study drugs Flashcards
What are study drugs
The term ‘study drugs’ typically refers to prescription-based psychostimulants used to enhance aspects of cognitive function in healthy individuals.
Psychostimulants are a broad class of psychoactive substances that can increase, for example, wakefulness and aspects of cognitive performance (e.g. attention, working memory) Psychostimulants include drugs of abuse (e.g. cocaine, methamphetamine) as well as prescription drugs (e.g. Ritalin®)
Psychostimulants also include caffeine and coca leaves, whose use for increasing wakefulness or performance enhancement dates back centuries…
Study drugs over the ages- caffeine and coca?
Coffee used for thousands of years (e.g., Africa/Arabian Peninsula) for stimulant effects
Used in newer products (e.g., gum) today to improve cognitive performance
Coca leaves also used for thousands of years (e.g., South America) for stimulant effects
In the West, cocaine was widely used toward latter half of the 19th century in coca wines, cigarettes, and medicines, including Coca-Cola
think gum increases memory enhancement
if you contrast think gum and normal gum- effects shown on control response in memory test
Khat and amphetamine over the ages
Khat usage dates back to at least the 11th century
Khat is a social mainstay in several countries (e.g., Yemen) to assist in work, study and social cohesion
Ephedra has been used in Traditional Chinese Medicine for around 500 years – used to treat asthma, although modern use associated with performance enhancement
Benzedrine is an amphetamine synthesised as an alternative to Ephedra in early 1900s – extensively used to fight fatigue and prevent sleep deprivation-related performance in US fighter pilots
who uses study drugs?
62% of all users reported taking Ritalin®
44% of all users reported taking Modafinil
15% of all users reported taking beta blockers (e.g., propranolol) – overlap between drugs
Most common alternative ‘study drug’ was Adderall®
why take study drugs?
Most popular reason for taking the drugs was to improve concentration
Ranking a close second was improving focus for a specific task (although difficult to distinguish from concentration)
A range of ‘other’ reasons also provided (e.g., managing jet-lag)
How do study drugs work? Dopamine and noradrenaline
There are four major dopaminergic pathways in the brain – the tuberohypophyseal, nigrostriatal, mesocortical and mesolimbic pathways.
Cognitive control
Motivation
Emotion
Reward
NA pathway:
The locus coeruleus is a small nucleus located bilaterally in the pons –noradrenergic projections to vast parts of the central nervous system (CNS).
LC in pons (2) contains 12,000 neurones
LC neurones innervate vast areas of the CNS including cerebral cortex, thalamus, cerebellum, spinal cord
Noradrenergic projections involved in regulating, for example:
Attention
Arousal
Sleep and wakefulness
Learning and memory
Pain
Mood
Inverted U shaped dose effect curve
The inverted U–shaped dose-effect curve is a graphical depiction of the cognitive effects of psychostimulants – also termed the optimal arousal theory
Moderate arousal is beneficial to cognition
However, too much arousal leads to cognitive impairment
As low doses, psychostimulants can initially promote cognitive enhancement
As dose increases further, a sense of power and euphoria can ensue; these are the effects addicts seek and are accompanied by cognitive deficits
Higher doses can result in psychosis, coma, and eventual circulatory collapse
Describe methylphedidate- ritalin
Introduced in1957 for a number of ailments (e.g., sleepiness, nasal congestion)
Primarily used today as a treatment for ADHD
Use as a treatment for narcolepsy
Cocaine is a non-competitive blocker of the dopamine transporter (DAT) and the noradrenaline transporter (NET)
This means less DA and NA are taken up into the pre-synaptic terminal
This leads to an increase in DA and NA in the synaptic cleft, leading to increased DA and NA post-synaptic receptor activation
ritalin is a non competitive blocker of DAT and NET (blocks reuptake of dopamine and noradrenaline)
increasing dopamine and noradrenaline in synaptic cleft
increased dopamine and NA post synaptic activation
