Psychobiology of Addiction

1
Psychobiology of Addiction

• LECTURE 16
•  
• Mechanisms of tolerance
• Dai Stephens
• See also
• http//www.acnp.org/g4/GN401000070/CH070.html

2
Different Forms of Tolerance

• Dispositional or Pharmacokinetic Tolerance
• Due to changes in the rate at which the drug is
  metabolised so that drug concentrations at the
  site of action are reduced
• Pharmacodynamic Tolerance
• Due to adaptive changes within affected systems,
  so that the response is reduced in the presence
  of the drug
• Tachyphylaxis acute tolerance which occurs
  within a short (up to say, 2h) time following
  drug exposure.
• Behavioural Tolerance
• If the drug has a behavioural effect, especially
  if this leads to loss of reward, or increase in
  punishment, (i.e. has a high cost to the animal)
  then tolerance can develop very quickly as a
  result of behavioural adaptation.

3
Storage Depots
Bone and Fat Free Bound
Target Site
Neuronal Receptor
Intestines, kidneys, lungs, sweat glands, etc
Absorbing tissue
Plasma protein Free bound
Absorbs metabolites from bloodstream Kidneys
clear some drugs from bloodstream
Membranes of oral cavity, GI tract, peritoneum,
skin, muscles, lungs
Metabolites
Drug Administration
Gall Bladder
Liver
Oral, intravenous, intraperitoneal, subcutaneous,
intramuscular, inhalation
Excretion
Biotransformation (drug metabolism)
Drug metabolites excreted with bile
Faeces, urine, water vapour, sweat, saliva
4
Pharmacokinetic tolerance

•         Alcohol is metabolised by liver enzymes,
  including alcohol dehydrogenase. Even low alcohol
  levels saturate the enzyme, so that the rate of
  metabolism is largely independent of the amount
  of alcohol absorbed.
•         Following chronic alcohol use there is
  evidence for an adaptation of the enzyme to make
  it more efficient in metabolising ethanol.
•         Some individuals predisposed to
  alcoholism, metabolise alcohol at a faster rate
  than others. This allows them to take in higher
  quantities of alcohol before becoming
  intoxicated. People of Asian origin are more
  likely to succomb quickly to the effects of
  alcohol because they lack an enzyme which breaks
  down alcohol into carbon dioxide and water.
•         In the case of barbiturates, the enzyme
  which metabolises the drug in the liver is
  induced by the drug, leading to more rapid
  metabolism.

5
Pharmacokinetic tolerance

•        Rat pups born to mothers morphine-treated
  weeks before impregnation, show reduced effects
  of morphine. Possibly due to the mothers
  developing antibodies to morphine (or
  morphine/protein complexes) which entered the
  offspring after conception.
•         Acutely, morphine reduces blood flow.
  Following chronic treatment, this effect
  disappears, so that blood flow is normal.
  Impaired blood flow leads to reduced clearance of
  drug from the bloodstream by the liver and
  kidneys, higher plasma concentrations, and higher
  brain concentrations.
•         NB Under pharmacokinetic tolerance, all
  effects of the drug will be diminished.

6
Pharmacodynamic tolerance

• Tachyphylaxis
•         Many drugs show a decline in their
  effects following administration, even though
  plasma and brain levels are increasing.
• Acute Functional Tolerance 

7
Pharmacodynamic tolerance

• Physiological adaptation
• Decremental and Oppositional forms of tolerance
  (within system, and between system tolerance)
• Decremental
• Opioid peptides in human cerebrospinal fluid in 3
  heroin addict groups compared to healthy
  volunteers
• (OBrien et al, Biol Psychiatr. 1988)

Opiates are known to act on locus coeruleus cAMP
systems to inhibit adenylyl cyclase. Opiate
tolerance is associated with upregulation of
cAMP.
8
Pharmacodynamic tolerance

• Oppositional
• Tolerance to benzodiazepines does not appear to
  be associated with changes in numbers of GABAA
  receptors, but may reflect increased activity in
  glutamatergic transmission which compensates for
  the increased inhibitory activity of GABA under
  benzodiazepines (Stephens, 1995).

