Current non-clinical models for assessment of drug dependency

Transcription

Current non-clinical models for
assessment of drug dependency
Pascal Champéroux
23 Sept 2006
Pascal Champéroux – Congrès de la SFT, 23 et 24 octobre 2006, Paris – Copyright © SFT – Tous droits réservés
Two major kinds of drug
dependency
Physical
dependency
Psychic
dependency
Each kind of drug dependency has different
pathophysiological mechanisms
Negative and positive
reinforcements
Withdrawal symptoms
(« feeling bad » avoidance )
Physical
dependency
RRepeated
consumption
R+
Compulsive drug
intake
Psychic
dependency
Positive feeling
(pleasure-seeking )
Drug
abuse
Molecules
Reinforcement - Reinforcement +
Heroin, morphine
nicotine, alcohol
Cocaine, THC
amphetamine
-,?
Benzodiazepines
-
LSD
-
-
Dependence potential of psychoactive drugs is related either to
physical dependency (R-), or psychic dependency (R+), or both at
various degrees depending on the underlying mechanisms
Dependence mechanisms for positive and negative reinforcing
properties are different
=> Needs of different models for assessment of drug dependence
potential
Positive reinforcement mechanisms
Molecules having positive
reinforcing properties lead to
an increased release of
dopamine in the CNS:
-through activation of presynaptic
receptors at the level of
dopaminergic neuronal endings
(cocaine, amphetamine,…)
- through interactions with
dopaminergic neurons causing
central release of dopamine
(opioids, nicotine,…)
From J. Le Houezec, A.I.M, N°43, 1997
Activation of « rewards » pathways
From J. Le Houezec, A.I.M, N°36 sup., 1996
Molecules having positive reinforcing properties activate
dopaminergic « rewards » pathways, in particular in the nucleus
accumbens and the ventral tegmental area
Neurobehavioural models for positive reinforcing properties
assessment (pleasure seeking behaviour) i.e. conditioned place
avoidance, drug discrimination and self administration models, will
be presented by R. Porsolt
Various mechanisms responsible for withdrawal
symptoms depending on addictive drugs
Drugs
Receptors
Cellular mechanisms
Heroin, morphine
µ opioid
Down regulation
Activation of anti-opioid
(cholecystokinine)
Crossed desensitisation with
adrenergic systems
Nicotine
nicotinic
Up regulation (no tolerance)
Benzodiazepines
GABA A
Receptor desensitisation
NMDA
GABA
Up regulation
Desensitisation
Crossed desensitization with
noradrenergic systems
Opioid like effects
Alcohol
No single mechanism for physical dependency
Example of mechanism causing withdrawal
symptoms : down regulation
Stimulation : full effect
Need for higher doses
for the same effect = tolerance
Internalisation or desensitisation
of receptors
=> decreased effect
Cessation of administration
=> Relative endogenous opioids deficit
Reappearance of receptors
=> Withdrawal symptoms
From J. Le Houezec, A.I.M, N°36 sup., 1996
Tolerance assessment
Tolerance assessment protocol
Principle : evaluation of the need for increasing doses to
achieve the same effect
Step 1 : characterisation of central effects by FOB procedure
and definition of a starting dose giving a clear and representaive
pharmacological effect : e.g. ataxic effect for diazepam
Step 2 : Start of repeated administration twice a day at
minimum or less depending on pharmacokinetic data
Each day of treatment : FOB at a fixed post dosing time (Tmax)
If decrease in the reference effect : increase of the dose by 1020 % from the next day
End of treatment : after 2 weeks, since tolerance phenomena
usually appear rapidly
Tolerance assessment protocol : example of choice
of reference effect
A FOB grid enabling
quantitative assessment of
clinical scores is preferable
Example : a median
score of 3 for ataxic gait
can be used for diazepam
A combination of several
scores can be used
The reference effect
must be sufficiently strong
but should allow recovery
between each drug
administration
Tolerance assessment : example with
chlordiazepoxide in rats
900
800
700
600
500
mg/kg
400
300
200
100
0
From Ryan and Boisse,