Ritalin mechanism of action in animal studies
rodent studies:
Dose-dependent increase in extracellular levels of DA and NA in prefrontal cortex (Berridge et al., 2006)
Higher doses increase DA in nucleus accumbens
human studies:
PET studies support DA and NA as critical to the mechanism of action of Ritalin®
Accordingly, Ritalin® blocks DAT and causes an increase in extracellular DA concentration
Dose leading to 70% DAT occupancy causes more than 80% NET occupancy - supports importance of NA in therapeutic effects of the drug
How does ritalin have dose dependent effects
lower doses of ritalin associated with higher cognitive performance
higher dose impairs spatial working memory
Studies (e.g., Arnsten and Dudley, 2005) have shown that lower doses improve cognitive performance, whereas higher doses impair cognitive performance – specifically spatial working memory
Reversed with co-administration of D1 receptor antagonist or a2-receptor antagonist – suggests drug improves performance by increasing availability of DA and NA, which stimulates D1 and a2 receptors
Intro to adderall
Adderall® - combination of amphetamine and dextroamphetamine salts
not prescribed in the UK
Adderall® is prescribed for ADHD in the USA
adderall taken up into presynaptically into nerve terminal via DAT and NET
and SERT a bit
less dopamine, NA and serotinin taken up as amphetamine taken up in its place
adderall mechanism of action
Amphetamines are competitively re-uptaken up into the pre-synaptic nerve terminal via the dopamine transporter (DAT) and the noradrenaline transporter (NET)
This leads to less dopamine (DA) and noradrenaline (NA) being taken up into the pre-synaptic nerve terminal as amphetamine is competitively taken up in its place
adderall taken up by VMATdisrupts pH gradient through amine group
VMAT becomes non functional
dopamine, NA and serotonin no longer pumped into presynaptic neurones, instead accumulate in cytosol
Amphetamines are taken up into vesicles by VMAT/2
Amphetamines accumulate in vesicles and disrupt the pH gradient required for transporters to function – VMAT1/2 become non-functional and DA/NA accumulate in cytosol
Amphetamines activate intracellular TAAR1 receptors, which can lead to the reversal of DAT and NET and the removal of DAT and NET from the plasma membrane
Increase in DA and NA in the synaptic cleft, leading to increased DA and NA post-synaptic receptor activation
describe the dose dependent effects of adderall
Studies (e.g., Wood and Anagnostaras, 2009) have shown that lower doses of amphetamine improve cognitive performance, whereas moderate-high doses impair cognitive performance – specifically associative memory
pavollonian fear conditioning
neutral stimulus paired with fear stimulus
low dose of amphetamine means mice freeze when presented with fear stimulus
higher dose of ampehtamine/aderall means mice don’t freeze due to cognitive impairemnt, reducing associative memory
Introduction to modafinil
First used as a treatment
for narcolepsy (UK)
Use for obstructive sleep apnoea and shift-work sleep disorder (USA)
Tested for other conditions including ADHD and depression
Modafinil mechanism of action
A clear mechanism of action for Modafinil yet to be established – primary action generally considered to be upon DA (and NA) signalling
Modafinil may directly interact with D1/D2 receptors, but current evidence suggests that its primary action is through inhibition of DAT
Supported by study showing Modafinil reduces the spontaneous firing rate of DA neurons in control mice, whilst not affecting DA neurons of mutant mice insensitive to DAT blocker cocaine
In addition to DA and NA, Modafinil also has actions on a host of other neurotransmitter systems
Modafinil has been shown to increase extracellular levels of 5-HT, glutamate, histamine and orexin and decrease extracellular levels of GABA
Modafinil acts on subcortical structures, namely the thalamus, hypothalamus and amygdala – reinforce physiological mechanisms involved in the activation and maintenance of wakefulness
Think about these questions
Compare and contrast the pharmacological mechanism of action of Ritalin® and Adderall®.
Discuss the effects of psychostimulant dose on cognitive function
