 mg/kg doses, driven by an increase in perseverative errors. In addition, DAD1-/- rats were protected from MDMA-induced task deficits. These findings challenge the assumption that MDMA's acute effects on memory performance are predominantly due to serotonergic mechanisms and provide support for the hypothesis that acute MDMA impairs memory performance in rats via overstimulation of D1 receptors by increasing perseverative behaviour.

Generalization of serotonin and dopamine ligands to the discriminative stimulus effects of different doses of ±3,4-methylenedioxymethamphetamine.

Studies that have attributed the discriminative stimulus effects of ±3,4-methylenedioxymethamphetamine (MDMA) to serotonergic mechanisms typically use a relatively low training dose of 1.5 mg/kg. The role of serotonin in the discriminative stimulus effects of higher doses of MDMA is, however, unknown. Separate groups of rats were trained to discriminate MDMA (1.5 or 3.0 mg/kg) from saline using a two-lever, food-reinforced drug-discrimination procedure. Generalization tests were carried out with a range of serotonin and dopamine ligands. Fluoxetine (0.3-3 mg/kg), clomipramine (1-10 mg/kg) and meta-chlorophenylpiperazine (0.3-2 mg/kg) dose-dependently substituted for the 1.5 mg/kg MDMA stimulus, but not the 3.0 mg/kg MDMA stimulus. 8-OH-DPAT (0.03-0.3 mg/kg) and RU-24969 (0.3-3 mg/kg) substituted for both the low-dose and the high-dose MDMA stimulus. The generalization dose-effect curve produced by 2,5-dimethoxy-4-iodoamphetamine (0.3-3 mg/kg) was shifted to the right for the 3.0 mg/kg MDMA-trained group. Amphetamine (0.25 and 0.5 mg/kg) and apomorphine (0.125 and 0.25 mg/kg) substituted for the 3.0 mg/kg, but not the 1.5 mg/kg MDMA stimulus. The results suggest some differences in the role of serotonin and dopamine in the discriminative stimulus effects of a low versus a higher dose of MDMA.

Attenuation of the disruptive effects of (+/-)3,4-methylenedioxymethamphetamine and cocaine on delayed matching-to-sample performance with D1 versus D2 antagonists.

Evidence suggests that acute exposure to (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces qualitatively similar effects on recognition task performance as other stimulant-type drugs. The current study examined whether there was a similar neurochemical basis to these memory effects by examining the effects of a D1 receptor antagonist (SCH23390) and D2 antagonist (eticlopride) on MDMA- or cocaine-induced impairments in delayed matching-to-sample performance in rats. At low doses it was shown that eticlopride was ineffective in antagonizing either MDMA or cocaine's effects, and at higher doses exacerbated their effects. In contrast, the D1 receptor antagonist SCH23390 was only able to significantly attenuate the disruption caused by MDMA, but not cocaine's effects. Therefore, although present evidence suggests that the effect of acute MDMA on memory-task performance may be related to its effects at D1 receptor sites, there may be differences between MDMA and cocaine in the precise neurochemical pathways involved despite their having similar cognitive effects.

Dopamine D1 receptor and effort-based decision making in rats: The moderating effect of sex.

Dopamine is a modulating factor in effort-based decision-making, and emerging evidence from pharmacological research suggests that the dopamine D1 receptor is the primary regulator. Given the limited selectivity of pharmacological tools, we further explored this hypothesis using dopamine D1 mutant (DAD1-/-) rats which have a specific genetic reduction in functional D1 receptors. Moreover, given the strong focus on males in neuroscience research in general and in the role of D1 receptors in effort-based learning, we compared both sexes in the present study. Adult male and female DAD1-/- mutant rats and wild type controls were trained to press a lever for a reinforcer. Once trained, subjects completed multiple fixed ratio, progressive ratio, and operant effort-choice (concurrent progressive ratio/chow feeding task [PROG/chow]) experiments. We predicted that DAD1-/- mutant rats would press the lever significantly less than controls across all experiments, have lower breakpoints, and consume more freely available food. As predicted, DAD1-/- mutant rats (regardless of sex) pressed the lever significantly less than controls and had lower breakpoints. Interestingly, there was a sex * genotype interaction for acquisition rates of lever pressing and change in breakpoints with free food available. Only 31% of DAD1-/- mutant males acquired lever pressing while 73% of DAD1-/- mutant females acquired lever pressing. Additionally, DAD1-/- mutant males had significantly larger decreases in breakpoints when free food was available. These findings extend the pharmacological research suggesting that the dopamine D1 receptor modulates decisions based on effort, which has implications for the development of treatment targeting amotivation in neuropsychiatric disorders. The sex * genotype interaction highlights the importance of including both sexes in future research, especially when there are sex differences in incidences and severity of neuropsychiatric disorders.

