Effects on rat sexual behaviour of acute MDMA (ecstasy) alone or in combination with loud music
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
European Review for Medical and Pharmacological Sciences 2008; 12: 285-292
Effects on rat sexual behaviour of acute MDMA
(ecstasy) alone or in combination with loud music
R. CAGIANO, I. BERA*, R. SABATINI**, P. FLACE^, D. VERMESAN^^,
H. VERMESAN^^, S.I. DRAGULESCU^^, L. BOTTALICO§, L. SANTACROCE#
Department of Pharmacology and Human Physiology, Faculty of Medicine, University of Bari, Bari (Italy)
*“Lucian Blaga” University, Medical School, Sibiu (Romania)
**Dept. of Obstetrics and Gynaecology, General Hospital Policlinico, University of Bari, Bari (Italy)
^Department of Human Anatomy and Histology, Faculty of Medicine, University of Bari, Bari (Italy)
^^University of Medicine and Pharmacy ”Victor Babes”, Timisoara (Romania)
§
School of Dental Hygiene, Faculty of Medicine, University of Bari, Bari (Italy)
#
Dept. of Internal Medicine, Infectious Diseases and Immunology, Faculty of Medicine,
University of Bari, Bari (Italy)
Abstract. – The effects on sexual behaviour gained increased popularity during the last
of acute low doses of methylendioxymethamphet- decade in many countries of the world despite
amine (MDMA) (0.3, 1, 3 mg/kg/i.p.), alone or in legislative action to limit its distribution. MD-
combination with exposure to loud music (1 h
stimulation), were investigated in Wistar rats. Re-
MA, structurally related to the stimulant amphet-
sults indicate that acute MDMA, at dose of 3 amine and the hallucinogen mescaline, is able to
mg/kg, notably impaired copulatory behavior of cause serotonergic and dopaminergic neural toxi-
sexually experienced male rats. city in every species tested and short term
In particular, MDMA-exposed animals exhibited changes in noradrenergic system. Its acute effects
a significant increase in intromission and ejacula- appear to be mediated by the release and reup-
tion latencies as well as a significant decrease in take inhibition of brain monoamines, particularly
percentage of rats displaying copulatory activity
(one intromission at least). Surprisingly, one hour serotonin and dopamine1-3. It is well known that
exposure to loud music, which per se resulted in- these biogenic amines have been implicated as
effective, antagonized the suppressive effect of facilitatory (dopamine) and inhibitory (serotonin)
MDMA by increasing the percent of animals dis- mediators of sexual desire, arousal and orgasm4,5.
playing sexual activity. However, combined treat- Furthermore, recent findings demonstrate that
ment of MDMA and music stimulation did not ful- serotonin is important for male reproductive de-
ly restore normal sexual behavior as the animals
reaching ejaculation still showed a marked reduc-
velopment6. Taken together, these evidences sug-
tion of copulatory efficiency. gest that the acute and long-term exposure to
These findings demonstrate that the systemic MDMA might affect sexual function and genital
administration of a single low dose of MDMA, morphology. In fact, in spite of its mentioning as
alone or in combination with loud music, which aphrodisiac, there are empirical and experimental
is commonly present in certain environments evidence that MDMA impairs human sexual dri-
such as rave parties, notably impairs copulatory ve and behaviour. However, several methodologi-
activity of male rats.
cal limitations associated with clinical studies
Key Words: such as the heterogeneity of human MDMA con-
sumption, confounding variables such as doses,
MDMA, Loud music, Sexual behavior, % of ejaculat-
ing rats, Copulatory efficiency. purity of the substance, duration and time of ex-
posure, indicate that preclinical studies are need-
ed in allowing a definitive account for the MD-
MA sexual properties. Surprisingly, to our
Introduction knowledge, only one study investigated, so far,
the effects of MDMA on sexual function in male
The recreational use of 3,4-methylen- rats7. In particular, Dornan et al. found a transient
dioxymethamphetamine (MDMA or Ecstasy) has disruption of male copulatory behaviour after a
Corresponding Author: Raffaele Cagiano MD; e-mail: r.cagiano@farmacol.uniba.it 285R. Cagiano, I. Bera, R. Sabatini, P. Flace, D. Vermesan, et al.
