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
give evidence for changes beyond a compromised reward circuit in addicts
evidence for changes beyond the VTA NA circuitry. Horizontal brain sections of control vs addicted subject. Looking at distribution of fluorodeoxyglucose, measuring brain glucose metabolism as a proxy for measuring levels of activity in the brain. you can see those high levels of activity in the Orbitofrontal cortex in the control but lower levels in the addicted subjects – this is thought to underly the craving for the drug as well as the poor decision making that occurs in individuals with addiction. They know the consequences but make the poor decision to continue to take the drug – thought to be because of the impaired circuitry in the orbitofrontal cortex
describe the evidence for the role of the amygdala in drug dependence
pharmacological and behavioural
Studying alcohol dependence in a rat ‘model’
msP alcohol preferring rats – a strain of rats that prefer rats, self administer alcohol without having been reconditioned
cross section in part of brain containing the amygdala, insitu hybridisation for the peptide CRF, corticotrophin release factor
BLA, basal lateral amygdala.
In alcohol dependent non selecting rats, once animal becomes dependent they will self administer without sweetening, there is much higher levels of CRF.
CRF increases when animals get to a point of self administering non sweetened alcohol
you can see the strain of alcohol preferring rats, have high levels of expression of CRF
Suggesting expression of CRF in the amygdala may effect the preference to alcohol ingestion in this rodent model
behavioural evidence:
rat has been trained to self administer alcohol
Alcohol is removed from solution, and rats stop pressing lever. Then animals are stressed via footshock, this reinstates the drinking of alcohol
A CRF receptor antagonist, Antalarmin, if pre administered it helps to reduce the stress induced relapse. Suggest is acting in the amygdala to reduce stress response which is coupled to the self administration of alcohol
give 5 actions of cocaine
local anaesthetic
causes euphoria
appetite suppressant
increasing the dose can elicit tremors, convulsions, CNS depression
in susceptible individuals cocaine may precipitate toxic psychosis - clinically has all apparent feature of a schizophrenic like episode
breifly how does cocaine have local anaesthetic properties
blocks voltage-gated Na channels
breifly how does cocaine cause euphoria?
by disturbing catecholamine transmission)
give three actions of amphetamine
- appetite suppressant
- causes euphoria
- raises blood pressure
can also cause psychosis
give three uses for amphetamine
weight control,
narcolepsy
and attention deficit disorder
why is amphetamine an indirect sympathomimetic?
it stimulates the release of catecholamines
describe the mechanism of action of amphetamine
induces reverse transport (of the high affinty uptake transporters) Amphetamine is taken back into the nerve terminal rather than the neurotransmitter so that the levels of catecholamines increase in the synapse
Dopamine, Noradrenaline, 5HT pathway originate in…________ and project anteriorly to innervate areas implicated in…________
Originate in the midbrain/medulla
Project anteriorly to innervate areas throughout the brain are implicated in mood & behaviour
what amino acid in dopamine transporters is important for high affinity cocaine binding?
F105 is important for high affinity cocaine binding but not for DA transport
if you remove the phenylalanine 105 then it removes cocaines ability to bind while still functioning as a dopamine transporter
If you introduce this single residue change, they generated a mouse knockin and then looked at the effects of cocaine
a single residue change at F105 of dopamine transporter generate knock in mice - what were the effects of cocaine on these mice?
Cocaine in the mutant DAT knock-in mice did not:
elevate extracellular dopamine (the cocaine binding site was knocked out)
or
increase locomotion
i.e. the knock-in mice are apparently insensitive to the neuropharmacological actions of cocaine as predicted
describe the conditioned place preference test
A cage with a mouse, two chambers, each with distinct visual cues, inject with either saline or a drug and put in one side of the cage until the animal has made an association of receiving the drug and being put in one side of the cage. You then put the animal in the cage and wait to see what way it goes. If the drug is reinforcing then they will choose to spend more time in the side of the cage where they received that drug
what is the conditioned place preference test used to assess?