D2 D5 D10 D35
JPET, vol 226, N°1, 1983
Doses of chlordiazepoxide causing an equipotent ataxic effect were
determined from D2 to D35 after starting chronic treatment
The equipotent dose of chlordiazepoxide on D35 was approximately 9
times greater than on D2
Tolerance is a strong indicator of physical dependency
No tolerance does not mean no physical dependency : e.g. nicotine (up
regulation)
Spontaneous withdrawal
Spontaneous withdrawal after short term treatment
in rats : examples of morphine and diazepam
Drugs
Clinical signs at the end of
treatment
Clinical signs following
cessation of treatment
Morphine 30
mg/kg p.o. for
9 days
Insensitivity to tail and ear
pinch
(analgesic effect)
Sedative effects were
observed within the first
days of treatment only
(tolerance)
Passivity to head touch in 20 %
of animals
Absent or reduced locomotor
activity
Recumbent position
Passivity (finger approach)
Decrease in abdominal tone
Exaggerated biting reflex
(irritability, aggressivity ?) in 50
% of animals
(From CERB,
2001)
Diazepam 20
mg/kg i.p. for
4 days
(From CERB,
2001)
From CERB, 2001
Short term treatment with fixed doses does not enable
observation of withdrawal symptoms because of no tolerance is
induced
Evaluation of signs of hypermotility in short term
studies with quantitative procedures : example with
morphine
250
NS: P>0.05
200
150
Classical signs of withdrawal syndrome
are due to a central hyperexcitability
causing signs such as hypermotility,
tremors, increased muscular tone,
increased reactivity
Precise measurement of locomotor
activity or anxiety state could be considered
as more sensitive than FOB for detection of
withdrawal symptoms
Sec.
100
50
0
D1
D2
Vehicle
D3
D4
Morphine
The bargraph presents results obtained
with the tail suspension test (Porsolt).
Results are expressed as time of immobility
after cessation of a 9-day treatment with
morphine 30 mg/kg/day
From CERB, 2001
No sign of hypermotility and/or anxiety was found. We found similar results with
the open-field test and other molecules such as diazepam in short term studies
Conclusion : Quantitative procedures for hypermotility or anxiety state
assessment does not significantly improve detection of symptoms of withdrawal
when compared to FOB procedures
Spontaneous withdrawal after subchronic treatment
in rats : example of chlordiazepoxide
Drug
Chlordiazepoxide
Increasing doses from
163 (D1) to 893 mg/kg
(D35) to maintain a
constant CNS
depression score
Clinical signs following
cessation of treatment
Twitches
Tremors
Increased muscle tone
Tail erection
High step gait
Piloerection
Increased struggle response
Increased startle response
900
800
700
600
500
mg/kg
400
300
200
100
0
D2 D5 D10 D35
JPET, vol 226, N°1, 1983
Several weeks of dosing and acquisition of tolerance were
necessary for observation of clear withdrawal symptoms after
abrupt cessation of treatment
Remark : such treatment protocol mimics more closely
conditions of drug abuse than does a fixed dose
Spontaneous withdrawal after subchronic treatment
in rats : chlordiazepoxide
JPET, vol 226, N°1, 1983
Signs of withdrawal appeared progressively from the 3rd day after cessation of
treatment and disappeared within 2 weeks
A silent period of 3 days (1 to 3) after cessation of treatment was noted by the
authors => symptoms of withdrawal should be investigated for 1 week at least
after cessation treatment (same remark for diazepam, Steppuhn et al, Proc. Natl.
Acad. Sci., Vol 90,1993)
Precipitated withdrawal
Principle of precipitated withdrawal
Stimulation : full effect
Need for higher doses
for the same effect = tolerance
Internalisation or desensitisation of
receptors
=> decreased effect
Cessation of administration
=> Relative endogenous opioids deficit
Reappearance of receptors
Endogenous opioids stimulation
suppressed by naloxone (opioid
antagonist)
=>enhancement of withdrawal
symptoms
Precipitated withdrawal by naloxone : protocol of
Sealens test in mice
Drug
Progression of doses
(mg/kg, p.o.)
Cumulated
dose over 4
days
LD50
(p.o.)