sub-chronic treatment with high doses (40 session, males with similar performance were
mg/kg) of the drug. Nevertheless, MDMA users equally distributed into eight experimental
typically consume much lower doses than those groups (10 per group).
used in animal studies8-10. Moreover, the effect of Four groups received three MDMA dose levels
acute low doses of MDMA on sexual behaviour (0.3, 1, 3 mg/kg) and MDMA-vehicle (control)
remained unexplored. Therefore, further investi- one hour before the test session. The drug was
gations on acute and chronic effects of low to dissolved in 0,9% saline and injected intraperi-
moderate doses of MDMA in rodents result nec- toneally (i.p.) at the volume of 1 ml/kg. Human
essary to reach a predictive clinical value. A fur- MDMA users typically consume 1-2 tablets of
ther source of variability in MDMA effects in hu- MDMA in a single session giving an estimated
mans that should be taken into account deals oral dose of 1-4 mg/kg. Allowing for interspecies
with the environmental conditions11,12. In particu- scaling effects and differences in route of admin-
lar, in most cases, ecstasy is abused in organised istration, the doses of MDMA employed in the
all-night dance parties known as “raves” where present study correspond to a low-moderate ex-
techno-music is played at a high volume. It has posure to “ecstasy” in man8-10. The other four
been demonstrated that music recruits neuronal groups were treated with the same MDMA doses
systems of rewards and emotions similar to those (0.3, 1, 3 mg/kg) and MDMA vehicle (saline) in
known to respond specifically to biologically rel- combination with 1 h exposure to loud music (s).
evant stimuli, such as food and sex and those that The acoustic stimulus (intensity = 88.2-91.8
are activated by drugs of abuse. Techno-music is dBA); frequency = 50 Hz-8 KHz) was delivered
able to activate the noradrenergic system and the for one hour in a sound-attenuating cabin (3.00 x
hyphotalamic-pituitary-adrenal (HPA) axis more 2.00 × 2.00 m) soon after each saline or MDMA
than slow music, producing a neuroendocrine administration. At the beginning of the experi-
pattern similar to that elicited by psychological ment, the sound pressure level was measured by
stress13,14. an integrated Bruel & Kjaer phonometer placed 3
The aim of the present study was to address meter far from the location of the animal rack.
both these issues, namely the acute effect of Male rats were then tested for sexual activity in a
moderate MDMA doses on rat sexual function 30 min test session.
and the concomitant exposure to loud music.
Drugs
MDMA, (±)-3,4-methylendioxymethampheta-
mine hydrochloride, (SALARS s.p.a., Como,
Materials and Methods Italy) was dissolved in 0,9% saline and injected
i.p. at a volume of 1 ml/kg. Control rats received
Procedure equivalent i.p. injections of saline.
The experiments have been conducted in ac-
cordance with guidelines released by Italian Min- Sexual Behaviour and
istry of Health (D.L. 116/92 and D.L. 111/94-B), Ultrasonic Emission
the Declaration of Helsinki, and the Guide for These study procedures had been performed
the Care and Use of Laboratory Animals as according with the original protocols by Ca-
adopted and promulgated by the National Insti- giano et al.15,16. As stimulus females we used
tutes of Health (USA). Male and female rats bilaterally ovariectomized rats in which oestrus
were housed under a reversed 12/12 light/dark had been induced by subcutaneous injection of
cycle (light on: 20.00h-08.00 h) for two weeks estradiol benzoate (8 µg/rat) and progesterone
before testing, with food and water ad libitum at (200 µg/rat) dissolved in 0.2 ml of sesame oil,
constant room temperature (20-22°C). Ninety 52 and 4 h before the test session, respectively.
