Addiction Flashcards
define addiction
” persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual”
what are the 3 key features of addiction?
- compulsion to take drug
- ‘withdrawal’ syndrome
- tolerance
pyschotomimetic drugs with abuse potential have common actions on the ________ of the brain
pyschotomimetic drugs with abuse potential have common actions on the limbic system of the brain
what is reward? how does it underly addiction?
3 points
- Selection of behaviours appropriate for survival is achieved by ‘reward’ and punishment’ systems
- These systems are fundamental to motivation and avoidance
- Inappropriate activation of these systems underlies addictive behaviour
describe the model of thereward circuit
food stimulates neural cicuit that detects stimulus which feed into neural circuits that control behaviour. there are also reinforcing systems that boost the signal from stimulus to bahaviour. the behaviour (eg eating) is a reinforcing stimulus that feeds into this reinforcing system
describe the experiment that accidentally provided the first evidence for pathawys involved in reward and motivation?
animal behavioural experiments conducted by James Old (1954)
Discovered accidently – interest in what would happen if hypothalamus was stimulated. He implanted the electrode in the wrong part of the brain, the medial forebrain bundle.
Rats implanted with stimulating electrodes in the reticular formation
when rat enters shaded area of the cage a stimulus is delivered to the electrode
Old observed that in some experiments the animals repeatedly returned to the shaded area
in these animals the electrodes was placed in the medial forebrain bundle
(bundle of axons from neurons in midbrain and project anteriorly via long axonal tracts into the limbic system)
describe the operant chamber and what it models?
allows a rat to self-deliver either a stimulus or drug by pressing a lever
these studies showed that rats would self-administer a stimulus if the electrode was placed in the medial forebrain bundle i.e. reinforcement
give examples of two drugs that block reinforcement behaviour
- spiroperidol (DA antagonist blocks reinforcement)(blocks D2)
- 6-OH-DA lesions block reinforcement ( a toxin taken up by dopaminergic neurons, if applied to rats into ventral tegmental area it blocks the reinforcement behaviour
dopamine axons in the medial forebrain bundle project to what brain area?
nucleus accumbens
why is cocaine profoundly addictive?
blocks reuptake of multiple neurotransmitters, extending the effects
Cocaine binds with high affinity to monoamine, including dopamine transporters
what evidence shows that there is another ‘reinforcing stimulus’ other than DA
Mice with DA transporter knockout have chronically elevated synaptic dopamine
cocaine administered to these animals produces no change in base-line DA (also no increase in locomotor activity)
nonetheless these animals will self-administer cocaine… therefore there may be another ‘reinforcing stimulus’ other than DA
Because they developed with the aberrant elevated dopamine, this may effect the results
Reinforcement (reward) is dependent on an increase in…
Reinforcement (reward) is dependent on an increase in dopamine signalling in the VTA/ nucleus accumbens pathway.
What are the common pathways for reinforcement/addiction for addictive drugs
Evidence for common involvement of limbic system
Evidence for common involvement of dopamine signalling especially the VTA projection to the nucleus accumbens
give 3 peices of evidence that shows how dopamine appears to be a common facto in drugs wiith abuse potential
Ethanol increases DA release in the nucleus accumbens
DA receptor antagonists block ethanol self-administration in animal models
Opiates also increase dopaminergic transmission in the limbic system
give evidence from PET studies, of altered dopamine signalling in addiction
Injected with radio labelled drug18F-fluoromethylspiroperidol to label D2 dopamine receptors in PET imaging studies on human subjects
You can see that in the control subjects there is a higher density of receptor than in those who are cocaine abuser
D2 receptor density is reduced in addicts, (even when you take age into consideration)
a similar result was obtained from scans from different drug addictions. – lead to idea that during continued use of drugs the elevated/excess levels of dopamine in the nucleus accumbus lead to a downregulation of dopaminergic signalling in the nucleus accumbens which results in compromised reward system and contributes to drug craving
give evidence that implicates D1 receptors rather than D2 associated with long term changes
D2 receptors are G protein coupled receptors and typically lead to a decrease in cAMP, bcos D2 are inhibitory for adenylate cyclase.
