Snmek 1

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Methamphetamine behavioural sensitization in
rodents interactions with selected drugs,and
gender Alexandra ulcová et al. Masaryk
University Brno, Faculty of Medicine, Department
of Pharmacology, Czech Republic
1st Global Conference on Methamphetamine 2008,
Prague. Czech Republic. NO CONFLICT OF
INTEREST
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S y n o p s i s

• behavioural sensitization to methamphetamine
  (MET) in rodents
• - to locomotor stimulation ("open field
  test")
• - to antiaggressive effects ("conflict
  dyadic social interactions")
• - to I.V. self-administration

• cross-sensitization to MET locomotor
  stimulation
• by morphine and MDMA (ecstasy)
• cross-sensitization to MET locomotor
  stimulation by cannabinoid
• CB1 receptor agonist, and inhibition by
  antagonist
• gender differences in behavioural sensitization
  to MET

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• behavioural sensitization to methamphetamine
  (MET) in rodents
• - locomotor stimulation ("open field
  test")
• - antiaggressive effects ("conflict
  dyadic social interactions")
• - I.V. self-administration

• phenomenon occurring after repeated exposure
  to drugs of abuse
• ( Robinson TE Berridge KC. Brain Res Rev
  1993 18247-291)
• it causes the progressive augmentation of
  behavioural responses
• to a drug persisting for long periods
• associated with adaptations in striatal
  neurotransmission, which
• is thought to play an important role in
  certain aspects of drug
• addiction (Ohmori T et al. Behav Pharmacol
  2000 11211-221)
• remarkably, even a single exposure to
  psychostimulant drugs
• such as amphetamines can be sufficient to
  elicit long-lasting
• behavioural sensitization

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• behavioural sensitization to methamphetamine
  (MET) in rodents
• - locomotor stimulation ("open field
  test")
• - antiaggressive effects ("conflict
  dyadic social interactions")
• - I.V. self-administration

Acti-track apparatus (Panlab, S. L., Spain)
Landa L. et al. European Neuropsychpharmacology,
2004, 14 (Suppl.1),  37
5
Singly-housed vs. Group-housed Male mice(The
Observer 3.1, Noldus Information Technology
b.v.,The Netherlands )

• behavioural sensitization to methamphetamine
  (MET) in rodents
• - locomotor stimulation ("open field
  test")
• - antiaggressive effects ("conflict
  dyadic social interactions")
• - I.V. self-administration

aggressive isolate exhibits tail rattling,
aggress. threat, attacks
non-aggressive partner
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Aggressive mice (n11) sensitized with saline
Acts sociable
timid aggressive
locomot.
Aggressive mice (n12) sensitized with MET
Acts sociable
timid aggressive
locomot.
ulcová A, Landa L Behav Pharmacol, 2003, 14
(Suppl.1), 59-60
7

• behavioural sensitization to methamphetamine
  (MET) in rodents
• - locomotor stimulation ("open field
  test")
• - antiaggressive effects ("conflict
  dyadic social interactions")
• - I.V. self-administration

Mean No of inj./session saline sensitized
16.5 MET sensitized 12.8 ?
syringe pump
active inactive nose pokes
after sensitization MET elicits higher effects
?? (correlates with amphetamine results Vezina
et al., 1990)
catheter
Kucerová J et al., Eur Neuropsychopharmacol,
2008, 18 (Suppl.1), 54-55
8

• cross-sensitization to MET locomotor
  stimulation by morphine

N
Mo
Mo / Met
N
Met
Met / Met
Landa et al., Homeostasis Health Dis, 2004, 43
(1), 43-44
9

• cross-sensitization to MET locomotor
  stimulation by MDMA (ecstasy)

MET 1x
MET 6x
vehicle
MDMA 6x
MDMA 1x
wash-out MET
wash-out MDMA
MDMA sens. MET
MET sens. MDMA
after wash-out MET
after wash-out MDMA
Kucerová J et al. Eur Neuropsychopharmacol,
2006, 16,  513
10

• cross-sensitization to MET locomotor
  stimulation by cannabinoid
• CB1 receptor agonist inhibition by
  antagonist

p lt 0.01
N naive mice M 1st dose of
methamphetamine MM methamphetamine challenge
dose after sensitization with methamphetamine C
1st dose of methananadamide CM
methamphetamine challenge dose after
sensitization with methanandamide
Landa L et al. Neuroendocrinol Lett 2006, 27
(1-2) , 63-69
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• cross-sensitization to MET antiaggressive
  effects by cannabinoid
• CB1 receptor agonist (CAN), and
  inhibition by antagonist (AM251)