Wistar adult male rats weighing 300-350 g were Sexual behaviour was recorded by a video-tape
used in the following experiments. Each male rat recording unit (JVC videocamera, Videotape
was given sexual screening tests during which it recorder and TV monitor). Ultrasonic calls, de-
was placed, on alternate days, with a sexual re- tected by a QMC ultrasonic microphone con-
ceptive female until one ejaculation was achieved nected to a receiver (QMC Bat Detector S200,
during each of the three-30 min tests. Only males London, UK) which transformed, in real time,
reaching this criterion were subsequently used. the ultrasonic calls into audible sounds, were
After successful completion of the last screening sent to the video tape-recorder through the mi-
286Effects on rat sexual behaviour of acute MDMA (ecstasy) alone or in combination with loud music crophone connection terminal of the video Statistical Analysis camera. The experiments, performed in the Depending on the omo or heteroschedasticity central part of the dark period (12.00h-16.00h), of the data, statistical analysis was based on para- were carried out in a sound-attenuating cabin metric (two-way ANOVA followed by Tukey’s (Amplifon G-type cabin) under red illumina- Multiple Comparison Test) or non parametric test tion provided by two 40 W fluorescent lamps. (Kruskal-Wallis ANOVA followed by Dunn’s Each male rat was observed alone for 5 min. Multiple Comparison Test). Fisher’s exact test An oestrous female was then introduced into was used where appropriate. the centre of the arena and the behaviour of the couple was then recorded. Each test lasted a maximum of 30 minutes if no ejaculation was achieved or until one ejaculation followed by Results an intromission was achieved. If no intromis- sion was displayed within the first 15 minutes, Sexual Behaviour and the test terminated and the male was considered Ultrasonic Emission a “non copulator”. Video tape-recordings were The results indicate that MDMA treatment no- later replayed and analysed (in slow motion tably impaired the copulatory behaviour of sexu- when necessary) and the following parameters ally vigorous experienced male rats only at the were measured: (ML) mount latency (time be- dose of 3 mg/kg. As far as the latency to the first tween the introduction of the female into the intromission, Kruskal-Wallis ANOVA gave the mating cage and the first mount in the first following significant difference: H=51.14, df=7; ejaculatory series); (IL) intromission latency p
R. Cagiano, I. Bera, R. Sabatini, P. Flace, D. Vermesan, et al.
Intromission latency (sec) Figure 1. Effects of acute
2000
MDMA (0,3-1-3 mg/kg, i.p.)
or MDMA vehicle (saline)
1800
treatment, given alone or in
combination with sound
1600 stimulation (s) on Intromis-
sion Latency (I/L) of sexual-
1400 ly experienced male rats. Da-
ta are expressed as median
1200 values and interquartiles.
(_ _ _ ). *pEffects on rat sexual behaviour of acute MDMA (ecstasy) alone or in combination with loud music
Figure 3. Effects of acute EjL (sec)
MDMA (0,3-1-3 mg/kg; 2000
i.p.) or MDMA vehicle
(saline) treatment, given 1800
alone or in combination
with sound stimulation (s) 1600
on Ejaculation Latency
1400
(EjL) of sexually experi-
enced male rats. Data are
1200
expressed as mean values ±
S.E.M. *pR. Cagiano, I. Bera, R. Sabatini, P. Flace, D. Vermesan, et al.
% of rats achieving ejaculation Figure 5. Effects of acute
1 MDMA (0,3-1-3 mg/kg;
i.p.) or MDMA vehicle
0.9 (saline) treatment, given
alone or in combination
0.8 with sound stimulation (s)
on copulatory efficiency.
0.7 Data are expressed as mean
values ± S.E.M. *pEffects on rat sexual behaviour of acute MDMA (ecstasy) alone or in combination with loud music
implicated in reward and emotion. The activation modulating sexual arousability and satiation. In-
of the reward system by music may maximize terestingly, clinical studies have shown an im-
pleasure, not only by activating the reward sys- pairment of sexual drive and performance after
tem, but also simultaneously decreasing activity MDMA-ingestion, which may be caused by the
in brain structures associated with negative emo- MDMA-induced secretion of prolactin leading to
tions and could explain the improvement of sexu- a psychophysical equivalents state of sexual sati-
al activity in presence of music stimulation, as ation compared to the post-orgasmic period20.
