psychostimulants Flashcards
what are psychostimulants
Psychostimulants are a class of psychoactive substances that increase the activity of the central nervous system (CNS).
Psychostimulants include legal substances (e.g., caffeine, nicotine), prescribed medication (e.g., Ritalin for adhd) and drugs of abuse (e.g., MDMA)
reasons why people take psychostimulants:
Multi-fold (for example):
Alertness
Energy
Social disinhibition
Pleasure
Key drug legislation associated with psychostimulants
The Misuse of Drugs Act 1971
Drugs are divided into three classes in accordance with the harmfulness attributed to a drug when it is misused
The Misuse of Drugs Regulations 2001
Drugs are divided into five schedules each specifying requirements governing activities concerning a particular drug (e.g., production, supply, possession, prescribing)
What are amphetamines and their structure
Amphetamines are a class of synthetic psychoactive drugs derived from the alkaloid ephedrine.
Ephedrine is an alkaloid extracted from the plant Ephedra – used to treat specific conditions (e.g., airway obstruction as a bronchodilator)
Ephedrine is a precursor for ALL synthetic amphetamines
Amphetamines share structural similarities with dopamine and noradrenaline
Mechanism of action of amphetamines
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
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
What is MDMA
MDMA (3,4-Methylenedioxymethamphetamine) is a synthetic psychoactive drug.
MDMA was first synthesised in 1912 by the pharmaceutical company Merck in attempts to develop a vasoconstrictor
MDMA was subsequently used in the 1970s by some underground psychiatrists within psychotherapy
MDMA shares structural similarities with dopamine and noradrenaline
MDMA mechanism of action
MDMA is competitively re-uptaken up into the pre-synaptic nerve terminal via the dopamine transporter (DAT) and the noradrenaline transporter (NET) and the serotonin transporter (SERT)
This leads to less DA, NA and serotonin (5-HT) being taken up into the pre-synaptic nerve terminal as MDMA is competitively taken up in its place
MDMA inhibits VMAT1/2 – DA, NA and 5-HT accumulate in the cytosol
MDMA activates intracellular TAAR1 receptors, which can lead to the reversal of DAT, NET and SERT and the removal of DAT, NET and SERT from the plasma membrane
Increase in DA, NA and 5-HT in the synaptic cleft, leading to increased DA, NA and 5-HT post-synaptic receptor activation
What is cocaine
Cocaine is an alkaloid derived from the coca plant (Erythroxylun coca).
Coca leaves used for thousands of years (e.g., South America) for stimulant effects – in the West, cocaine widely used toward latter half of the 19th century in coca wines, cigarettes, and medicines
Cocaine typically extracted in a paste and converted into a hydrochloride or sulfate salt – salt can be prepared in a variety of ways to facilitate intake (e.g., coke, crack)
Cocaine shares minor structural similarities with dopamine and noradrenaline
Mechanism of action of cocaine
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
Introduction to Khat
Khat (Catha edulis) is a naturally-occurring plant that contains the alkaloid cathinone
Khat usage dates to at least the 11th century and is a social mainstay in several countries (e.g., Yemen) – leaves chewed with effects similar (but lesser) to amphetamines
Cathinone shares structural similarities with dopamine and noradrenaline
Cathinone compounds have more recently been synthesised (e.g., mephedrone)
Synthetic cathinones are chemically related to khat –however, the effects of these drugs are heightened
mechanism of action of khat
Cathinones are non-competitive blockers 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
Compare and contrast the effects of (a) amphetamines and (b) MDMA on disrupting the function of synaptic vesicles within neurons (5 marks)
Outline the effect of psychostimulants on dopaminergic and noradrenergic neurotransmission
Amphetamine, MDMA, cocaine, khat all work to increase dopamine in the synaptic cleft
Metabotropic receptors (GPCRs): D1 & D5 couple to Gs proteins to stimulate adenylate cyclase D2, D3 & D4 couple to Gi/o and inhibit adenylate cyclase
Dopamine metabolised by monoamine oxidase (MAO)
Dopamine recaptured into nerve endings by a selective dopamine active transporter
4 major dopaminergic pathways
Nigostriatal pathway- neurones from substantia niagra projects to dorsal striatum (comprises of 2 basal ganglia structures- caudate and putamen). Dopaminergic neurones in substantia niagra are invovled in initiation of voluntary movement- associated with parkinsons
Tuberophyseal pathway- neurones project from ventral hypothalamus to pituitary gland, regulating secretion of prolactin
Mesocortical pathway- neurones in VTA, near the substantia niagra in the midbrain. Project to brains frontal cortex. Involved in cognitive control, motivation and emotion
mesolimbic pathway- particular sensitive to psychostimulants. dopaminergic neurones in VTA projecting to limbic system, particularly nucleus accumbens. Involved in mediating feelings of reward. Activation fo mesolimbic pathway leads to feelings of reward and pleasure+ compulsion to take drug. Plays role in drug and alcohol addiction
Noradrenergic signalling
amphetamine, mdma, cocaine and khat also all increase noradrenaline
Receptor subtypes:
α1 couples to Gq proteins to activate phospholipase C
α2 couples to Gi/o and inhibits adenylate cyclase
β1 and β2 couple to Gs and activate adenylate cyclase
The locus coeruleus is a small nucleus located bilaterally in the pons –noradrenergic projections to vast parts of the central nervous system (CNS).
Noradrenergic projections involved in regulating, for example:
Attention
Arousal
Sleep and wakefulness
Learning and memory
Pain
Mood
Snorting of stimulants (most associated with cocaine), causes degradation of the septum
Essentially, repeated use causes constriction of the blood vessels in the nose, leading to ischaemia and loss of nasal passage tissue