A genetic deletion of the serotonin transporter differentially influences the behavioural effects of MDMA.

BACKGROUND: While (±)-3,4-methylenedioxymethamphetamine (MDMA) primarily induces serotonin release, it also affects dopamine and noradrenaline transmission. It is, however, unclear what role each of these neurotransmitters play in the behavioural profile of MDMA. METHODS: In this study we used the drug discrimination (DD) and the acoustic startle (ASR) paradigms to examine the behaviour of rats with and without a genetic deletion of the serotonin transporter SERT (SERT-/- and SERT+/+ rats). In DD, rats were trained to respond on different levers following an injection of 1.5 mg/kg MDMA, or saline. After acquisition, they were given a challenge dose of 0.5 mg/kg amphetamine (AMPH). In the ASR paradigm, SERT+/+ and SERT-/- rats were given 0, 5 or 10 mg/kg MDMA. RESULTS: In DD, significantly fewer SERT-/- rats acquired MDMA discrimination. When the acquirers were challenged with AMPH, SERT+/+ showed partial, while SERT-/- rats showed full generalisation to MDMA. In the ASR paradigm, MDMA significantly reduced prepulse inhibition and startle habituation in SERT+/+ rats, while having no effect in SERT-/- rats. CONCLUSION: Together these data suggest that in wildtype rats the interoceptive cues of MDMA are primarily mediated by serotonin and to a lesser extent by dopamine and noradrenaline, while the effects in the startle paradigm are almost exclusively mediated via serotonin. Together, these data contribute to our understanding of the complex pharmacodynamics of MDMA.

Psychotropic placebos create resistance to the misinformation effect.

Can a placebo for a psychotropic drug help participants resist the misinformation effect? To answer this question, we gave participants a mixture of baking soda and water and told half of them that the mixture was a cognition-enhancing drug called R273 and told the other half that it was an inactive version of the drug. Shortly thereafter, all participants took part in a three-stage misinformation experiment. Compared with participants who were told that they had taken the placebo, the participants who were told that they had taken the drug reported improved cognitive abilities and were less susceptible to the misinformation effect. We provide source-monitoring and mindfulness accounts of our findings.

Attenuation of the disruptive effects of (+/-)3,4-methylene dioxymethamphetamine (MDMA) on delayed matching-to-sample performance in the rat.

Recent evidence suggests that the disruptive effects of acute exposure to (+/-)3,4-methylene dioxymethamphetamine (MDMA) on memory performance may be the result of increased confusion between previous-trial and current-trial events. The current study tested this hypothesis by examining the effects of MDMA on performance of rats in a delayed matching-to-sample procedure when the length of the intertrial interval (ITI) was altered. Consistent with the possibility that limiting the conditions under which responses made on a previous trial would interfere with current-trial choice, a 15-s ITI ameliorated the disruptive effects caused by MDMA on trial performance when the ITI was 5 s. Therefore, the disruptive effects of MDMA on memory can be attenuated by methods that separate current-trial "to-be-remembered" events from previous-trial events.

Dopamine agonists and antagonists can produce an attenuation of response bias in a temporal discrimination task depending on discriminability of target duration.