obtained in our experiments. The main limitation Therefore, the results of our study, showing a
of the present study is clearly the lack of neuro- marked impairment of sexual performance in ex-
chemical analysis of the brain of rats treated with perienced MDMA treated rats, which is in line
both low MDMA doses and music stimulation. with clinical data, could explain the frequent ob-
The hypothesis that the observed effects on sexu- servations of 22 kHz calls in non-copulating
al performance are related to the action of MD- MDMA-treated animals, mainly in the absence
MA on brain 5HT and DA systems, needs further of music stimulation (data not shown). These
scientific demonstration. The neurobiological post-orgasmic vocalizations (22 kHz) occur con-
substrate of human sexuality is, up to now, still currently with the absolute refractory period dur-
poorly understood. Current hypothesis suggest ing which the male is incapable of renewed sexu-
that dopaminergic activity in nucleus accumbens al activity. Even if their communicative function
(NAc) is associated with sexual desire and erec- is not yet established, it has been suggested that
tile response while central serotonergic activity is 22 kHz calls serve to discourage other males
inhibitory to erectile and orgasmic function5. The from mating with the same female or to keep the
stimulant and rewarding properties of MDMA female at a distance during the total postejacula-
are in part thought to arise from the activation of tory refractory period21.
mesolimbic dopaminergic neurons in the Ventral In conclusion, these data demonstrate that
Tegmental Area (VTA) which project to NAc. MDMA, even in low doses, can disrupt sexual
MDMA causes simultaneous release of 5-HT and performance of experienced male rats and that
both transporter-mediated and impulse-mediated this effect is blunted by strong sensorial stimula-
DA release, this latter depending on 5-HT trans- tion. Our results, therefore, further confirm the
mission and may be explained by the stimulatory role of environmental factors in modulating the
effect of 5-HT 1B/2A and inhibitory effect of 5- central effects of MDMA, even if the underlying
HT 2C. receptors. Recent findings suggest that mechanisms remain to be elucidated.
MDMA-mediated dopamine (DA) increases,
within the NAC shell, are dampened by the in-
creases in VTA GABA levels subsequent to acti-
vation of 5-HT 2B/2C receptors 19. Furthermore,
pharmacological studies demonstrated that drugs References
which enhance serotonergic activity elevate
serum corticosterone and/or prolactin (PRL) con- 1) KOCH S, GALLOWAY MP. MDMA induced dopamine
centrations making these as sensitive indicators release in vivo: role of endogenous serotonin. J
of 5HT receptor stimulation. Serum level of PRL Neural Transm 1997; 104: 135-146.
were significantly increased by MDMA at doses 2) SHANKARAN M, GUDELSKY GA. Effect of 3,4-methyl-
ranging from 1 to 20 mg up to 4 h after ingestion enedioxymethamphetamine (MDMA) on hip-
of the drug. Recent neuroendocrine studies, ex- pocampal dopamine and serotonin. Pharmacol
amining the effects of sexual arousal and orgasm Biochem Behav 1998; 61: 361-366.
in humans, demonstrated a marked elevation of 3) STEELE TD, MCCANN UD, RICAURTE GA. 3,4-Methyl-
plasma prolactin in both males and females im- enedioxymethamphetamine (MDMA, "Ecstasy"):
mediately after orgasm. As prolactin was shown pharmacology and toxicology in animals and hu-
mans. Addiction 1994; 89: 539-551.
to be a robust marker of orgasm, it may act as pe-
ripheral neuroendocrine reproductive reflex (im- 4) K APLAN HS. Psychogenic impotence. Curr Ther
proving fertility and conception) and/or as a Endocrinol Metab 1994; 5: 323-328.
feedback signal to neuronal systems that may 5) S CHIAVI RC, S EGRAVES RT. The biology of sexual
mediate sexual arousability and satiation follow- function. Psychiatr Clin North Am 1995; 18: 7-23.
ing orgasm. Prolactin may be able to down regu- 6) ARAGÓN MA, AYALA ME, MARÍN M, AVILÉS A, DAMIÁN-
late the dopaminergic activity in certain areas, MATSUMURA P, DOMÍNGUEZ R. Serotoninergic system
291R. Cagiano, I. Bera, R. Sabatini, P. Flace, D. Vermesan, et al.