Rather it is thought D1 receptors, often found coexpressed in same neurons as D2 receptors, respond to dopamine by increasing cyclic AMP. cAMP binds to CREB, a transcription factor leading to changes in gene expression, which may lead to down regulation in dopamine receptors
animal studies sugest changes in gene expression are associated with long term changes caused by addiction, how does this come about?
^ DA -> ^ cAMP -> CREB ->immediate early gene expression
this may alter levels of receptor expression
why are some individuals more suseptible than others to addiction?
multiple genes carry polymorphisms or mutations that confer a level of risk
give three example fo genes that suggest there is a genetic basis for drug addiction
- ALDH2
- D2
- OPRM1
how could ALDH2 implicated in drug addiction?
ALDH2 encodes enzyme, aldehyde dehydrogenase involved in metabolism of aldehyde. When alcohol is metabolised is is first converted to aldehyde by alcholhol dehydrogenase.
Aldehyde is toxic so is rapidly removed by aldehyde dehydrogenase. In individuals who carry this polymorphism, drinking alcohol can be an unpleasant experience because it leads to a build up of aldehyde, so they tend to drink less) ie less susceptible
how is OPRM1 implicated in addiction?
OPRM1
polymorphisms in this opiate receptor, encodes a mew subtype, may lead to increased susceptibility,
it is expressed on the nerve terminals of GABAergic neurons, these have inhibitory effect on dopaminergic ventral tegmental area to nucleus accumbens pathway. Inhibit release of dopamine in the nucleus accumbens.
This polymorphism disrupts the inhibitory action of GABA on the dopaminergic pathway leading to excess dopamine in this pathway maybe predisposing the individuals to addictive behaviour)
describe the common neurobiological mechanism for drug reward
Major reward and motivating pathway
Dopamine neurons project to the nucleus accumbens, having an inhibitory action. These neurons in term project to the cortex and have an inhibitory effect.
In effect the ventral tegmental area to nucleus accumbens dopaminergic pathway is acting to disinhibit the cortex, because activity in the pathway will lead to cortical excitation.
Stimulants act directly at the nerve terminal – they will increase dopaminergic signalling at the nerve temrinals in the nucleus accumbens and lead to activity in the circuit by increasing synaptic dopamine
describe the role of glutamate in the reward and motivating pathway
inputs from outside VTA to NA
glutamate input form the cortex impact on neurons in NA and glutamatergic inputs from the amygdala. The role of glutaminergic inputs is encoding this learned behaviour around addiction. Experimental evidence shows that during addiction, eg alcohol, show changes in expression in partciular classes of glutamate receptors thought to underpin the learned behaviour of addiction
This circuitry is thought to be particularly important for chronic drug use, predisposing the individual to addictive behaviour
describe how addiction is a progressive disease
addiction is a progressive disease; during drug use an individual progressing through impulsive stage, drug taking is underpinned by the pleasurable effect they experience when they take the drug leading to a craving for more of that pleasurable effect, ie reward circuitry. During periods of abstinence there is no negative effect there is just a neutral effect, but they crave the reward which perpetuates the drug taking. In psychology this is called positive reinforcement.
Over a period of time as the individual progresses from left to right on this figure, they go through periods of heavy use which brings about the phenomenon of early dependence where the brain has begun to become maladapted to the continued exposure to the drugs and the involvement of circuitry beyond the reward circuit. The person transitions from a period of impulsive drug use to a compulsive stage. During this they may go through prolonged intoxication and then have a period of abstinence., during this abstinence they will experience negative effects. This comes about because of a disturbance in the circuitry of the brain. The circuit essentially reset their signalling for the presence of the drug, so when the drugs is not present then the adaptation is revealed as withdrawal phenomenon. The only way to get release from this withdrawal is to begin taking the drug again. (bcos helps reset the balance of signalling in the brain)
This is what gives rise to the craving, called negative reinforcement. reinstating drug taking to feel better
