David N. Harper’s research while affiliated with Victoria University of Wellington and other places

What is this page?


This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.

Publications (65)


The role of the dopamine D1 receptor in anticipatory pleasure and social play
  • Article

November 2024

·

5 Reads

Neuropharmacology

Kate M. Witt

·

David N. Harper

·

Bart A. Ellenbroek

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

September 2022

·

19 Reads

·

3 Citations

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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.


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

December 2020

·

20 Reads

·

6 Citations

Neurobiology of Learning and Memory

(±) 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.


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

October 2020

·

6 Reads

(±) 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 task, delayed non-matching to position (DNMTP). 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.


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

January 2019

·

75 Reads

·

2 Citations

Journal of Psychopharmacology

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.


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

December 2016

·

15 Reads

·

6 Citations

Behavioural Pharmacology

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.


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

November 2016

·

11 Reads

·

1 Citation

Pharmacology Biochemistry and Behavior

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
  • Article
  • Publisher preview available

January 2016

·

35 Reads

·

3 Citations

Behavioral Neuroscience

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

View access options

Analysis of the Acquisition of Drug Discrimination Reveals Differences Between a High Versus Low Training Dose of ±3,4-methylenedioxymethamphetamine (MDMA)

January 2016

·

23 Reads

·

2 Citations

Journal of Drug and Alcohol Research

Background. Studies of the discriminative stimulus effects of the recreational drug, ±3,4-methylenedioxymethamphetamine (MDMA), typically use a dose of 1.5 mg/kg during training. This dose is relatively low compared to those used in other behavioral paradigms. Purpose. The present study assessed the ability of this low dose of MDMA and a higher dose of 3.0 mg/kg to support drug-discrimination learning in rats. Procedures. Daily training sessions were preceded by an injection of either MDMA (1.5mg/kg or 3.0mg/kg) or saline. Injections alternated in a pseudorandom fashion for a total of 63 sessions. Criteria for the acquisition of the MDMA/saline discrimination were increased from 4 to 10 successive, and successful, discriminations. As the acquisition criteria became more stringent, the impact on the low dose discrimination was greater than the impact on the high dose discrimination. Conclusions. These results suggest that the drug discrimination produced by 1.5mg/kg MDMA may be less reliable than when a higher dose is employed, especially when the number of training sessions is limited. The data further suggest that 3.0mg/kg MDMA produced a robust discriminative stimulus effect which may be better suited to experiments of this nature.



Citations (55)


... The reconstructive mnemonic processes are rarely explored in non-human animals, [10][11][12] although some studies implicitly investigated reconstruction through features binding, 13,14 source memory [14][15][16] or re-ordering memories. 17 Very few studies on false memories have been conducted in animals [18][19][20][21] ; some focusing on false context fear memory, 22,23 but none have used false memories to explore the reconstructive nature of episodic memory. In order to explore reconstructive memory abilities, we studied common cuttlefish (Sepia officinalis), a cephalopod mollusc. ...

Reference:

False memories in cuttlefish
Pigeons, Rats, and Humans Show Analogous Misinformation
  • Citing Article
  • January 2009

International Journal of Comparative Psychology

... Their findings shed light on the dysregulated T-cell responses and potential autoimmunity implicated in brain inflammation and brain cell dysfunction in PD. This study's insights pave the way for further investigations into the immunological foundations of PD and the development of targeted measures to adjust defense responses and halt disease progression [53]. ...

The role of dopamine D1 receptors in MDMA-induced memory impairments
  • Citing Article
  • December 2020

Neurobiology of Learning and Memory

... Increasing evidence that physiological paradigms such as startle response are a reliable differentiator of fear or distress [65] suggests that a more biologically-grounded conceptualisation of NVS constructs is simply AT vs non-AT. This is further supported by evidence implicating only serotonin (and not dopamine or noradrenaline) in the startle response [66], as well as meta-analytic studies reporting reboxetine to be effective in MDD [40], but not panic disorder [67]. ...

A genetic deletion of the serotonin transporter differentially influences the behavioural effects of MDMA
  • Citing Article
  • January 2019

Journal of Psychopharmacology

... Similar work assessing the effects of pre-exposure to other drugs on fluoxetine-induced avoidance is limited (see [20]; for a review, see [53]); however, drug discrimination learning (DDL) procedures that are also used to determine shared stimulus properties (albeit not necessarily those associated with the drugs' aversive effects; see [54]) support the fact that fluoxetine's stimulus effects are primarily mediated by its actions on 5-HT. Establishing discriminative control when fluoxetine is used as a training drug in the DDL procedure has proven difficult, likely due to its long half-life (see [55]; though see [56] for a discussion of other SSRIs that have been successfully demonstrated in this design); however, several studies have demonstrated that fluoxetine generalizes to serotonergic compounds ( [57,58]; though see [59]) and potentiates the discriminability of several compounds with serotonergic activity [58,60,61]. Further, drugs with primarily dopaminergic activity do not typically generalize to fluoxetine [60,62], indicating that fluoxetine's stimulus effects are not likely mediated by DA (though see [20]). ...