The current study examined the effects of the D2 agonist (quinpirole) and D2 antagonist (eticlopride) on temporal discrimination performance in a conditional discrimination task (Experiment I) and a delayed conditional discrimination task (Experiment II). In both experiments rats discriminated between a scheduled stimulus duration of 3 s versus 9 s. Consistent with previous reports, overall discrimination performance decreased in a dose-dependent manner with both drugs. Changes in response bias (the tendency to choose-short or choose-long irrespective of actual stimulus duration), however, were best characterized in terms of both drugs tending to attenuate the bias effects normally observed during baseline drug-free performance. Specifically, the 'choose-short' bias observed in Experiment I and at a relatively short, 0.1 s, delay in Experiment II became less extreme with increasing doses. In addition, the 'choose-long' bias observed at a relatively long, 6 s, delay in Experiment II also became less extreme with increasing doses. Thus, whether there was an apparent shift from a short response bias to long, or vice versa, was the product of the delay interval between stimulus presentation and choice rather than whether the drug in question was a D2 agonist or antagonist. Such an attenuation of bias may have arisen because of subjects confounding the delay interval with the actual discriminative stimulus duration.

Differential effects of 3,4-methylenedioxymethamphetamine, methamphetamine, meta-Chlorophenylpiperazine, and scopolamine on behavioral repetition versus variation in rats.

Acute administration of drugs of abuse, such as MDMA and methamphetamine, disrupts performance on many operant tasks, for example, those used to study memory. This might occur in part because drugs make behavior, in general, more repetitive or more variable, or because they produce a more global disruption to performance. The current study explored this across two experiments by employing Neuringer's 'reinforced variability' procedure. Varied behavior was reinforced at some times during the session and repetitive behavior at other times; lights signalled the behavior required. This procedure allowed an investigation of whether a particular drug made behavior more variable (affected behavior when repetition was required), more repetitive (affected behavior when variability was required), or produced a global disruption (affected both components). In Experiment 1, MDMA increased variability while methamphetamine affected both components. In Experiment 2, m-CPP affected both components while scopolamine affected both components at lower doses and increased variability at higher doses. These results indicate both that the reinforced variability procedure can be used to isolate the specific effects of drugs of abuse on the variability of behavior, and that the specific impact of a given drug needs to be considered when interpreting pharmacological disruptions to operant task performance.

The effect of MDMA on sensitivity to reinforcement rate.

Administration of (±)3,4-methylenedioxymethamphetamine (MDMA) causes memory errors by increasing proactive interference. This might occur because MDMA alters sensitivity to reinforcement. The current 2 experiments investigated this directly by assessing the acute (Experiment 1) and chronic (Experiment 2) effects of MDMA on sensitivity to reinforcement. We presented 5 pairs of concurrent variable interval schedules within each session and calculated sensitivity to reinforcement for 3 acute doses of MDMA. In contrast to the related drug, d-amphetamine, and in spite of producing reductions in response rate, MDMA did not reduce sensitivity to reinforcement rate. Chronic administration of a fixed dose of MDMA following each session reduced response rate but did not affect sensitivity to reinforcement rate. In combination with previous research, these results indicate that related drugs may have different effects on sensitivity to reinforcement and that these effects should be considered when interpreting disruptions to operant task performance caused by drug administration. (PsycINFO Database Record

(+/-)3,4-methylenedioxymethamphetamine, d-amphetamine, and cocaine impair delayed matching-to-sample performance by an increase in susceptibility to proactive interference.

This study compared the effects of (+/-)3,4-methylenedioxymethamphetamine, d-amphetamine, and cocaine on performance of rats in a delayed matching-to-sample procedure using a variety of indices of performance to determine the mechanism by which working memory task impairments arise. All 3 drugs produced an overall delay-independent decrease in accuracy rather than a delay-dependent increase in the rate of forgetting. This impairment arose as a result of current-trial choice responses being progressively more affected by responses made in the immediately preceding trial as drug dose increased. Therefore, all 3 drugs produced qualitatively similar disruptions in memory task performance best characterized as an impairment arising from proactive sources of interference.

The disruptive effects of methamphetamine on delayed-matching-to-sample performance reflect proactive interference and are reduced by SCH23390.