blockage in the prepubertal rat inhibits spermato- 14) GERRA G, ZAIMOVIC A, FRANCHINI D, PALLADINO M,
genesis development. Reproduction 2005; 129: GIUCASTRO G, REALI N, MAESTRI D, CAC-CAVARI R, DEL-
717- 727. SIGNORE R, BRAMBILLA F. Neuroendocrine responses
of healthy volunteers to “techno-music”: relation-
7) DORNAN WA, KATZ JL, RICAURTE GA. The effects of ships with personality traits and emotional state.
repeated administration of MDMA on the expres- Int J Psycho-physiol 1998; 28: 99-111.
sion of sexual behavior in the male rat. Pharma-
col Biochem Behav 1991; 39: 813-816. 15) CAGIANO R, BARFIELD RJ, WHITE NR, PLEIM ET, WEIN-
STEIN M, C UOMO V. Subtle behavioural changes
8) BOOT BP, MCGREGOR IS, HALL W. MDMA (Ecstasy) produced in rat pups by in utero exposure to
neurotoxicity: assessing and communicating the haloperidol. Eur J Pharmacol 1988; 157: 45-50.
risks. Lancet 2000; 355: 1818-1821.
16) CAGIANO R, ANCONA D, CASSANO T, TATTOLI M, TRABACE
9) TOPP L, HANDO J, DILLON P, ROCHE A, SOLOWIJ N. Ec- L, CUOMO V. Effects of prenatal exposure to low
stasy use in Australia: patterns of use and associ- concentrations of carbon monoxide on sexual be-
ated harm. Drug Alcohol Depend 1999; 55: 105- haviour and mesolimbic dopaminergic function in
115. rat offspring. Br J Pharmacol 1998; 125: 909-915.
10) VOLLENWEIDER FX, GAMMA A, LIECHTI M, HUBER T. 17) B UFFUM J, M OSER C. MDMA and human sexual
Psychological and cardiovascular effects and function. J Psychoactive Drugs 1986; 18: 355-
short-term sequelae of MDMA (“ecstasy”) in MD- 359.
MA-naïve healthy volunteers. Neuropsychophar-
macology 1998; 19: 241-251. 18) ZEMISHLANY Z, AIZENBERG D, WEIZMAN A. Subjective
effects of MDMA (“Ecstasy”) on human sexual
11) GESI M, SOLDANI P, LENZI P, FERRUCCI M, GIUSIANI A, function. Eur Psychiatry 2001; 16: 127-130.
FORNAI F, PAPARELLI A. Ecstasy during loud noise ex-
posure induces dramatic ultrastructural changes 19) BANKSON MG, YAMAMOTO BK. Serotonin-GABA in-
in the heart. Pharmacol Toxicol 2002; 91: 29-33. teractions modulate MDMA-induced mesolimbic
dopamine release. J Neurochem 2004; 91: 852-
12) GESI M, FERRUCCI M, GIUSIANI M, LENZI P, LAZZERI G, 859.
ALESSANDRÌ MG, SALVADORINI A, FULCERI F, PELLEGRINI
A, FORNAI F, PAPARELLI A. Loud noise enhances ni- 20) PASSIE T, HARTMANN U, SCHNEIDER U, EMRICH HM,
grostriatal dopamine toxicity induced by MDMA KRÜGER TH. Ecstasy (MDMA) mimics the post-or-
in mice. Microsc Res Technique 2004; 64: 297- gasmic state: impairment of sexual drive and
303. function during acute MDMA-effects may be due
to increased prolactin secretion. Med Hypotheses
13) BLOOD AJ, ZATORRE RJ. Intensely pleasurable re- 2005; 64: 899-903.
sponses to music correlate with activity in brain
regions implicated in reward and emotion. Proc 21) BARFIELD RJ, GEYER LA. Sexual behavior: ultrasonic
Natl Acad Sci USA 2001; 98: 11818-11823. postejaculatory song of the male rat. Science
1972; 176: 1349-1350.
292You can also read