for assessing reinforcing properties
describe the experiment that showed that the dopamine transporter is involved in the reinforcing properties of cocaine
Used conditioned-place preference test to assess reinforcing properties of cocaine
In the wild type mice, they show a preference for the chamber that cocaine was associated with
The knock in mice (f105 single residue change) don’t show this preference
Additctive drugs increase release of dopamine in the ___________
nucleus accumbens
This seems to be common for all addictive drugs: nicotine, ethanol, opiates (heroin), cocaine, amphetamine
But not for aversive drugs
describe the experiment that revealed common downstream effects of addictive drugs is increased dopamine in the nucleus accumbus
using ethanol
Used rats, tube through the brain and back to the tube, you can diffuse the brain and analyse what you collect to see the composition. Monitor levels of neurotransmitter in a regions of the brain. if look at percentage basal release of dopamine in nucleus accumbus and caudate nucleus. Administered ethanol, higher ethanol doses showed slightly higher levels in the caudate nucleus, but in the nucleus accumbus you see a drastic dose dependent increase. This was similar in the other addictive drugs.
describe the evidence that shows altered dopamine receptor density 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
Density is reduced one month and 4 months after use. Even after they have been drug free for a few months the density is still much lower. This suggests there is a down regulation in D2 dopamine receptors in those who have abused cocaine – point to a reward system that is compromised in these individuals.
A number of studies show even if you take into consideration the age of individuals the D2 receptor density is still reduced
describe the mechanims that result in compromised reward system and contribution to drug craving
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
an example of the plasticity in the brain
describe one mechanism of regulation of dopaminergic signalling that is not through D2 receptors
(alteration of dopamine receptors)
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 suggest the long term changes associated wtih addiction are a result of changes in gene expression as a result of what biomolecular series of events
^ DA > ^ cAMP > CREB > immediate early gene expression
this may alter levels of receptor expression
e.g. changes in dopamine receptors
describe how the neurosdaptive changes occur in response to morphine
morphine inhibits adenylate cyclase leading to a decrease in cyclic AMP causing upregulation in adenylate cyclase expression therefore over time there is an increase in the activity of adenylate cyclase contributing to the neuroadaptive changes that occur in response to morphine.
Why are some individuals more susceptible than others to addiction?
Familial history of addictive behaviours, 40% of risk for addiction is genetic.
As with a number of psychiatric disorders there are multiple genes that carry polymorphisms or mutations that confer a level of risk that when combined lead to the expression of the disorder
what receptors does nicotine act on?
to influence addiction pathways
Nicotine acts on nicotinate acetylcholine receptors acting on the dopaminergic neurons directly activating the neurons
what neurons does alcohol increase activity of
ventral tegmental area dopaminergic neurons.
what is cocaine?
naturally occuring plant compound
a stimulant and local anaesthetic
describe the mechanism of action of cocaine
blocks (high affinty) reuptake of catecholamines
therefore increases the levels of the catecholamines in the synapse,
this underpins its euphoric and stimulant properties
when the neurotransmitter is released it is taken back up into the presynaptic terminal by a high affinity transporter ( ) then it is repackaged in the presynaptic vesicles
what are the actions of cocaine?
local anaesthetic (blocks voltage-gated Na channels)
causes euphoria (by disturbing catecholamine transmission)
appetite suppressant
increasing the dose can elicit tremors, convulsions, CNS depression
in susceptible individuals cocaine may precipitate toxic psychosis - clinically has all apparent feature of a schizophrenic like episode
how does cocaine carry out its local anaesthetic properties?
by blocking voltage-gated Na channels
how does cocaine carry out euphoria
by disturbing catecholamine transmission
describe the mechanism of action of MDMA
reuptake inhibitor of presynaptic serotonin (5-HT), dopamine (DA), and norepinephrine (NE).
net effect of increase in 5HT
what are the long term effects of mdma?
toxicity arises from prolonged exposeure.
it leads to reduction in activity and maybe even lesion of the certain neurons, raphe neurons
what drugs affect the nucleus accumbens to cause addiction?
cocaine
amphetamine
opiates
THC
what drugs affect the ventral tegmental area to cause addiction
ethanol
nicotine
opiates
THC
what is antalarmin?
a novel CRH receptor type 1 antagonist
reduces the release of ACTH in response to chronic stress