Different drugs produce different patterns of impairment on delayed matching-to-sample tasks. For example, (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces an increase in proactive interference. That is, subjects are less accurate when they are required to make a response different to the one they made on the immediately previous trial. The current study assessed whether methamphetamine also produces this particular pattern of disruption in delayed matching-to-sample performance in rats. Methamphetamine primarily reduced accuracy on trials where the correct response differed from the one made on the previous trial. Thus methamphetamine, like MDMA and other stimulant-based drugs of abuse, increased proactive interference. This impairment was reduced by prior administration of the dopamine D1 antagonist SCH23390. These results further extend a general conclusion that a range of stimulant-based drugs may disrupt working memory function indirectly via a tendency to repeat previously made responses and that this disruption is related to D1 receptor activity.

The effect of reinforcer magnitude on probability and delay discounting of experienced outcomes in a computer game task in humans.

Delay and uncertainty of receipt both reduce the subjective value of reinforcers. Delay has a greater impact on the subjective value of smaller reinforcers than of larger ones while the reverse is true for uncertainty. We investigated the effect of reinforcer magnitude on discounting of delayed and uncertain reinforcers using a novel approach: embedding relevant choices within a computer game. Participants made repeated choices between smaller, certain, immediate outcomes and larger, but delayed or uncertain outcomes while experiencing the result of each choice. Participants' choices were generally well described by the hyperbolic discounting function. Smaller numbers of points were discounted more steeply than larger numbers as a function of delay but not probability. The novel experiential choice task described is a promising approach to investigating both delay and probability discounting in humans.

Choice with initial and terminal link reinforcement: an alternative self-control paradigm.

Self-control is demonstrated when a less desirable immediate outcome is chosen to ensure a substantially better future. In a novel animal analogue of this situation, primary reinforcement was delivered in both the initial and terminal links of a concurrent chain schedule. Rats made initial link choices between equal amounts of ethanol-free or ethanol-containing milk. Choosing the ethanol-free reinforcer resulted in delivery of the larger terminal link reinforcer and was thus analogous to self-control. Self-control decreased as the delay between initial and terminal links increased. The results have implications for human choice situations where decisions are made between two immediately available reinforcement alternatives each associated with a different delayed outcome.

A 3-lever discrimination procedure reveals differences in the subjective effects of low and high doses of MDMA.

Drug discrimination studies have suggested that the subjective effects of low doses of (±)3,4-methylenedioxymethamphetamine (MDMA) are readily differentiated from those of d-amphetamine (AMPH) and that the discriminative stimulus properties are mediated by serotonergic and dopaminergic mechanisms, respectively. Previous studies, however, have primarily examined responses to doses that do not produce substantial increases in extracellular dopamine. The present study determined whether doses of MDMA that produce increases in synaptic dopamine would also produce subjective effects that were more like AMPH and were sensitive to pharmacological manipulation of D1-like receptors. A three-lever drug discrimination paradigm was used. Rats were trained to respond on different levers following saline, AMPH (0.5mg/kg, IP) or MDMA (1.5mg/kg, IP) injections. Generalization curves were generated for a range of different doses of both drugs and the effect of the D1-like antagonist, SCH23390 on the discriminative stimulus effects of different doses of MDMA was determined. Rats accurately discriminated MDMA, AMPH and saline. Low doses of MDMA produced almost exclusive responding on the MDMA lever but at doses of 3.0mg/kg MDMA or higher, responding shifted to the AMPH lever. The AMPH response produced by higher doses of MDMA was attenuated by pretreatment with SCH23390. The data suggest that low doses and higher doses of MDMA produce distinct discriminative stimuli. The shift to AMPH-like responding following administration of higher doses of MDMA, and the decrease in this response following administration of SCH23390 suggests a dopaminergic component to the subjective experience of MDMA at higher doses.

Novel object recognition memory: measurement issues and effects of MDMA self-administration following short inter-trial intervals.