9
Adaptation to alcohol
10
Behavioural toleranceChen (1968)
Psychopharmacology 12 433

• Design
• Train rats to perform maze to obtain spaghetti
  reward.
• Following stable performance, rats given blocks
  of trials in maze on successive days
• Trial 1 injected with saline
• Trial 2 injected with alcohol (1.2 g/kg)
• Trial 3 no injection
• Trial 4 injected with saline.
• Each animal received a further injection of
  saline 10 mins before entry to maze.
• Two groups
• Behavioural Group alcohol given 10 min before
  rat placed in apparatus.
• Physiological Group alcohol given after trial.
•  4 blocks of trials

11
Behavioural toleranceChen (1968)
Psychopharmacology 12 433
No. Errors
Total trials
No. Correct trials
 
 Behavioural group
Control
30.1
2.5
33.5
0.5
6
8
1st EtOH
26
10
34
4th EtOH
  Physiological group
12
Behavioural tolerance Instrumental
ConditioningCampbell Seiden PBB 1 703 (1973)

• Train rats on DRL schedule, then treat them with
  amphetamine, either immediately before DRL
  session, or after it.
• Amphetamine disrupts DRL performance because the
  animals overrespond. With repeated experience of
  amphetamine given immediately before the session,
  the animals develop tolerance, and show
  unimpaired DRL performance.
• If those rats which received amphetamine after
  the DRL sessions on the same number of occasions
  were now given it immediately before the session,
  DRL performance was disrupted.
• Cannot be due to pharmacokinteic or
  pharmacodynamic tolerance the before group must
  have learned how to compensate for the
  amphetamine in order to obtain maximum reward.

13
Behavioural tolerance Instrumental
ConditioningSchuster (1966)

• Used a schedule with two components, FI and DRL,
  to study amphetamine effects.
• In two rats, tolerance developed to the stimulant
  effects of amphetamine in the DRL component, but
  not in the FI component in which high rates of
  responding had no effect on the numbers of
  reinforcers obtained.
• Since both components were running at the same
  time, tolerance attributable to pharmacodynamic
  or pharmacokinertic explanations can be ruled
  out some form of learning is occurring.

14
Behavioural tolerance Instrumental
ConditioningVogel-Sprott (1981)

• Gave male volunteers treated with alcohol a
  pursuit rotor task. One group, was rewarded with
  money for exceeding their baseline accuracy.
  These subjects developed tolerance, whereas a
  group which did not receive reward showed no
  tolerance.
• Some evidence from the same group that simply
  mentally rehearsing the pursuit rotor task under
  drug gave rise to tolerance

15
Behavioural tolerance Classical Conditioning

• Some idiosyncrasies of drug-related classical
  conditioning 
• Normally expect that the drug acts as an
  unconditional stimulus (UCS), that elicits
  unconditional responses (UCR). The UCS will be
  paired with environmental stimuli which may
  become drug-predictive stimuli (CS), which if
  presented alone will elicit conditional responses
  (CRs) which should resemble drug UCRs.
• In many cases, the CS elicits an opposite effect
  to the drug UCS.
• Siegel proposes that tolerance develops when a
  drug UCS elicits two responses its own UCR, and
  a compensatory response which counteracts the
  drug effect. Over repeated treatments,
  environmental stimuli become associated with the
  compensatory response, so that they elicit a CR
  which acts to oppose the effect of the drug.

16
Behavioural tolerance Classical Conditioning

• If compensatory CRs mediate tolerance, classical
  conditioning theory predictstolerance will be
  situationally specific.
•  
• Case of NE who administered his father morphine
  4x daily for pain control, under the direction of
  a physician. Administration normally occurred
  in bedroom, which was kept dimly lit, and
  contained hospital equipment for the fathers
  treatment. 
• On day in question, the morphine was administered
  in the living room, which was brightly lit, and
  differed in many ways from the sickroom. Reaction
  to drug was particularly severe, and despite
  medical attention the patient died some hours
  later.
• More formal experiments in animals have
  demonstrated situational-specific tolerance for
  opiates, barbiturates, ethanol, nicotine,
  benzodiazepines, using temperature regulation,
  pain, drinking, motor activity, etc as measures.

17
(No Transcript)
18
Behavioural tolerance Classical Conditioning

• More formal experiments in animals have
  demonstrated situational-specific tolerance for
  opiates, barbiturates, ethanol, nicotine,
  benzodiazepines, using temperature regulation,
  pain, drinking, motor activity, etc as measures.
•  

19
Tests of conditioned tolerance

• Presentations of the CS in the absence of the
  drug UCS will reveal the opponent process
•  
• Situationally-specific withdrawal can be elicited
  by cues repeatedly associated with drug
  administration
•  
• 2. Tolerance should be extinguished by
  repeated presentation of CS in absence of drug
  UCS
• Tolerance to morphines analgesic effects can be
  reversed by repeated exposure to the hotplate and
  placebo injections (Siegel JCPP 89 498, 1975)

20
Conditioned opponent process theory