What is sensitisation

1
What is sensitisation?

• Many drugs of abuse, including the psychomotor
  stimulants, nicotine, caffeine, opiates, and
  alcohol, induce increases in locomotor activity.
  
• If the same dose of these drugs is given on
  several occasions, the increase in locomotion
  becomes greater with each successive drug
  treatment.
• Furthermore, there is a shift of the dose
  response curve for the drugs ability to
  stimulate locomotor activity to the left.
• For some drugs, there is also an increase in the
  asymptotic ability of the drug to increase
  locomotor activity.
• This general phenomenon is known as behavioural
  sensitisation.

2
Behavioural sensitisation to cocaine
3
Does sensitisation occur to all drugs of
addiction?

• Psychostimulants - Yes
• Dopamine agonists - Yes
• Alcohol - Yes, but not impressive
• Opiates - Yes
• Dissociative anaesthetics - Yes
• Benzodiazepines - No

4
Characteristics of Behavioural Sensitisation

• requires intermittent exposure to drug
•  very long lasting - months, and possibly
  life-long

5
During sensitisation, both associative and
non-associative mechanisms appear to be at play

•   animals which experience the drug repeatedly
  in one environment, and show sensitisation, but
  then receive it in a novel environment, may not
  show sensitisation relative to animals receiving
  the drug for the first time (Stewart and
  colleagues, Robinson and colleagues).
•        animals which repeatedly experience drug
  in a particular environment, and are then tested
  drug free in that environment, show increased
  levels of activity relative to animals which had
  not received drug in that environment

6
Amphetamine-induced locomotion following
sensitisation in circular runways
Test in same environment as
sensitisation
100
75
Activity in circular
runways
50
25
0
Saline
Amphetamine
7

• Such data suggest that behavioural sensitisation
  depends partly on conditioning.
• Nevertheless, sensitisation can occur when
  animals receive drugs in different environments,
  consistent with sensitisation resulting directly
  from the drugs interaction with the brain.
• It is difficult to rule out a role for
  conditioning in such circumstances since
  presumably the CS could be the feel of the drug,
  or the enhanced locomotor activity, or a number
  of other commonalities between the different test
  situations.

8
Neural substrates of Behavioural Sensitisation
(see also Psychopharmacol 15199-120 (2000)

• Two major correlates of amphetamine sensitisation
  are enhanced dopamine release in accumbens, and
  increased sensitivity to dopamine D1
  receptor-mediated responses .
• The neural sites of drug action necessary for the
  induction of sensitisation are different from
  those important in the expression of
  sensitisation. Although behavioural sensitisation
  is neurochemically expressed in accumbens, the
  induction of sensitisation seems to depend on
  events in VTA.

9
Neural substrates of Behavioural Sensitisation

•          daily microinjections of amphetamine
  into accumbens, striatum or prefrontal cortex do
  not induce sensitisation, whereas daily
  microinjection into VTA does. Thus amphetamine
  acts at the somatodendritic region of the VTA to
  induce sensitisation, whereas the action of the
  drug at the terminal regions are necessary for
  the expression of sensitisation
•          but, behavioural sensitisation induced
  by repeated amphetamine administration to VTA, is
  associated with increased DA release in accumbens
  (as it is with sensitisation from intra VTA
  morphine, enkephalin, etc.)
•          and blocking VTA dopamine receptors
  with D1 antagonist SCH23390 prevents
  sensitisation to systemic amphetamine or
  morphine.

10
Which neural systems are involved?

• Sensitisation occurs in the neural systems
  important in mediating the incentive motivational
  effects of drugs, i.e., in the mesolimbic system
• Sensitisation resembles other forms of neuronal
  plasticity, such as long term potentiation it
  can be blocked by antagonists acting at
  NMDA-types of glutamate receptor.

11
Co-administration of an NMDA antagonist into VTA
with amphetamine blocks sensitisation
Cador et al,1999
12
Neuronal plasticity and sensitisation?

• Behavioural sensitisation to psychomotor
  stimulants can be blocked by
• glutamate antagonists
• calcium channel blockers
• protein synthesis inhibitors such as anisomycin
• These sorts of observation suggest that the
  mechanisms underlying behavioural sensitisation
  resemble the mechanisms underlying synaptic
  plasticity involved in long term potentiation
  (LTP), certain forms of learning, and epilepsy
  (kindling).
• A feature of several of these phenomena is that
  the increase in synaptic efficiency involves NMDA
  subtypes of glutamate receptor, but that once the
  synaptic change has taken place, then the
  increased efficiency of transmission is no longer
  dependent on NMDA receptors, but on AMPA types of
  glutamate receptor.

