Symp 2 - Basic Science of Substance Misuse

Question 1

• Why do humans misuse drugs?
• Why do animals misuse drugs? (as this is where a lot of evidence comes from)
• The basic science suggests (at least) two distinct mechanisms - what are they?

Answer 1

Tolerance (the basis of physical dependence)

Reward centre (the basis of psychological craving)

very distinct mechanisms

Question 2

what is tolerance?

Answer 2

Defined as “Reduced responsiveness to a drug caused by previous administration”

An example of homeostasis - the body likes things the way they were (Body doesn’t like change and tries to put it back to the way it was)

Mechanisms underlying tolerance can vary

Question 3

what can cause tolerance?

Answer 3

•Develops in response to many types of drug - eg opioids, ethanol, barbiturates, benzodiazepines

Take a drug certain effect, then take it again and a smaller effect etc

Not all drugs but a lot of drugs

Question 4

what are the different mechanisms of tolerance?

Answer 4

does the drug actually reach the receptor? if not, this is called dispositional tolerance

Less drug absorbed = less drug getting in body

Also drug may get to receptor but has less effect when at action site, this is called pharmacodynamic tolerance

Question 5

what ways may dispositional tolerance occur?

Answer 5

Less drug absorbed

Drug metabolised faster (or..) (Less of the active bit around for less time)

More drug excreted

Question 6

what ways may pharmacodynamic tolerance occur?

Answer 6

Fewer drug receptors

Less efficient drug receptors

Question 7

Mechanisms of Tolerance - what is dispositional tolerance and how can it occur?

Answer 7

• less drug reaches the active site, eg:
• decreased rate of absorption
• increased rate of metabolism to inactive metabolites
• decreased rate of metabolism to active metabolites
• increased rate of excretion

Question 8

Mechanisms of Tolerance - what is pharmacodynamic tolerance and how can it occur?

(aka tissue or functional tolerance)

Answer 8

• site of action is less affected by the drug, eg:
• down-regulation or internalisation of drug receptors
• reduced signalling down stream of drug receptors
• some other compensatory mechanism

Question 9

Tolerance = dependence?:

Development of tolerance may also lead to __________ symptoms

Answer 9

withdrawal

Tolerance is closely related to dependence

See saw is normal function of the body (we are talking about transmitter release but lots of examples) - follows on for the next few slides

Question 10

what happens if there is reduced transmitter release?

Answer 10

Body sense it and doesn’t like it so produces an adaptive response to balance it out

Bigger response to the transmitter that is released

This would be the tolerance state – drug given but less effect from when given at the start

Question 11

what happens if the drug effects is taken away?

Answer 11

Stop taking drug and adaptive response still there and it tips in the other direction

Development of tolerance leads to dependence

Question 12

descirbe what can be seen here:

Answer 12

A practical example

Presynaptic terminal release neurotransmitters (in green) – may be releasing acetylchloride

Then give the drug in yellow and this binds to presynaptic receptors and this inhibits transmitter release and therefore fewer receptors being activated

If body develops tolerance to the reduced transmitter release, then give more receptors for the transmitter to bind to with causes normal gut motility and this is the tolerance state and as you have developed tolerance you also have dependence

Now if you take the drug away you have more transmitter released and more receptors so now increased gut motility

Question 13

•Withdrawal phenomena:

Therefore the withdrawal effect of a drug is usually the _________ of the acute effect

• Tolerance & dependence are closely ________
• Development of tolerance may lead to physical dependence in order to avoid the (unwelcome) _________ effects

Answer 13

reverse

linked

withdrawal

Question 14

what is the reward centre and why has it evolved?

Answer 14

•The reward pathway

• Neurones project from the ventral tegmental area to the nucleus accumbens & prefrontal cortex
• When VTA neurones are stimulated they release dopamine is released
• This causes a sensation of pleasure/reward

•Why has the reward pathway evolved?

• The reward pathway is normally activated by eating, drinking and sex
• It therefore encourages those “healthy” behaviours that lead to propagation of your genes

•It is a powerful thing

Question 15

Reward centres:

Some drugs of abuse tap into the reward pathway and increase ________ levels eg:

• heroin increases firing rate of dopaminergic neurones
• amphetamine increases dopamine release
• cocaine inhibits dopamine uptake
• alcohol

•This produces the __________ component of addiction - “craving”

Answer 15

dopamine

psychological

Question 16

Reward Centres:

•The so whats?

• Does it matter if you artificially stimulate your reward pathway?
• Can you use drugs to treat addiction?
• Is there such a thing as an addictive personality?
• Can this ever circumvent free-will?

Answer 16

Societal reason – decided addictive drugs are illegal as they can encage in illegal activities and if they are artificially doing it through drugs then they don’t need to do it through the natural way so leads to people not doing natural ways

In some sense that is correct – can block the reward pathways – side effects of it thought is nor acceptable

Knowing the mechanisms – lots of papers failed and some succeeded

Genetic makeup can have an effect on the strength of someone’s reward pathway

Question 17

Summary:

•Animal studies show that drug dependence has at least two distinct components:

• _______ dependence which develops as a consequence of ________ to the drug
• ___________ craving which is a result of stimulation of the reward pathways in the brain

•In humans it is almost certainly more complex - eg discriminative (cue) effects

Answer 17

Physical

tolerance

Psychological