1) Over the last decade, the pattern of MDMA ingestion by humans has often involved repeated..
The predominant acute adverse event following MDMA ingestion is hyperthermia and this can lead to other associated clinical problems. In animal studies, Green reported,.. And Baumann similarly showed
No sig dif in the basal LMA before treatment. 3mg/kg MDMA did not sig alter LMA compared to control. 6mg/kg MDMA produced sig hyperactivity following each 3 injections compared with saline and 3mg/kg MDMA. Peak activity at 40min after 1 st , 2 nd , and 3 rd injections, remained elevated after the 3 rd injection
3mg/kg MDMA sig decreased Tc after each injections compared to saline. Temp returned back to normal 1h after the final injection. 6mg/kg MDMA sig decreased Tc after the 1 st injection. Tc progressively increased after the 2 nd injection and sustained hyperthermia following the 3 rd injection.
Basal 5-HT 0.73 fmol/ul, 0.84 fmol/ul, 0.48 fmol/ul. 6mg/kg MDMA produced a sig increase in 5-HT 40 and 60 min after the 1 st injection (485% and 555%). 3mg/kg MDMA produced a more transient increase in 5-HT with the peak being 134% at 40min after the 1 st injection. The 2 nd injection of 6mg/kg MDMA produced a maximal increase (389%). 3mg/kg MDMA produced a slightly larger increase in 5-HT (284%) 60min after the 2 nd injection. 3 rd injection, 3mg/kg and 6mg/kg MDMA produced an increase about 292% and 315% above baseline. The higher dose of MDMA produced a greater release of 5-HT than the lower dose after the 1 st injection while the magnitude of 5-HT release was similar after the 2 nd and 3 rd administration of both doses. An attenuation of 5-HT release at higher dose of MDMA might be due to inhibition of tryptophan hydroxylase activity and depletion of 5-HT from synaptic vesicles. MDMA-induced 5-HT release has been associated with increase in LMA, but the current study found no apparent relastionship of 5-HT and LMA, since the 3 rd dose produced a marked increase in LMA but no simultaneous increase in 5-HT.
In the familiarisation trial, rats spent a comparable time exploring each of the two objects. In the choice trial, rats treated with saline or 3mg/kg MDMA spent significantly more time exploring the novel object than the familiar object. Rats treated with 6mg/kg MDMA failed to discriminate the novel from the familiar object, spending an equal time exploring both objects. Analysis of the discrimination ratio showed 6mg/kg MDMA rats has sig low ratio. Although 6mg/kg MDMA group spent an equivalent total time exploring both objects in the first trial, they spent sig less total time during the choice trial. In addition to being unable to differentiate the novel and familiar objects during the choice trial, they also spent less time attending both objects specifically during the 2 nd trial, suggesting that a change in motivation and attention span might contribute to the impairment in recognition memory.
1) Repeated injection of either doses of MDMA had no sig effect on the post-mortem 5-HT concentration in the hippocampus, striatum or frontal cortex.
Journal club 15aug11
Rodsiri R, Spicer C, Green AR, Marsden CA, Fone CF (2011) Psychopharmacology 213: 365-376
Background <ul><li>In humans, MDMA was taken in repeated low-dose over a single short time period – ‘binge use’. </li></ul><ul><li>Enhances MDMA subjective effects and sustains the actions of the drug over time. </li></ul>
Background <ul><li>Hyperthermia </li></ul><ul><ul><li>Dose-dependent hyperthermia following repeated MDMA (2, 4 and 6 mg/kg X 3 every 3h). (Green et al., 2004) </li></ul></ul><ul><ul><li>A sustained increase of body temperature (Tc) following MDMA (7.5 mg/kg X 3 every 2h). (Baumann et al., 2008) </li></ul></ul><ul><li>Hyperactivity </li></ul><ul><ul><li>Repeated MDMA (5 mg/kg X 3 every 3h). (Kindlundh-Hogberg et al., 2007) </li></ul></ul><ul><ul><li>Enhanced activity in the centre of the open arena, indicating reduced anxiety or enhanced impulsivity – altered 5-HT neuronal activity. </li></ul></ul>
Background <ul><li>Long-term cognitive deficits </li></ul><ul><ul><li>Previous studies measured behaviour only 7 days after MDMA which used total cumulative MDMA doses of between 40 and 60 mg/kg </li></ul></ul><ul><ul><li>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. </li></ul></ul>
Aims <ul><li>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. </li></ul><ul><li>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. </li></ul>
Methods <ul><li>Male Lister-hooded rats (100-130g) </li></ul><ul><ul><li>Pigmented iris – good visual acuity required for the novel object discrimination task </li></ul></ul><ul><li>Implanted with a transmitter and given 1 week recovery in an individual cage. </li></ul><ul><li>Then, each cage placed over a receiver and normal activity and body temperature monitored continuously for 1 week. </li></ul>
Methods <ul><li>Microdialysis probe (4mm) implanted in hippocampus 14days after transmitter implantation. </li></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>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. </li></ul></ul>
Methods <ul><li>Mean body weight of rats was 260-300g. </li></ul><ul><li>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). </li></ul><ul><ul><li>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) </li></ul></ul><ul><ul><li>In rats, 3mg/kg of MDMA produced a peak plasma of 330 ng/ml. </li></ul></ul><ul><ul><li>5mg/kg X 3 at 2h intervals produced a plasma concentration of 700ng/ml. (Starr et al., 2008; Goni-Allo et al., 2008) </li></ul></ul><ul><ul><li>MDMA Cmax 3239ng/ml. (Jaehne et al., 2011) </li></ul></ul>
Methods <ul><li>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 . </li></ul>
Methods <ul><li>Novel object discrimination </li></ul><ul><ul><li>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) . </li></ul></ul><ul><ul><li>2 consecutive 3 min trials (familiarisation and choice) </li></ul></ul><ul><ul><li>24h prior to testing, each rat was habituated for 60min in the absence of any object. </li></ul></ul><ul><ul><li>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. </li></ul></ul>
Methods <ul><ul><li>In the familiarisation trial, rats were exposed to the 2 identical objects followed by a 2h inter-trial interval. </li></ul></ul><ul><ul><li>In the choice trial, one object was replaced with a novel object. </li></ul></ul><ul><ul><li>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). </li></ul></ul><ul><ul><li>Discrimination ratio was calculated (novel/ (novel + familiar). </li></ul></ul>
Conclusion <ul><li>‘ Binge-type’ MDMA administration produced locomotor hyperactivity, changes in Tc and an elevation in hippocampal 5-HT release </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>