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

Abstract

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.

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

“…For example, administration of the D1-like agonist SKF 81297 into the PFC of rats impaired their performance on a spatial working memory alternation task predominantly due to increases in perseveration. 31 Similarly, in our laboratory Harper 4 found that MDMA-induced deficits on the DMTS task were predominantly due to an increase in perseveration, which is consistent with other studies as well. 13,32,33 Taken together, these findings strongly suggest that some of MDMA's effects on memory may be mediated by non-serotonergic mechanisms, particularly via overstimulation of the DA D1 family of receptors leading to a perseverative pattern of responding.…”

“…on an operant delayed matching-to-sample (DMTS) working memory task were ameliorated via concurrent administration of the DA D1-like receptor antagonist, SCH 23390 (i.p). 4 The finding that D1like receptors may be involved in MDMA's effects on memory corroborates extensive research showing that these receptors are important neural substrates for learning and memory. [27][28][29][30] Overstimulation of D1-like receptors during acute MDMA exposure may interfere with memory by increasing behavioural perseveration, rather than by impairing memory processes directly.…”

“…Additionally, MDMA-induced memory impairments only tend to emerge following doses where there is a relatively greater increase in extracellular DA than 5-HT (which occurs at ~3 mg/kg via intraperitoneal (i.p.) injection), [4][5][6]9,13,14 compared with lower doses. 24 Lower doses of MDMA, ~1 mg/kg, generally preserve memory function 5,9 despite still substantially stimulating 5-HT release.…”

“…Acute MDMA administration reliably impairs memory performance in humans, [1][2][3] as well as in rats across a variety of procedures including delayed matching to sample (DMTS), [4][5][6] the radial arm maze, [7][8][9] passive avoidance learning, 10,11 the double Y-Maze, 12 repeated acquisition procedures, 13,14 and the olfactory span task. 15 Investigations into the neural mechanisms responsible for MDMA's disruptions to memory and cognition have generally focused on the role of serotonin (5-HT; 5-Hydroxytryptamine).…”

“…25 Several studies have directly implicated DA in MDMA-induced memory deficits. 4,8,26 In our laboratory, memory deficits in rats following 3 mg/kg MDMA (i.p.) on an operant delayed matching-to-sample (DMTS) working memory task were ameliorated via concurrent administration of the DA D1-like receptor antagonist, SCH 23390 (i.p).…”