Generalization of serotonin and dopamine ligands to the discriminative stimulus effects of different doses of ±3,4-methylenedioxymethamphetamine
  • Citing Article
  • December 2016

Behavioural Pharmacology

... Rats with mammillary body lesions and mammillothalamic tract lesions are impaired on this task (Jarrard, Okaichi, Steward, & Goldschmidt, 1984;Neave, Nagle, & Aggleton, 1997;Sziklas & Petrides, 1993; and this impairment reflects the ineffective use of distal allocentric cues . Using a modified task in the radial-arm-maze, designed to assess memory for "lists", mammillary body lesions disrupt both the primacy and recency effects shown by normal animals on this task (Harper, Dalrymple-Alford, & McLean, 1993). In contrast to the frequently reported spatial memory impairments, mammillary body lesions in rats do not affect object recognition (Aggleton et al., 1995), again consistent with some dual-models of recognition memory (e.g. ...

The effect of medial septal and mammillary body lesions on the serial position curve in rats
  • Citing Article
  • June 1993

Psychobiology

... We therefore hypothesized that tonic dopamine may modulate policy complexity, which in matching tasks would alter the degree of undermatching. Although the literature is scarce, there is some extant data to argue that pharmacologic manipulations of dopamine have the expected effect on undermatching (Soto et al., 2014;Lie et al., 2016). To address this question, we reanalyzed data from human subjects performing a dynamic foraging task, similar to the mice (Rutledge et al., 2009). ...

The Effect of MDMA on Sensitivity to Reinforcement Rate

Behavioral Neuroscience

... Other studies that did not employ persistence-based methodologies have found similarly varied results ranging from support (Kurucz and Koermendi 2012;Tan et al. 2015) to lack of support (Witts et al. 2015) for a near-miss effect. Interestingly, Sundali et al. (2012) examined real casino data from electronic roulette terminals. ...

Derived relations and the slot machine near-win effect

European Journal of Behavior Analysis

... Finally, we summarize the included delays across all studies (excluding studies with unbounded duration), by reporting maximum delays included (expressed in days) in Table 3. Maximum delays range from 0.00013 to 36,500 days, with a mean of 4173 days (SD = 6394) The maximum delay is right-skewed, with many methods having maximum delays between 30 and 366 days (25 out of 86). The shortest delays were being considered in Greenhow et al. (2015), i.e. 1.5 seconds, and the longest in Cropper et al. (1994), i.e. 100 years. Note that studies varied in the descriptors used for describing delays, with frequencies differing between descriptors. ...

The effect of reinforcer magnitude on probability and delay discounting of experienced outcomes in a computer game task in humans
  • Citing Article
  • September 2015

Journal of the Experimental Analysis of Behavior

... Our behavioral finding that participants were more likely to persist in choosing the same slot-machine following nearwin (and win) outcomes is conceptually consistent with previous studies showing that near-wins prolong gambling sessions (Cote et al., 2003;Ghezzi et al., 2006;Kassinove & Schare, 2001;MacLin et al., 2007) and produce longer postreinforcement pauses (Belisle & Dixon, 2016;Daly et al., 2014; but see Dixon et al., 2013). Our findings are novel, however, in showing an effect of near-win outcomes on immediate preferences for re-choosing an individual machine. ...

Slot machine near wins: Effects on pause and sensitivity to win ratios

·

G. Tan

·

·

[...]

·

... A response to the previously illuminated lever will be reinforced, whereas responses to other levers will terminate the trial without reward. A longstanding research domain using these tasks has detailed the adverse effects on short-term memory of diverse drugs of abuse, including alcohol (Mello, 1971), cannabinoids , psychomotor stimulants (Branch & Dearing, 1982;Harper, Wisnewski, Hunt, & Schenk, 2005;Jedema et al., 2021;LeSage, Clark, & Poling, 1993) and, in the latter drug class, how pretreatment with other drugs might mitigate such undesirable effects on memory (Harper, 2013;Macaskill, Harrow, & Harper, 2015). Studies examining the effects of ongoing chronic drug treatment on delayed matching-to-sample performance are less common but have documented evidence of tolerance to the memory disruptive effects of illicit drugs, such as cocaine (Kangas & Branch, 2012). ...

The disruptive effects of methamphetamine on delayed-matching-to-sample performance reflect proactive interference and are reduced by SCH23390
  • Citing Article
  • November 2014

Pharmacology Biochemistry and Behavior