Psychoactive drugs

types of drugs

• Psychotrophic – mind bending

• Psychoactive – something that has an effect on the mind

• Psychomimetics – mimic psychosis

psychoactive drugs 

• Pharmacological models for schizophrenia include LSD, PCP, ketamine and amphetamine as the hallucinations bear similarities with psychosis

• Psychoactive drugs may be a treatment for neuropsychiatric disorders

  • Psilocibin may be prescribed for psychedelic assisted treatment for depression

  • But this can be challenging to proceed past clinical trial – people know if they’ve taken a psychedelic

  • Also not regulated by the FDA so is often rejected. E.g: MDMA

pyschomimetic drugs

• Used to create models of psychosis

• nterface between neurology and psychology

• Biochemical basis for changes in perception, mood and behaviour

• By studying these drugs what can they tell us about how the brain operates normally and in disordered states

hallucinogens

Hallucinogens

Many naturally occurring

• Ayahuasca – active ingredient harmaline

• Peyote – active ingredient mescaline

• Magic mushrooms – active ingredient psylocibin

Synthetic halluconagens

• E.g: LSD – lysergic acid diethylamide

• Dose is much lower, much more potent so is more likely to directly bind a receptor

• Rye bread contaminated with fungus caused ergotism (peripheral vasoconstriction) known as St Anthony’s fire

• Aim was to derive ergot alkaloids like compounds (which were causing the vasoconstriction) to treat haemorrhage —> didn’t work, discovered LSD

effects of LSD

mechanism of action for LSD

• in the peripheral vasculature LSD binds to the 5HT2A receptor acting as an antagonist, but can act as an agonist on other receptor types such as 5HT2B

• in the brain LSD is a 5HT receptor agonist

• Cross tolerance of LSD and mescaline – if you take lots of LSD develop a tolerance, means you also need to take higher doage of mescaline

• Suggests that they both work through the same pathway

how does LSD alter perception

• LSD binds to serotonin receptors which increaase glutamatergic input to the locus coeruleus therefore increasing activity 

•  adrenaline is sent throughout the brain which causes increased actitivy in certain areas of the cortex 

NOTE:

• originally observed that LSD decreases the firing rate of Raphe neurons (5HT1A receptors) and Raphe neurons send extenisve projections to the forebrain

• BUT mescaline doesnt affect Raphe neuron firing but shows a cross tolerance with LSD —> doesnt support this theory

what kinds of serotonin receptors are important?

• Expect that if receptor responsible for psychedelic effects of LSD it would also be bound by mescaline

• A meta-study mapped the correlation of affinity for 5HT receptor subtype with hallucinogenic potency – found that most hallucinogenic compounds have the highest affinity with 5HT2A receptors 

• 5HT2A receptors highly expressed in pyramidal neurons —> 5HT2A receptor signalling seems to be present in the more recently evolved regions of the brain

human LSD imaging

• Discovered that LSD increased visual cortex cerebral blood flow

• Expanded primary visual cortex functional connectivity

• Correlated strongly with ratings of visual hallucinations

• Decreased connectity between the parahippocampus and the retroslpenial cortex (responsible for spatial navigation, scene construction and memory) which is correated strongly with self ratings of “ego-dissolution” and “altered meaning”

addiction 

• Persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the affected individual

Features

• Compulsion to take the drug

• Tolerance – if a drug elicits a response on a system the brain tries to downregulate that system to counteract it

• Withdrawal syndrome – opposite effects of those experienced in the presence of the drug as the receptors in the brain have been downregulated as a maladaptation to the drug

These different stages of the addiction cycle implicate different brain regions

reward

• Addiction essentially hijacks the reward system

• Reward drives your behaviour towards things that are essential for survival

  • E.g: drinking water when youre really thirsty is pleasurable

• Inappropriate activation of the reward system drives us to seek out things that are not necessarily good for us, leading to addiction

• A stimulus activates a neural circuit which drives behaviour causing you to seek out something (E.g: eating). This is then followed up by a reinforcing system telling you something was pleasurable.

•  Addictive drugs hack into the reinforcing system without something actually being good for you.

Reward centres in the brain - medial forebrain bundle 

• experiment where rats were placed in operant chambers show repeated self stimulation behaviour when the electrode is placed in certain regions of the brain 

• occured most notably in septal area, also known as medial forebrain bundle 

• No clear understanding of where the medial forebrain is in humans, but well characterised in rodents

• Medial forebrain bundle is a large bundle of axons:

• Variety, bidirectional, some myelinated, some unmyelinated

• Number of pathways involved (green = dopaminergic, red = glutamatergic, blue = GABAergic)

• Innervates areas of the brain such as

  • 5HT axons from raphe nuclei

  • Noradrenergic axons from LC neurons

  • Dopaminergic axons from VTA

Striatum

• Divided into 2 main regions, the dorsal striatum and the NAcc

• The NAcc is typically associated with limbic areas, regulates affective components of behaviour, including motivational and emotional processes

• The dorsal striatum regulates habit behaviours

neurons important for reinforcing behaviour

• no reinforcing (repeated self stimulation) behaviour if you have problems with dopamine → suggests dopamine is important 

  • 6-hydroxydopamine taken up by dopaminergic neurons and kills them —> once contaminated with drugs and caused chemically induced Parkinson’s

• If you administer spiroperidol then you no longer get these reinforcing behaviours —> is a DA2 receptor antagonist

optogenetics 

• temporally precise non-invasive control of activity in well defined neuronal populations

