B - Neurotransmitters and Drugs

Question 1

Number of neurons in adult brain

Answer 1

approx. 100billion

Dr Herculano-Houzel, 2009 - suggests that in fact there are only 86 billion neurons in the human brain

Question 2

2 main type of cell

Answer 2

Neurons - basic signalling units (specialised units)
- Soma, dendrites, axons
Glial cells - non-neuronal cells, serve various functions, produce myelin
- CNS = oligodendrocytes - PNS = Schwann cells
- Astrocytes, oligodendrocytes , microglia

Question 3

Neuronal communication

Answer 3

message transmitted across synapses
neurons referred to as pre- or post-synaptic
signalling is within or between neurons

Question 4

Membrane potential

Answer 4

neuronal membrane = bilayer of fatty lipid molecules - separates cytoplasm from extracellular milieu
two types of protein in membrane - ion channels and ion pumps

Question 5

Action potential

Answer 5

excitatory post-synaptic potentials (EPSPs) at synapses cause ionic currents to flow in volume of cell body
action potential works to pass signals along a chain as one neuron alone could not get this signal that far
so it is rapid de-polarisation and re-polarisation of small region of membrane caused by opening and closing of ion channels

Question 6

Two types of synapses

Answer 6

electrical

chemical

Question 7

Neurotransmitters

Answer 7

molecules made and stored in pre-synaptic neuron
some neurons only produce one neurotransmitter, others produce multiple
some have EPSP others have IPSP

Question 8

Removal of neurotransmitters

once a neurotransmitter has done its job it must be removed…

Answer 8

1. active reuptake of neurotransmitter back into pre-synaptic terminal - done for dopamine, norepinephrine and serotonin
2. enzymatic breakdown of transmitter in synaptic cleft - done for ACh
3. diffusion of neurotransmitter away from region of synapse/area of action

Question 9

The bigger picture

Answer 9

neurons rarely work in isolation
some neural circuits show plasticity
CNS = brain and spinal cord
PNS = actions of muscles, heart and various glands

Question 10

Drugs and neurotransmission

5 ways in which drugs can affect synapses

Answer 10

• increasing firing rate of neurons (methamphetamine)
• mimic action of endogenous neurotransmitters (L-DOPA)
• prevent neurons from releasing their neurotransmitters - would reduce effect of certain neurotransmitters (cocaine)
• block re-uptake of released neurotransmitters i.e. SSRIs
• release neurotransmitters from neuron to next neuron regardless of whether it is fired

*we don’t know exactly how most drugs work

Question 11

How do addictive drugs work?

Answer 11

• depends on the function of the neurotransmitter being disrupted by the drug
• most psychoactive drugs either mimic natural neurotransmitters (i.e. heroin, prescription opioids) or alter normal synaptic transmission (i.e. cocaine)
• methamphetamine alters dopamine
• – increase release of dopamine into the synapse
• – blocks dopamine from going back into pre-synaptic neuron
• – results in dopamine innervation of nucleus accumbens and PFC increasing

Question 12

Sherman, 2017

Answer 12

some drugs primarily affect one neurotransmitter or class of neurotransmitters

• • dopamine is highly concentrated in regions regulating motivation and feelings of reward - strong motivator for drug use because if targeted can increase these feelings
• • cocaine attaches to structures that regulate dopamine - so leads to higher dopamine activity and production of euphoria - also changes norepinephrine and glutamate systems causing stimulant effects

Question 13

McKenna, 1987

Answer 13

excess of dopamine caused by drug use (mainly drugs like cocaine that increase dopamine) is thought to be an underlying part of schizophrenia

• • the basal ganglia, ventral striatum, septo-hippocampal system and PFC (sites of mesotelencephalic dopamine innervation) were examined
• • argued that their dysfunction could form the basis of particular schizophrenic symptoms classes

Question 14

Reward pathways

Answer 14

Important in understanding effects of drugs on the brain
Involves several parts of the brain - ventral tegmental area, nucleus accumbens, PFC
Activation of these areas by rewarding stimulus (i.e. food, sex) information travels from VTA to nucleus accumbens to PFC
Reward pathway may be even more important in the craving associated with addiction, compared to the reward itself

Question 15

Addiction

Answer 15

State in which an organism engages in a compulsive behaviour, even when faced with negative consequences
This behaviour is reinforcing or rewarding

Question 16

Olds and Milner, 1954

Answer 16

rat studies were first to tell us about reward pathways
self-stimulation of VTA (dopamine nucleus) - provides feelings of pleasure
rats will choose to continue electrically stimulating their VTA rather than eating or drinking - even though this will lead to death
shows the VTA leads to such a high - so drugs may also provide this much of a high that people would rather continue using drugs to recreate these highs than stop
- drugs, such as cocaine, produce these pleasurable feelings in the brain that motivate further drug use

Question 17

Drug withdrawal - the basics

Answer 17

there is a delicate balance in the brain of neurotransmitters - done by numerous feedback mechanisms
drug substances disturb this balance
drugs have ‘keys’ that let them open certain ‘locks’ between neurons
the brain automatically adjusts to these substances by producing fewer of its own natural ‘keys’
thereby it achieves a new state of equilibrium maintained until the body starts to miss the external substance as it is not producing enough natural ‘keys’
at this point the person experiences cravings for the drug
brain circuit most affected = area associated with pleasure - uses dopamine - so no surprise that most drugs causing dependencies alter dopamine in rewards circuit

