lecture 34

Question 1

What are some particularly powerful determinants of behaviour?

Answer 1

• small molecules
• e.g.
• ethanol
• nicotine
• valium
• LSD
• cocaine
• heroin
• prozac
• caffeine

interesting that drugs/v small molecules work at all

Question 2

Why do people use recreational (or abused) drugs? What do these drugs provide to the user?

Answer 2

• pleasure
• hedonic drugs are typically addictive and users exhibit tolerance along with addiction
• novelty or unreality
• pyschedelic drugs are less commonly considered to be addictive (phencyclidine, betel nut, marijuana, caffeine, gamma-hydroxybutyrate, yage, psilocybin, and LSD)
• some drugs that are highly addictive (tobacco) are not associated with tolerance

Question 3

What aspects of brain function do these drugs affect?

Answer 3

1. behaviour
   - e.g. people who take opiates become extremeley vegetative
2. mental state
   - motivation
   - perceived salience
   - meaning and significance
   - arousal/vigilance
   - hedonic experience (pleasure)
   - emotional states and experiences

Question 4

Why do drugs work?

Answer 4

• must mimic some endogenous chemical interactions in the brain
• particularly between neurons
• neurotransmitters are also small but affect many aspects of behaviour

Question 5

What are psychoactive drugs?

Answer 5

• drugs with “mind altering” effects are called psychoactive
• these can, from a users point of view, be considered as either hedonic, psychadelic or stimulant
• many abused drugs appear to act by modulating neurotransmission at the synapses of the diffuse modulatory systems, particularly serotonin, dopamine and noradrenaline
• a well known psychedelic drug, LSD, is a hallucinogen, producing distortions of sensations and abnormal associations between sensory experiences
• in the 60s and 70s (when it was legal) it was widely promoted by users as being “mind expanding”
• the structure and pharmacology of LSD suggests it acts as a serotonin agonist, but its action is complex and not fully understood
• stimulants such as amphetamines and cocaine seem to act on aminergic transmission (noradrenaline and dopamine)
• howeber, heroin is a hedonic opiate the also modulations aminergic systems
• in much of the world, traditional mood-altering substances such as cocaine and heroin are in decline. But a pharmacopoeia of synthetic drugs is rapidly taking their place
• cumulative number of new psychoactive substances identified globally - over 300
• a lot of them haven’t been subject to any sort of drugs
• synthetic cannabinoids
• synthetic amphetamines
• ketamine is now a major part of drug economy

Question 6

Why are hedonic drugs addictive?

Answer 6

• the fundamental principle that unites addictive drugs appears to be that each enhances dopamine by means that dissociate it from normal behavioural control, so that they act to reinforce their own acquisition
• amphetamines affect dopamine: DAT substrate, VMAT substrate, MAO inhibitor, TH activator collapse of vesicular pH gradient
• cocaine: DAT blocker
• ethanol - maybe? possible disinhibition, addictive property is probably
• nicotine: nAChR agonist
• opioids: µ opioid receptor agonists
• sedatives: GABAa receptor coactivators benzodiazepines/agonists
• solvent inhalents: unclear, may enhance release probability

Question 7

Why do drugs work in subtle ways?

Answer 7

• if not, too much damage to brain
• act via metabotropic coupled receptors which modulate the excitability
• few percent difference rather than on/off
• clearly more complicated because doesn’t affect whole brain etc

Question 8

Of what is paranoia a symptom?

Answer 8

• common symptom in schizophrenic illness
• also can be side effect of medication or recreational drugs such as marijuana
• particularly stimulants such as methamphetamine and crack cocaine

Question 9

What is the projection that makes drugs addictive?

Answer 9

• VTA to nucleus accumbens

Question 10

What is the biggest drug problem?

Answer 10

alcohol

• 2 billion users of alcohol, world wide
• WHO estimates worldwide that 3.2% of deaths and 4% of total years of life lost are caused by alcohol abuse ( and most preventable)
• the annual cost of alcohol-caused problems in Australia has been estimated to be 4.5 billion dollars (about 2.6 times the cost for illicit drugs)
• about 2/3 of the costs are alcohol dependence-related

Question 11

What is invovled in alcohol consumption and outcome?

Answer 11

• patterns of drinking average volume
• toxic and beneficial biochemical effects
• intoxication
• dependence
• chronic disease
• accidents and injuries (acute disease)
• acute social and psychological problems
• chronic social and psychological problems

Question 12

What is chronic alcohol related disease?

Answer 12

• cancer (mouth and oropharyngeal, oesophageal, liver, breast)
• neuropsychiatric diseases (AUDs, unipolar major depression, epilepsy)
• diabetes, cardiovascular diseases
• gastrointestinal diseases (cirrhosis of the liver)
• conditions arising during the perinatal period

Question 13

What are examples of common comorbid conditions?

