Neural Pathways Flashcards
Mental disorders classification
The Diagnostic and Statistical Manual of Mental Disorders (DSM) was published by the American Psychiatric Association. It provides diagnostic frameworks.
The International Classification of Diseases (ICD) is maintained by the World Health Organisation. “Disorders due to substance use and addictive behaviours are mental and behavioural disorders that develop as a result of the use of predominantly psychoactive substances, including medications, or specific repetitive rewarding and reinforcing behaviours.“
Disorders due to substance use “include disorders that result from a single occasion or repeated use of substances that have psychoactive properties, including certain medications.”
DSM-5 criterus is the most influencial for characterisingsubstance use disorders. For diagnosis, there must be a pattern of use causing significant impairment or distress, as characterised by two or more of the following criteria in a given year:
Use in larger amounts or during longer periods than initially intended
Persistent desire or unsuccessful attempts to restrict use
Great deal of time devoted to procuring, consuming, and recovering from use
Craving, strong desire to use
Recurrent use resulting in failure to fulfill obligations at work, school, or home
Continued use despite persistent social problems caused by use
Important social or professional activities given up in favor of use
Recurrent use in situations in which it is physically hazardous
Continued use despite knowledge of substance-related problems → aware of the harmful effects of the substance they are using, but they do not care about these consequences
Tolerance
Withdrawal
The severity of the disorder is classified as:
2-3 symptoms = mild
4-5 = moderate
>6 = severe
The use of animal models of addiction
Describing the human experience of addiction is difficult as there is no controlled environment and genetic differences can play a role. Standardised animal tests are therefore required to study this.
DSM-5 criteria manifests differently in animal studies of substance addiction.
Animal tests also allow us to measure the effectiveness of different interventions.
According to DSM-5, substance use disorder is “the recurrent use of alcohol and/or drugs in a manner that causes clinically significant impairment, including health problems, disability, and failure to meet major responsibilities at work, school, or home”.
This can be tested using:
- Unconditioned behaviours
- Intracranial self-stimulation
- Conditioned place preference/aversion
- Drug self-administration
- Drug discrimination
Animal models of reward and addiction - early studies
To understand addiction, we must understand cellular and molecular brain pathways.
1950s (Olds & Milner) - Animals repeated acts that were associated with electrical stimulation of the brain
1960s (Glowins& Iversen) - Rat brain regional studies and catecholamine turnover identified - used for pathway association
1970s (Roy Wise) - Link between catecholamines and reward
Glowinski J, Iversen LL (1966) - Introduced the idea of sectioning the rat brain in a reproducible manner
Neurotransmitters
Serotonin is synthesised from tryptophan through enzymatic conversion by TPH and AADC.
5-HT is more abundant in the gut than the brain, and it is also found in platelets
5-HT can also undergo further enzymatic conversion to melatonin, which shows diurnal control.
Catecholamines are synthesised from tyrosine. TH and AADC are involved in the formation of dopamine, involved in the pleasure response. This can be further concerted to adrenaline by DBH and then noradrenaline by PNMT.
The catecholamine cell bodies in the brain stem are involved in neurotransmitter synthesis. The cerebellum is involved in locomotion. There is a wide distribution of neuronal terminals and therefore complexity.
Dopamine - anticipation of reward
D1 and D5 receptors are Gs-coupled - difficult to distinguish from each other pharmacologically
D2, D3,and D4 are Gi-coupled. D2 receptors can also be Gq coupled.
Most drugs to treat schizophrenia are D2 receptor antagonists. Dopamine signalling in the prefrontal cortex is therefore important in mood regulation.
Dopamine agonists are used in Parkinson’s therapy. Impulse control disorders can develop in treated patients.
The DRD4 gene is polymorphic and particular variants may be associated with novelty-seeking, but this is more difficult to predict than previously expected.