Question 18

Drug withdrawal

Answer 18

Robinson and Berridge, 2003
- drugs alter brain structures
- addictive drugs take over neural circuitry normally involved in pleasure, incentive motivation and learning
Wise, 2008
- reward circuits involve dopamine
- this plays a major role in reinforcements of response habits and synaptic plasticity
Sherman, 2017
- stress increases likelihood that former cocaine addict’s single lapse will turn into extended relapse
- stress hormone corticosterone increases the dopamine surge caused by cocaine

Question 19

Dopamine levels during drug withdrawal

Answer 19

dopamine levels drop during withdrawals

• in some cases withdrawal can be worse than drug itself
• drug withdrawal can result in neurotransmitter levels being lower than normal
• drug withdrawal may mean responses to other pleasurable things is reduced - especially if dopamine is reduced

Stewart and Wise, 1992
- the withdrawal may not be as motivating for drug-seeking behaviours as previously thought

dopamine AND serotonin AND GABA go down
reduced dopamine and serotonin - dysphoria (sadness)
reduced GABA = greater anxiety

Question 20

Food

Answer 20

drugs are not the only thing that cause addition, food can as well
Schultz et al., 1990
- dopamine neurons implicated in food reward respond to food reward and predictors of food rewards (before food has been presented)

Question 21

Schultz et al., 1990 - furthered

Answer 21

animal learns that environmental stimulus predicts food reward - food reward triggers 200 millisecond burst of dopamine
eventually the 200 ms burts of dopamine becomes linked to food-predictive stimulus that come before the food-presentation
the stronger the probability of prediction, the stronger the response to the predictor and the weaker the response to the food presentation

Question 22

Depression and serotonin

Answer 22

depression associated with 5-HT levels in the brain
serotonin system supplies brain areas with various functions
SSRIs modulate 5-HT function - increasing amount of serotonin receptors available in synapse
leads to modified activity and changes in 5-HT system and alters relevant behaviours

Question 23

Paul and Skolnick, 2003

Answer 23

depression and serotonin
look at post-mortem studies
found that glutamatergic-transmission had been increased in the PFC in depression
after effctive anti-depressant treatment there is evidence to show that there is a de-sensitisation of NMDA (N-methyl-D-aspartate - a glutamate receptor) receptors in the PFC

Question 24

Dombeck, 2002

Answer 24

Agonistic drugs = enhance messages carried by neurotransmitters
Antagonistic drugs = interfere with the transmission of neurotransmitter messages

^ different drugs have different effects

Question 25

Price and Drevets, 2010

Answer 25

HPA-axis function is elevated in some mood disorder sub-groups
the pituitary and adrenal glands appear enlarged in those with MDD
MDD patients also show reduced GABA levels
these abnormalities may impair modulation of endocrine, autonomic, emotional and behavioural responses to aversive and reward-related stimuli –> may account for disturbances in these domains in mood disorders
mood disorders have been associated with changes in function of serotonin, dopamine and GABA - and others

Question 26

Serotonin treatment for depression

Answer 26

SSRI = selective serotonin re-uptake inhibitors
most common drug for depression
usually reabsorbed after carrying a message
work by preventing re-absorption - blocking - this allows more serotonin to be available to bind to post-synaptic receptors
thought to have a good influence on emotion, mood and sleep
Fournier, 2010 - suggests that the effect of SSRIs increases as severity of depression increases

depression is not caused by low serotonin levels but rise in serotonin levels can improve symptoms

Question 27

Long-term effects of drugs on neurotransmission

Answer 27

Sherman, 2017

• repeated drug use = changes in neuronal structure and function
• causes long-lasting/permanent neurotransmission abnormalities - alterations underlie drug tolerance, withdrawal and addiction
• brain may respond to repeated drug-induced dopamine surges by reducing its complement of dopamine receptors
• this alleviates drug’s over-stimulation of dopamine system but contributes to features of dependence
• drugs cannot change genes but can push some genes to increase/decrease production of proteins = changes in neuron functions or reshaping or physical structures of neurons may result

Safety Net Recovery, 2016

• drugs alter brain stem, cerebral cortex and limbic system
• MDMA damages axons that release serotonin so may underlie memory problems (may also link to depression)
• drugs reduce activity level of neurons so depression is a common withdrawal symptom

Question 28

Dopamine
Serotonin
Acetylcholine (Ach)
GABA

Answer 28

Dopamine - involved in reward and punishment, pleasure and energy - cocaine, amphetamine, opiates, heroin
Serotonin - regulation of mood, impulsivity - alcohol, hallucinogens, stimulants, anti-depressants
Ach - inhibitory neurotransmitter, memory - hallucinogens, marijuana, stimulants
GABA - inhibitory neurotransmitter, arousal, judgement, impulsivity - depressant drugs, marijuana

Question 29

Dopamine and Parkinson’s disease

Answer 29

Parkinson’s disease is linked to the death of dopamine-producing cells
L-DOPA treats Parkinson’s because it compensates for the loss of endogenous dopamine
- in a sense acts mimics a dopamine neurotransmitter

Question 30

Volkow, 1999

Answer 30

results represent first clear demonstration that stimulant-induced high is associated with increases in brain dopamine
low D2 receptors contribute to psycho-stimulant abuse by favouring pleasant response
Cocaine abusers have sig decreases in dopamine transporters release, add to reduction in D2 receptors
= decreased activation of reward circuits by physiological reinforcers - may maintain cocaine use to compensate for deficit

Question 31

Reward Pathway - area implicated

Answer 31

mesolimbic dopamine pathway - core part of reward or pleasure circuit
mesocortical pathway also implicated in effects of drug abuse