Landa L et al. Neuroendocrinol Lett 2006, 27
(6), 703-710
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Behavioural sensitization to MET affects
expression of cannabinoid CB1 and dopamine D1
receptors in mouse midbrain
Relative D1 gene expression using real time PCR
Relative CB1 gene expression using real time PCR
V
M
MM
MM
M
V
V mice after application of vehicle M mice
after the 1st application of MET MM mice
sensitized by MET
Landa L, Jurajda M. Int J Neuropsychopharmacol,
2008, 11, Suppl. 1, 234
Landa L, Jurajda M. Eur Neuropsychopharmacol
2007, 17, Suppl. 4, S557
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Expression of cannabinoid CB1 receptors in mice
sensitization and cross-sensitized with
cannabinoid to MET
V
M
CM
V mice after application of vehicle M mice
after the 1st application of methamphetamine
CM mice cross-sensitized with cannabinoid
methanandamide
14
The mechanisms that regulate CB1 receptor
modifications are far from being completely
understood e.g. there is evidence that
internalization of CB1 receptors following
agonist treatment can occur (Hsieh et al., 1999
Coutts et al., 2001) adaptations vary by brain
region (Sim-Selley, 2003).
Detection of CB1 receptors in VTA after
behavioural sensitization to MET I.V.
self-administration in rats using
immunofluorescent method
15
Detection of CB1 receptors in VTA followed by
quantitative assessment using image analysis
system Lucia-G v4.21 (Laboratory Imaging Ltd.,
Prague, Czech Republic)
A part of cryostat sections through the
mesencephalon (stained by Cresyl Violet)
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CB1 receptor density MEAN IMMUNOFLUORESCENCE
BRIGHTNESS OF VTA NEURONES ? Significant
difference when compared with control group
(plt0.05) No significant gender differences.
?? down-regulation ?? - ?? internalization ??
ulcová A et al. Behav Pharmacol, 2007, 18
(Suppl 1),S44
17

• gender differences in behav. sensitization to
  MET

MET elicits higher rewarding effect (intake of
lower doses) in the sensitized animals with
estrus-like conditions estrogen deprivation
attenuated sensitivity to sensitization increase
d vulnerability of females to MET abuse
vs. males estrogen. sens. .
vs. males estrogen. non-sens..
???
???
???
??
???
???
SN
males non- sens.
estrogen. castr. females non-sens.
estrogen. castr. females sens.
castrated females non-sens.
castrated females sens.
males sens.
Kucerová J et al. Eur Neuropsychopharmacol,
2008, 18 (Supl. 1), 54-55
18
Thanks
Department of Pharmacology, Faculty of
Medicine, Masaryk University Brno, Czech
Republic _________________________________________
_ ulcová Alexandra, M.D., Ph.D., Prof. of
Pharmacology Jurica Jan, Pharm.D., Ph.D. Kucerová
Jana, Pharm.D. Landa Leo, MVDr., Ph.D. Nemecek
Michal, M.D. Nováková Jana, M.D.,
Ph.D. Pistovcáková Jana, M.D., Ph.D. lais Karel,
M.D. Vrková Dagmar, MVDr., Ph.D. Zendulka
Ondrej, Pharm.D., Ph.D. Havlícková
Kveta Kucírková Marcela Oplatková Zenka Sedlárová
Kveta Pokludová Marie
Thank you for your attention
19
Further 3 slides are included just for a case of
using during the disccussion.
20

• I.V. self-administration of MET in the model
  of depression
• ( "olfactory bulbectomy" ),
• and effects of selected potential
  antidepressants

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Depression is a heterogenous disorder with
manifestation of pathophysiological changes in
multiple systems

• Bilateral Olfactory Bulbectomy in rats or mice
• Animal Model of Depression

• - psychologist Watson J.B., 1907
• - Caincross K.D. et al., 1975, Pharmacol.
  Biochem. Behav., 3 1063-1067
• Leonard B.E., 1984, Pol J Pharmacol Pharm
  36561-569
• Kelly, J.P. et al. , 1997 , Pharmacol. Ther. ,
  74 299316
• Changes
• behavioural - maladaptation, increased
  irritability
• neurochemical - aminergic neurotransmission
  disorders
• neuroendocrine - increased levels of
  adrenosteroids
• immune - deficits
  

correlate with changes in depressed patients
DEPRESSION DRUG ABUSE
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• I.V. self-administration of MET in the model
  of depression
• ( "olfactory bulbectomy" ),
• and effects of potential antidepressant
  ARIPIPRAZOLE

vs. non- sensit.
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vs. non- sensit.
vs. sham operated
Kucerová J et al., Eur Neuropsycho pharmacol,
2008, submitted
vs. sham operated
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