Morphine
D1: 20, 30, 40, 50, 50
D2: 75, 75, 75, 75
D3: 75, 75, 75, 75
D4: 100, 100
990 mg/kg
~900 mg/kg
Codeine
D1: 20, 30, 40, 50, 50
D2: 75, 75, 75, 75
D3: 75, 75, 75, 75
D4: 100, 100
990 mg/kg
~500 mg/kg
Loperamide
D1: 5, 10, 10, 10,10
D2: 15, 15, 15, 15
D3: 20, 10,10,20
D4: 25, 25
215 mg/kg
~200 mg/kg
From CERB,
S. RICHARD, 1985
A rapid tolerance is induced by giving increasing doses over a short
period
The cumulative doses should approach acute toxic doses
Precipitated withdrawal by naloxone 30 mg/kg i.p.
70
60
50
Number 40
of jumps 30
20
10
0
Naloxone alone
Morphine
Codeine
Loperamide
From CERB,
S. RICHARD, 1985
Administration of naloxone causes immediately a precipitated
withdrawal syndrome characterised by a large number of jumps over the
10 min period of observation
Precipitated withdrawal by RO-15-1788 in mice
100
90
80
% of
70
60
animals
50
exhibiting 40
convulsions 30
20
10
0
RO-15-1788 10mg/kg
alone
RO-15-1788 2.5 mg/kg
RO-15-1788 5 mg/kg
RO-15-1788 10 mg/kg
From Patel et al. Pharmacol.
Biochem. Behav. Vol 29, 1988
A rapid tolerance is induced by giving increasing doses over a short 9
day period (twice a day, starting from 50 mg/kg to 450 mg/kg, p.o. on D9)
On D10, administration of a benzodiazepine antagonist, RO-15-1788
immediately causes a precipitated withdrawal syndrome characterised by
convulsions
Spontaneous and precipitated withdrawal :
conclusions
Tolerance should be assessed prior to withdrawal studies (preliminary
study)
If a tolerance appears, it must be further induced for demonstration of
withdrawal symptoms, whatever the model (spontaneous or precipitated)
Precipitated withdrawal with selective antagonist enables a shorter and
more sensitive evaluation of physical dependency potential
For new classes of molecules with new mechanisms of action:
- precipitated withdrawal models might not be feasible (if no
antagonist is available)
- use of selective antagonist may be useful to detect crossed
dependence
Alternative model
EEG threshold to hexobarbital in rats : example of
diazepam and lorazepam (Kormaz et al., 1997)
Principle : withdrawal symptoms, i.e. hypermotility, convulsions,… are
signs of a central hyperexcitability. Central hyperexcitability could be an
earlier marker of physical drug dependency. Central hyperexcitability is
assessed from the threshold of suppression of EEG activity caused by
an anaesthetic, hexobarbital
Animals were dosed for 4 days or 4 weeks twice a day at fixed doses
with diazepam (20 mg/kg, i.p.) or lorazepam (2 mg/kg, i.p.)
1, 4, 7 and 14 days after cessation of treatment, anaesthesia was
induced with hexobarbital (15 mg/kg/min., iv infusion)
Cortical EEG was recorded from previously implanted electrodes
Time for complete suppression by hexobartital of EEG activity ( burst
suppression) for one second was noted
EEG threshold to hexobarbital in rats : example of
diazepam and lorazepam (Kormaz et al., 1997)
Marked increases in doses of
hexobarbital were required after cessation
of treatment whatever the duration of
previous treatment (4 days or 4 weeks),
suggesting a central excitation
This effect lasted 4 to 7 days, in
accordance with duration of withdrawal
periods found with such benzodiazepines
Measurement of central excitation levels
by the method of EEG threshold to
hexobarbital could be envisaged as the
basis for a short term study for evaluation
of physical dependence potential
Other physical dependence inducers
should be tested to confirm the reliability of
this test for other classes of molecules
From Korkmaz et al.
J. Stud. Alcohol, vol 60, 1997
Acknowledgements :
S.Richard
Anne Maurin
Catherine Beaughard
Emmanuel Bracq

Current non-clinical models for assessment of drug dependency

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