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

Abstract

(±) 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.

The Impact of Aerobic Training on Some Brain Neurotransmitters and Brain-Derived Neurotrophic Factor in Addicted Women

“…Serotonin is an indoleamine that regulates mood and initiates sleep. Low serotonin activity is associated with depression, while its high activity is associated with aggressive behaviors [8,9].…”

Unravelling the Role of the Dopamine D1 Receptor in Anhedonia, Asociality, and Avolition

“…Firstly, due to dopamine's role in motor activity, the DAD1 -/mutants might exhibit locomotor impairments leading to a reduction in lever pressing. However, male DAD1 -/mutants showed normal motor, sensory, and neurological characteristics along with normal exploratory behaviour in previous studies (Homberg et al, 2016;Squire et al, 2020). In the current study we did not measure locomotor activity during operant procedures, so it is possible that the DAD1 -/mutants have a locomotor impairment not seen in previous experiments.…”

“…A major limitation of the previous research is that available pharmacological manipulations do not selectively act on the D1 receptors-they show an affinity for D5 receptors and several, including SCH23390, also bind to serotonin receptors (Zhang et al, 2009;Homberg et al, 2016;Undieh, 2010;Squire et al, 2020). To specifically examine the role of the dopamine D1 receptor, the present study utilised rats with a genetic reduction in the D1 receptor, dopamine DAD1 -/mutant rats (Homberg et al, 2016;Undieh, 2010;Squire et al, 2020). These rats have a point mutation in the third transmembrane of the D1 receptor, resulting in a reduction in D1 receptor function and expression, while not impacting the other four dopamine receptors (Homberg et al, 2016;Squire et al, 2020).…”

“…To specifically examine the role of the dopamine D1 receptor, the present study utilised rats with a genetic reduction in the D1 receptor, dopamine DAD1 -/mutant rats (Homberg et al, 2016;Undieh, 2010;Squire et al, 2020). These rats have a point mutation in the third transmembrane of the D1 receptor, resulting in a reduction in D1 receptor function and expression, while not impacting the other four dopamine receptors (Homberg et al, 2016;Squire et al, 2020). The DAD1 -/mutant rats allow us to examine the specific role of the dopamine D1 receptor in effort-based decision-making.…”