Answer 13

• medical conditions such as malnutrition and diseases of the liver and the cardiovascular system
• neurological conditions such as head injury, inflammation of the brain (i.e. encephalopathy), and foetal alcohol syndrome (or foetal alcohol effects)
• psychiatric conditions such as depression, anxiety, post-traumatic stress disorder, schizophrenia, and the use of other drugs (Petrakis et al. 2002)

Question 14

What is the mechanism of action of alcohol?

Answer 14

• know big picture and small picture but not how they link together
• acts on GABA-gated Cl- channel (GABAa receptor)
• ethanol is an agonist and an antagonist

Question 15

What are the acute effects of alcohol on the brain?

Answer 15

• the literature on the mode of action on brain excitability and neurotransmitter interactions is complicated and incompletely resolved
• alcohol is claimed to both potentiate and antagoise GABA’s effects (which can be used to explain sedation and disinhivition response)
• chronic alcohol consumption decreases GABA receptor density in the brain - which is consistent with anxiety (and the use of benzodiazepine) in alcohol withdrawal
• alcohol has been show to interfere with glutamate action
• chronic alcohol consumption increases glutamate receptor sites in the hippocampus, an area that is crucial to memory
• alcohol directly stimulates release of the neurotransmitter serotonin, which is important in emotional expression, and of the endorphins, natural substances related to opioids, which may contribute to the “high” of intoxication and the craving to drink
• alcohol also leads to increases in the release of dopamine (DA), a neurotransmitter that plays a role in motivation and in the rewarding effects of alcohol

Question 16

What are the chronic effects of alcohol on the brain?

Answer 16

• alcoholics have a reduced brain weight compared to controls and the degree of brain atrophy has been shown to correlate with the rate and amount of alcohol consumed over a lifetime
• an unexpected pathological finding was that the reduction in brain volume was largely accounted for by a reduction in white matter volume, but it is clear there is neuronal loss in specific regions of the cerebral cortex (superior frontal association cortex), hypothalamus and cerebellum in alcoholics
• quantitative studies also showed that many of the changes are exacerbated by thiamine deficiency
• it was once considered that thiamine deficiency is the principle factor causing brain damage in alcoholics, but it is now well established that even uncomplicated alcoholics (those without liver diseases) show signs of regional brain damage and cognitive dysfunction
• microscopically, there are no obvious white matter lesions in the cerebral hemispheres of uncomplicated alcoholics

Question 17

What are changes in cortical grey matter volumes in alcoholics?

Answer 17

• young: some loss but fairly similar across the board
• older: more loss but biggest in prefrontal cortex
• posterior temporal seems to be relatively unaffected
• more sulci, less gyrus

Question 18

What are complications of alcohol during the perinatal period?

Answer 18

• alcohol readily gets through blood brain barrier
• ethanol is small and a bit lipid soluble
• also gets through blood/placental barrier

Question 19

What are external features associated with FAS?

Answer 19

• collection of features/signs
• morphologically identifiable features
• e.g. simian crease across whole palm of hand
• low nasal bridge
• small eye openings
• short nose
• thin upper lip
• underdeveloped jaw
• smooth philtrum
• flat midface
• epicanthal folds
• small head

Question 20

How is FAS diagnosed?

Answer 20

• evidence of a complex pattern of behavioural or cognitive abnormalities inconsistent with developmental level in the following CNS domains:
• learning disabilities, academic achievement, impulse control, social perception, communication, abstraction, math skills, memory, attention, judgement
• general cognitive deficits (e.g. IQ) at or below 3rd percentile

Question 21

What has been revealed by autopsies of infants known to have FAS?

Answer 21

• as of 2002, there were 25 reports of autopsies on infants known to have FAS
• the first was in 1973, on an infant who died shortly after birth
• the examination revealed extensive brain damage, including microcephaly, migration anomalies, callosal dysgenesis (corpsum callosum didn’t form properly), and a massive neuroglial, leptomeningeal heterotopia (major glial/meningial structure growing where it shouldn’t) covering the left hemisphere

in 1977, a second infact was described whose mother was a binge drinker

• the infant died ten days after birth
• the autopsy showed severe hydrocephalus (expansion of the vesicles), abnormal neuronal migration, and a small corpus callosum and cerebellum

Question 22

Take home message?

Answer 22

little agents can have large, and largely coherent effects, but the suggestion that some global brain property (or mental state) is associated with the action of a single neurotransmitter is wrong, e.g.:

• serotonin levels are highly correlated by mood, but serotonin is merely important in mediating brain functions that, among other things, have a role in mood
• dopamine agonists can be very effective in treating schizophrenia, but dopamine is not a neurotransmitter for “thought”
• dopamine and noradrenaline agonists have powerful effects on behaviour and motivation, but dopamine is not the producer of “reward” or pleasure
• the connection between these components/agents/lesions and their effects on mental state is complex because they are mediated by the most complex structure in the known universe: the brain