The present study was undertaken to examine effects of self-administered MDMA on novel object exploration (NOR) memory. Self-administration was conducted during daily 2 h tests that continued until a total of 165 mg/kg was self-administered (range = 13-41 days for individual rats). Control rats were placed in the self-administration boxes during daily sessions but did not receive any drug. One or 10 weeks following the last self-administration session, memory was assessed using a standard NOR task. When exploration time was used as the dependent measure for the control rats, there was no consistent pattern of change as a function of inter-trial interval (ITI) and exploration times failed to reveal decay in the function relating exploration to ITI. When number of approaches was examined as a function of ITI, however, there was a preference for the novel object following the short ITIs (1-15 min) and the function relating preference to ITI decayed with longer ITIs. When tested 7 days following the last self-administration session, rats that self-administered MDMA failed to demonstrate NOR even following the shortest ITI of 1 min. The data support the idea that MDMA self-administration produces cognitive deficits and are consistent with the idea that attentional processes become disrupted. There was, however, recovery of NOR memory when rats were tested following an extended drug-free period of 70 days. Thus, the deficits are transient and recovery was apparent.

Whatever gave you that idea? False memories following equivalence training: a behavioral account of the misinformation effect.

The misinformation effect is a term used in the cognitive psychological literature to describe both experimental and real-world instances in which misleading information is incorporated into an account of an historical event. In many real-world situations, it is not possible to identify a distinct source of misinformation, and it appears that the witness may have inferred a false memory by integrating information from a variety of sources. In a stimulus equivalence task, a small number of trained relations between some members of a class of arbitrary stimuli result in a large number of untrained, or emergent relations, between all members of the class. Misleading information was introduced into a simple memory task between a learning phase and a recognition test by means of a match-to-sample stimulus equivalence task that included both stimuli from the original learning task and novel stimuli. At the recognition test, participants given equivalence training were more likely to misidentify patterns than those who were not given such training. The misinformation effect was distinct from the effects of prior stimulus exposure, or partial stimulus control. In summary, stimulus equivalence processes may underlie some real-world manifestations of the misinformation effect.

Anchoring effects in the development of false childhood memories.

When people receive descriptions or doctored photos of events that never happened, they often come to remember those events. But if people receive both a description and a doctored photo, does the order in which they receive the information matter? We asked people to consider a description and a doctored photograph of a childhood hot air balloon ride, and we varied which medium they saw first. People who saw a description first reported more false images and memories than did people who saw a photo first, a result that fits with an anchoring account of false childhood memories.

Human performance on a two-alternative rapid-acquisition choice task.

Davison and Baum [Davison, M., Baum, W. M., 2000. Choice in a variable environment: every reinforcer counts. Journal of the Experimental Analysis of Behavior 74, 1-24.] developed a concurrent-schedule procedure where, within each session, different reinforcer ratios were arranged across components separated by brief black-outs. Behaviour adapted quickly to the reinforcer ratios and reinforcers also had local effects on responding. This procedure has been used with pigeons and rats. In the present experiment, we adapted the Davison and Baum procedure to study the effects of reinforcement on human choice behaviour. Eighteen participants were presented with four different reinforcer ratios within a single 50-minute session. Mean sensitivity to the reinforcer ratios increased within components, and preference was greater for the just-reinforced response alternative immediately following reinforcer delivery, similar to the results from non-human experiments. Although there were limitations to the current procedure, the local time scale analyses are a novel way of examining human operant behaviour.

Psychotropic placebos reduce the misinformation effect by increasing monitoring at test.

A psychotropic placebo can help people resist the misinformation effect, an effect thought to be caused by a shift to more stringent source monitoring. When this shift occurs has been unclear. To address this issue we gave some people - but not others - a phoney cognitive-enhancing drug we called R273. Shortly afterwards, everyone took part in a misinformation effect experiment. To gather evidence about source monitoring we surreptitiously recorded time to read the misleading postevent narrative, and response time at test. Our findings suggest that people shifted to more stringent source monitoring at test. Moreover, people with higher working memory capacity (WMC) performed better than people with lower WMC - but only when they were told they had received R273, a finding that fits with research showing that WMC can confer advantages in situations demanding effortful control, but not when automatic heuristics suffice.