Rodsiri R, Spicer C, Green AR, Marsden CA, Fone CF (2011) Psychopharmacology 213: 365-376

Background In humans, MDMA was taken in repeated low-dose over

a single short time period – ‘binge use’. Enhances MDMA subjective effects and sustains the

actions of the drug over time.

Background Hyperthermia

Dose-dependent hyperthermia following repeated MDMA (2, 4 and 6 mg/kg X 3 every 3h). (Green et al., 2004)

A sustained increase of body temperature (Tc) following MDMA (7.5 mg/kg X 3 every 2h). (Baumann et al., 2008)

Hyperactivity Repeated MDMA (5 mg/kg X 3 every 3h). (Kindlundh-Hogberg et al., 2007)

Enhanced activity in the centre of the open arena, indicating reduced anxiety or enhanced impulsivity – altered 5-HT neuronal activity.

Background Long-term cognitive deficits

Previous studies measured behaviour only 7 days after MDMA which used total cumulative MDMA doses of between 40 and 60 mg/kg

Many studies demonstrated long-term neurotoxicity of 5-HT nerve endings and changes in behaviour following MDMA administration, but changes in learning and memory and anxiety-related behaviour may occur following exposure to lower doses of MDMA than those inducing 5-HT neurotoxicity.

Aims To use combined radiotelemetry and microdialysis to

allow simultaneous measurement of changes in locomotor activity (LMA), Tc, and 5-HT overflow following ‘binge-type’ repeated administration of low doses of MDMA.

To investigate the long-term consequences of this dosing regime on brain tissue levels of 5-HT and dopamine together with recognition memory using the novel object discrimination task.

Methods Male Lister-hooded rats (100-130g)

Pigmented iris – good visual acuity required for the novel object discrimination task

Implanted with a transmitter and given 1 week recovery in an individual cage.

Then, each cage placed over a receiver and normal activity and body temperature monitored continuously for 1 week.

Methods Microdialysis probe (4mm) implanted in hippocampus

14days after transmitter implantation. Not a primary regulator of either MDMA-induced LMA or

hyperthermia, it would have been difficult to perform microdialysis in multiple areas, such as striatum, hippocampus, and hypothalamus which may be more directly linked to the behavioural parameters recorded.

Since MDMA induces a rapid release of 5-HT in all forebrain regions, it is likely that changes in hippocampus mirror those produced in other brain regions.

Methods Mean body weight of rats was 260-300g. The following day, each rat received either MDMA (3 or 6

mg/kg i.p.) or saline (1 ml/kg i.p.) every 2h over 6h at normal ambient temperature (21 ± 2°C). Blood samples taken from recreational users of MDMA

revealed a mean plasma MDMA of 310 ng/ml (n = 27), with some subjects had a concentration of 750 ng/ml. (Irvine at al., 2006)

In rats, 3mg/kg of MDMA produced a peak plasma of 330 ng/ml.

5mg/kg X 3 at 2h intervals produced a plasma concentration of 700ng/ml. (Starr et al., 2008; Goni-Allo et al., 2008)

MDMA Cmax 3239ng/ml. (Jaehne et al., 2011)

Methods Microdialysis samples were collected every 20min for 1h

before the first injection and until 2h after the last injection at flow rate 1.6µl/min and samples analysed with HPLC-ECD.

Methods Novel object discrimination

Comprised a clear Perspex box in which 2 objects to be discriminated were plastic bottles covered in white masking tape alone (familiar object) or white with 3 horizontal black masking tape rings (novel object).

2 consecutive 3 min trials (familiarisation and choice) 24h prior to testing, each rat was habituated for 60min in

the absence of any object. On the test day, each rat was placed in the arena for 3min

in the absence of any object before being returned to its own cage for 1 min.

Methods• In the familiarisation trial, rats were exposed to the 2

identical objects followed by a 2h inter-trial interval.• In the choice trial, one object was replaced with a novel

object.• Object exploration was recorded (defined as the time spent

sniffing, licking, chewing, or touching the object or directed attention with the nose within 1cm and active vibrissae).

• Discrimination ratio was calculated (novel/ (novel + familiar).

Results

Results

Results

Results

Results

Conclusion ‘Binge-type’ MDMA administration produced locomotor

hyperactivity, changes in Tc and an elevation in hippocampal 5-HT release

No obvious relationships between each other in the magnitude of these changes, suggesting no direct functional association between these parameters and the extracellular 5-HT concentration.

Bing-type dosing also induced a long-term change in recognition memory which occurred without any evidence of simultaneous neurotoxicity of 5-HT nerve endings.