Monoamine transporters
The SLC6 monoamine transporter superfamily includes:
- NET/SLC6A2
- DAT/SLC6A3
- SERT/SLC6A4
These are very similar structurally and there is substrate overlap at high concentrations.
Plasma membrane monoamine transporter - PMAT/SLC29A4
Vesicular monoamine transporters include:
- VMAT1/SLC18A1
- VMAT2/SLC18A2
Drugs can target these pathways
CNS dopaminergic pathways
The ventral tegmental area signals with areas of the forebrain.
The shell of the nucleus accumbens, innervated by the VTA through the medial prefrontal cortex, is involved with substance abuse. We can investigate this in humans by using PET radioligands and looking at their displacement by dopamine.
Adenosine and dopamine receptors are located in the same places in the brain. Adenosine can temporarily reduce dopamine release. Radiography and an adenosine receptor antagonist can be used as a proxy for imaging dopamine-rich brain areas. This just highlights that we are able to pick up dopamine-rich areas.
There are large changes in dopamine in the NAc when there is an anticipation of an award.
Measuring dopamine release
We can measure dopamine release in the nucleus accumbens in vitro, for example by measuring electrically-evoked release of 3H-dopamine from the rat nuc accum slices in vitro. Slices are pre-labelled and then electrically stimulated, and dopamine is measured as an excess of overflow. Istradefylline is a selective adenosine A2A receptor antagonist. This increases dopamine release to stimulation. Istradefylline may be used to treat Parkinson’s, but it may also initiate reward responses.
Dopamine is a catecholamine and therefore oxidising, so we can use electrochemistry to measure it using redox potential.
We can also measure dopamine release in vivo in freely-moving animals. An electrode and perfusion apparatus with a canula is inserted into the brain. The perfusion apparatus has both an inlet and an outlet, allowing us to deliver drugs and also measure responses, such as dopamine release. This allows us to measure how drug modify dopamine release and what behavioural changes are seen at the same time.
An electrode can be placed in the brain after the animal is killed.
Istradefylline causes a 400% increase in dopamine release, which is larger than the known drug of abuse cocaine. TTX abolishes the response, telling us that dopamine is released from neurons.
Behavioural models - Rodent Conditioned Place Preference (CPP)
There is a complexity in animal testing of addiction behaviour, which may be because human behaviours themselves are highly complex and difficult to quantitatively assess.
The Conditioned Place Preference (CPP) model looks as weather the animal can link exposure to a drug to its environment. Thick and thin stripes are used to make the environment as neutral as possible, to ensure that the animal is not responding to the environment itself, and these two environments are separated by a removable partition.
Following habituation, the animal is exposed to either the drug or the vehicle in a specific region. After conditioning, it is placed in the middle and you observe which side it goes to.
Following administration of 10mg of cocaine, the animals show a preference for the chamber which they associate with drug administration. The rats treated with cocaine also travel further.
Behavioural models - Drug self-administration
George Koob developed the method of operant conditioning
An in-dwelling catheter which delivers drugs is used.
Drug administration is triggered by the animal performing a task, often a lever press.
Variants of this include different routes of drug administration (IV, intracerebroventricular, intra-accumbens), increasing the complexity of the task or the need for repetition for drug administration (tests for responses when there is a failure to receive the reward), enforcing a period of abstinence before returning, providing different environmental cues.
Behavioural models - Drug discrimination
Drug discrimination allows he differentiation of drugs with distinct molecular mechanisms.
Animals are trained daily to lever press to obtain food pellets
The animals are injected with a training drug or vehicle before the test.
They are then given a choice of 2 levers, a ‘drug-appropriate’ lever and a ‘vehicle-appropriate’ lever.
After reliable responses are obtained, we can test if another drug mimics the effects of the training drug and if the ‘right’ lever is pressed.
The responses are functionally relevant but does not necessarily align with the molecular mechanism.
We can also assess the dose dependance of the drug.
Drugs that cross-substitute for each other in animal discrimination procedures match very well with drugs that humans report having similar subjective effects.