13
Cocaine-sensitised rats show changes in
expression of AMPAergic GluR1 subunits in N.
Accumbens
Churchill et al, 1999
14
Cocaine-sensitised rats show increased expression
of GluR1 and NMDAR1 subunits in VTA
Churchill et al, 1999
15
Changes in AMPA receptor- mediated effects after
sensitisation

• Cocaine induces glutamate release in accumbens,
  and this effect is enhanced in sensitised animals
  (Pierce et al, 1996).
• Sensitised rats show increased locomotor
  stimulant effects of AMPA infusions into
  accumbens (Pierce et al, 1996).
• Accumbens receives glutamate inputs from several
  areas Activation of hippocampal afferents leads
  to behavioural activation, amygdala to freezing
  (Pierce Kalivas, 1997).

16
Effects of AMPA Antagonist NBQX on amphetamine (1
mg/kg) -conditioned activity
150

Vehicle
100
mean activity counts (sem)
NBQX (15 mg/kg)

50
0
control
CS
17

• Does GluR1 deletion prevent appetitive
  conditioning?
• Which properties of conditioned stimuli are
  impaired?

18
Facilitated behavioural sensitisation and
impaired responding for a conditioned reinforcer
in Gria1 knockouts
19
What has all this to do with drug abuse?

• Does an organism's vulnerability to drug abuse
  relate to the state of the neurobiological
  systems underlying sensitisation, conditioning,
  etc.?
• Does sensitisation occur in human addicts?
• Little evidence that human addicts show
  sensitisation to the rewarding effects of
  psychomotor stimulants (tolerance may occur).
• Some indication that repeated use of psychomotor
  stimulants may lead to sensitisation to
  stimulant-induced psychosis, but relevance to
  drug abuse unclear.
• Schenk and colleagues have suggested that if
  sensitisation plays a part in addiction, then
  children who receive psychomotor stimulants for
  the treatment of attention deficit
  disorder/hyperactivity syndrome (ADHD) might show
  increased incidence of psychomotor stimulant
  addiction as adults. Studied 3 groups of adults
  who were diagnosed as ADHD and received Ritalin
  (methylphenidate), or did not receive
  pharmacological treatment, or controls. Some
  evidence of a higher incidence of cocaine use
  among the Ritalin group.

20
Addiction as aberrant learning

• Positive incentive theories of drug abuse invoke
  the ability of environmental cues conditioned to
  rewards to influence behaviour.
• Cues conditioned to rewards may influence
  behaviour in several different ways
• strengthening drug seeking behaviour
• acting as rewards in their own right
• inducing relapse following abstinence
• Sensitisation of pathways serving these
  behaviours may facilitate drug taking

21
Behavioural Sensitisation

• Repeated drug administration leads to facilitated
  transmission in neuronal pathways underlying
  stimulant drug effects
• Does a related sensitisation occur in pathways
  subserving incentive to take drug (Robinson and
  Berridge)?

22
Incentive sensitisation theory of addiction

• Robinson and Berridge (1993) suggest that the
  significance of sensitisation lies in the fact
  that environmental stimuli associated with drug
  taking also come to modulate activity in the
  dopaminergic mesolimbic pathways, leading to
  enhanced dopamine release.
• If the neuronal pathways which mediate these
  conditioned effects are neurobiologically
  sensitised, they will exert a much more powerful
  control over behaviour.
• N.B. This notion, as it stands, depends on the
  assumption that the pathways which subserve the
  ability of cues conditioned to drug taking to
  influence drug-seeking behaviour are the same as
  those which subserve locomotor sensitisation.
  This does not seem to be true (Mead et al, Eur J
  Neuroscience, 11 4089-4098 1999).

23
Robinson/Berridge Hypothesis
Pleasure
Pleasant stimulus
Drug US
Liking
Affective actions
Associative Learning
Craving
Incentive Salience Attributor
Incentive CS/ Wanting
Attraction
CS
Consumption
Drug
Drug withdrawal
24
Does sensitisation have implications for drug
self-administration?

• Presensitising rats to amphetamine, increases the
  rate of acquisition of cocaine self-administration
  (Horger et al, P,BB (1990) 37
  707Psychopharmacol (1992) 107 271).
• Blocking the behavioural sensitisation to cocaine
  by treating with an NMDA antagonist, prevents
  prior treatment with cocaine from having
  facilitatory effects on acquisition of
  self-administration
• Mendrek et al (Psychopharmacol (1998) 135 416)
  showed that pre-sensitising rats to amphetamine
  resulted in them achieving higher break-points on
  a PR schedule.