• Channel rhodopsin isolated from algal populations inserted into specific neurons via adenovirus vector —> integrated into genome so now the cell responds to blue light

• Can be controlled by a cell-type specific promoter so is only expressed in a specific subset of neurons

Cre/Lox systems

• Another way of optogenetically controlling neurons

• Cre is a site specific recombinase which acts on LoxP sites

• LoxP is a 34bp sequence which Cre binds to

• Cre and channel rhodopsin inserted into dopaminergic neurons

• Cre controlled by cell-specific promoter

• Cre bind to LoxPforming stite specific recombination – removing the intervening STOP sequence. When Cre is bound it allows channel rhodopsin to be transcribed, controlled by the promoter

• Cells where Cre is not expressed, channel rhodopsin is also not expressed as theres a STOP cassette between the promoter and channel rhodopsin

Cre/lox systems in reward experiments

• Cre under the control of a tyrosine hydroxylase promoter which is specifically expressed in DA neurons (so Cre only found in DA neurons)

• Two nose ports – when they press one of them it stimulates the dopaminergic neurons with blue light, the other one nothing happens

• Total nose pokes at the active port (one that delivers stimulation of DA neurons) increases drastically over number of days

• An extinction phase is introduced – where if either port is pressed, nothing happens —> as a result the rats stop this behaviour and as soon as the posrt is activated again, nose pokes increase rapidly

•  proving that it’s not simply a learned behaviour

cocaine and amphetamines linked to reward

• In operant chambers where rats are allowed to self-administer cocaine or amphetamine straight into the ventricles, they will self-stimulate to the point of toxicity

• Alternative lever activates the blue light optogenetic activation. They dont choose to self administer this

• Proves that they do like the drugs rather than just the stimulation of these reward pathways

• Flies don’t like cocaine because its bitter, if they knock out this bitter taste receptor, flies will choose to ingest the cocaine

cocaine

• Comes from the coca plant

• Appetite suppressant

• Stimulant – causes this euphoric feeling

• Local anaesthetic and has vasoconstrictive properties so used in some eye, ear nose and throat surgeries

• Binds to voltage gated sodium channels and blocks them to exhibit anaesthetic effects

• but highly toxic – tremors, convulsions, CNS depression

• Wears off quickly

• Modern anaesthetics like lidocaine come from our understanding of cocaine

• Highly addictive

Effects 

• Binds to a high affinity transporter on presynaptic terminals

• Prevents recycling of catecholamines

• Increased levels of catecholamine in synaptic space

conditioned place preference tasks

• 3 chambers which rodents are allowed to explore – they look different so the rodent can tell the difference

• When the rodent goes into one of the chambers you administer the drug

• If they like the drug they’ll have a bias for the chamber they were originally administered the drug

• If they don’t they’ll wander round all 3 chambers

Results

• Since cocaine binds to dopamine transporter channels, made mice which lack this dopamine transporter (emulating the block in cocaine)

• If you gave these mice cocaine, you would expect It to have no effect as they dont have this uptake transporter to block

• Mice with dopamine transporter knockout have chronically elevated synaptic dopamine and increased locomotor activity (what you would expect to see with cocaine)

• BUT they do show conditioned place preference to cocaine as well as self-administration behaviour

• Might be a reinforcing stimulus other than dopamine

improvements to this experiment

• BUT these animals have has this knockout all their life —> not the same as how cocaine is administered to humans or mice

• Tweaked by replacing a mutated (cocaine insensitive) dopamine transporter with mutations at F105, and at positions 104 and 109

• The transporter can transport dopamine but can no longer bind cocaine

• Dopamine knockin mice have no elevated dopamine in the synaptic cleft —> don’t exhibit elevated locomotion

• Cocaine in the mutant DAT knockin mice did not produce reinforcement as measured by CPP —> they were unaffected by the cocaine

• The same experiment was done with amphetimaine to prove that the receptor still worked, did show a sensitivity and preference for amphetamine

can we apply this to humans?

• Is dopamine important in human drug abuse

• Use PET imaging —> 11C radiolabelled carbon binds to D2 receptors to see receptor availability

• Uses fluorosprioperidol (DA receptor antagonist)

2 theories to explain the decrease in D2 receptors in barins of cocaine users

A)

• In cocaine users D2 receptors in the basal ganglia downregulated: when cocaine administered you get blocking of reuptake at presynaptic cleft —> more dopamine in synaptic cleft —> downregulation of receptors

• Even if you’ve been a regular cocaine user and stopped, you still have the downregulation of D2 receptors up to 4 months

B)

• However, we view this as a consequence but could this be a cause —> another hypothesis is maybe everyone has variable levels of D2 receptors and if you have lower levels it makes you more vulnerable to addiction

theory B - natural variation in D2 receptors

Evidence disproving thsi hypothesis

D2 receptors and Age Insigh

• D2 receptors are mapped from birth and the number of D2 receptors declines with age

• Pink is control, green is drug users —> pink consistently above the green

• Also found that in the experiment which proves thqt drug administration downregulates these receptors (next slide) thqt in male monkeys decreased initial receptor levels resulted in increased succeptibility to addiction, but in female monkeys the opposite was true

theory A - cocaine causing downregulation 

evidence for this hypothesis 

• Measutre the levels of D2 receptors using 11C PET

• Allow them to self-administer cocaine

• Gradually increase the dosage of cocaine given and measure the number of D2 receptors

• Found that with increased dosage causes the decrease in D2 receptors.

• This gives evidence for the hypothesis that cocaine causes this downregulation of D2 receptors