25
Sensitisation of drug reward

• Sensitisation (S) decreases the dose at which
  animals learn to self-administer a drug
  (d-Amphetamine Pierre and Vezina, 1008)
• S produces increase in break point (Lorrain et
  al, 2000)
• S increases learning in place preference (Lett,
  1989)
• S increases the reinstatement sensitivity of a
  priming dose
• S can increase the value of other rewards
  (sucrose Wyvell and Berridge, 2001)
• Open Q What about other rewards (sex, food,
  gambling)

26
hippocampus
pFC
Pallido-Thalamo-Cortical circuit
Amygdala
NAc
Glutamate
Dopamine
VTA
GABA
(Adapted From Jentsch and Taylor 1999)
27
Are some individuals predisposed to being
sensitised?

• Piazza et al (Science 245 1511-1513 (1985)
•          classify rats exposed to a novel
  environment as high or low responders
•          low responders show less sensitivity to
  amphetamine, but following repeated
  administration, eventually sensitise to the same
  level of sensitivity as the high responders
•          low responders did not acquire
  amphetamine self-administration as quickly as
  high responders, but could be converted into fast
  acquiring animals by prior sensitising to
  amphetamine
• Thus, the high responders behave as though they
  are already sensitised to amphetamine.
• Repeated experience of stressful events may
  presensitise some individuals to the psychomotor
  stimulant effects, and thus to drug-taking
  behaviour.

28
Stress and neuronal adaptation within reward
systems.

• Stress (e.g. restraint stress) induces
  sensitisation to behavioural effects of
  amphetamine and apomorphine (e.g. Badiani, P,BB
  43 53 (1992)
• Mild stress (foot shock) given before an
  acquisition session for self-administration of
  heroin gives rise to higher rates of lever
  pressing for heroin at stable performance, and
  higher breakpoints in progressive ratios.
  (Shaham and Stewart, Psychopharmacol 114 523
  (1994)
• Stress causes increase in dopamine release,
  preferentially in prefrontal cortex vs accumbens
  (Sorg and Kalivas)
• NMDA antagonists prevent the ability of
  restraint stress to sensitise mice to apomorphine
  (Mele Psychopharm 117313 (1995)
• Action of stressful stimuli on changes in
  terminal field dopamine transmission may also
  require NMDA receptor-mediated activation in VTA
  (Sorg and Kalivas)
• NMDA antagonists block restraint-stress induced
  increases in DA release in accumbens (Sorg and
  Kalivas).

29
Is facilitated self-administration evidence for
incentive sensitisation, or wanting or craving?

30
Does facilitated self-administration reflect
increased motivational, or increased psychomotor
stimulant effects of drugs?

• For many reinforcement schedules, operant rate
  will be influenced by both motivational
  properties, and stimulant properties of drugs.
• Facilitation of lever pressing by prior
  sensitisation procedures may thus reflect
  psychomotor sensitisation rather than
  sensitisation of incentive properties
• This will especially apply when priming doses are
  given

31
Effect of cocaine administration on operant
responding for sucrose or ethanol
5 mg/kg cocaine
15 mg/kg cocaine
Vehicle
sucrose
ethanol
32
(No Transcript)
33
If incentive sensitisation occurs, then
responding maintained by conditioned reinforcers
should be enhanced

• Prior amphetamine sensitisation facilitates
  acquisition of pavlovian approach during
  conditioning a light to food.
• Acquisition of instrumental responding to obtain
  the CS not facilitated by prior behavioural
  sensitisation (Harmer Phillips, 1996)
• But, prior sensitisation to cocaine facilitated
  potentiation of conditioned reinforcement by
  intra-accumbens amphetamine (Taylor Horger,
  1999)

34
Post-conditioning sensitisation facilitates
pavlovian-instrumental transfer
100
CR

• Training 8 sessions consisting of 90 CS-US
  presentations in operant chambers
• Sensitization Saline (control) or 1.0 mg/kg
  amphetamine for 4 days in operant chambers
  (paired) or different environment (unpaired)
• Test Levers introduced, responding for CS
  assessed
• Mead AN, Crombag HS Rocha BA (Neuropsychopharmac
  ology, 2004)

NCR
75
mean responses (sem)
50
25
0
CONTROL
UNPAIRED
PAIRED
35
Sensitisation-Humans
36
Wild Rat and Wild Human Problem

• Laboratory animals can be pre-sensitised to
  stimulants by stressful events
• Are animals reared in the stressful conditions of
  the wild already pre-sensitised to
  psychostimulants?
• Are wild humans also pre-sensitised by
  srressors?
• If so, does behavioral sensitisation to drugs
  play any role ?