psychomotor stimulants

definition of psychomotor stimulants

drugs associated with increased motor output and euphoria

Examples of psychomotor stimulants

• amfetamine

• cocaine

• caffeine

Describe the mechanism of amphetamines [4 marks]

1. Amfetamine enters through dopamine transporter DAT, outcompetes dopamine for the transporter (DAT) so more DA left behind.

2. Inhibition of internal transporters (VMAT) leads to increased cytosolic concentration of dopamine

3. High amphetamine concentrations inhibit monoamine oxidase A, so dopamine is not broken down in the presynaptic terminal

4. Movement of DA is reversed by high [amfetamine] outcompeting DAT. DA is pushed out down the concentration gradient, increasing synaptic [DA].

Draw the mechanism of amphetamines [10 marks]

Name and describe the clinical uses of amphetamine derivates/ amphetamine-like compounds? [4 marks]

• modafinil is used for ADHD and epilepsy - Inhibits amine reuptake, increases activity of orexin neurons

• methylphenidate might treat hyperactivity of ADHD

• atomexetine - SNRI for ADHD

Why are amphetamines not used to treat ADHD [2 marks] ? What are the alternatives? [2 marks]

• amphetamines have strong dependence and addiction potential, often administering to young children

• amphetamine-like drugs which are CNS stimulants are used instead that have stronger selectivity compared to amphetamines

• atomexetine - SNRI

• modafinil - selective amine reuptake inhibitor

Which symptoms of ADHD do amphetamine like drugs target?

• inattentive symptoms

• hyperactivity/impulsivity

What can atomexetine be used in combination with? What is the benefit of this?

• can be used in combination with methyphenidate at lower doses

• covers both impulsivity and inattentive phenotypes

• reduces side effects, addiction, tolerance and dependence

What symptoms in chronic use of amphetamines are associated with overactivation of dopaminergic signals within the striatum?

• repetitive, stereotypical behaviours eg punding - biting, scratching

• acute schizophrenia, psychosis

Tolerance definition

• decrease in behavioral response when the drug is used repeatedly

• euphoric and anorexic actioins

general effects of psychomotor stimulants

• act on the CNS primarily for cognitive effects

• increase alterness, mood, sense of wellbeing, euphoria

• decrease fatigue, appetite

potential harms of psychomotor stimulants

• significant abuse potential

• prolonged abuse can be neurotoxic

  • cardiovascular system impacted

• repeated use leads to tolerance and dependence in some individuals

  • changes in response

amfetamine and related compounds structure

• small ring structure with proximal amine group

Related structures are chemically similar to dopamine, serotonin noradrenaline found in the brain, and similar to cocaine

key regions of noradrenergic pathway

• LC - locus coeruleus, projections to cerebellum (arousal, movement), limbic structures (amygdala and hypothalamus), up and around through the cerebral cortex - widespread

• LTA - lateral tegmental area, descending projections through the NTS

mechanism of amfetamines

• increased availability of noradrenaline and dopamine

• binds and blocks NET and DAT

• inhibits VMAT

• at higher conc inhibit MAO

behavioural effects of amfetamines

• locomotor stimulation through nigrostriatal

• euphoria and excitement

  • intense, particularly if injected

• insomnia

• inc stamina

• can affect appetite - short term anorexia

mental performance with amfetamines

• better for simple tasks

• impair performance on complex tasks

  • reduce speed quality on decision making, frontal cortex executive function

  • particularly seen in chronic users

peripheral effects of amfetamines

• raised BP

• inhibition of GI motility

adverse side effects of amfetamines

• anxiety, restlessness - due to dopamine and attention

• high doses - paranoia and panic

naroclepsy

• disabling state

• falling asleep at unpredictable times within the day

• 4 subtypes of narcolepsy

  • daytime sleepiness, cataplexy, sleep paralysis and hyponopompic hallucinations

• modafinil can treat this

modafinil mechanism for narcolepsy

• inhibits amine reuptake

  • structurally different to amfetamine

  • increases activity of orexin neurons in rat

  • nausea, headache, insomnia

amfetamine for ADHD

• characterised by low attention span and hyperactivity

• amphetamine like drugs induce impulsivity and improve attention

  • methylphenidate, atomexetine, modafinil

atomexetine

• newer drug to treat adhd

• selective noradrenaline reuptake inhibitor

• reduced potential of addiction, fewer side effects and reduced tolerance

modafinil for ADHD treatment

• selective amine reuptake inhibitor for adhd

• activates a2 adrenoreceptors, inhibition of gaba, modulates serotonin, glutamate, histamine release

amfetamine psychosis

• acute schizophrenia - hallucinations, paranoia, aggression

• overactivation of dopamine signals into striatum

repetitive stereotypical behaviours with amphetamines

• from stimulation of serotonin in striatum and serotonergic receptors interaction with striatum

• punding

tolerance and amfetamines

• develops rapidly

• euphoric, anorexic actions

dependence with amfetamines

• reduced basal levels of dopamine once withdrawn from the drug

  • need larger stimulation to maintain normal levels of dopamine

  • mice readminister until the cardiovascular side effects cause death

types of dependence with amfetamines

• physiological - system adjusts to lower dopamine release, more amfetamine is needed to replace

• psychological - persistent ‘memory’ of euphoria

cocaine origins

• plant alkaloid from coca plant

• historically used for fatigue

mechanism of action for cocaine

• acts equally on uptake of noradrenaline, dopamine and serotonin

• also a local anaesthetic - blocks sodium channels

absorption of cocaine

• rapidly absorbed

  • nasal intake destroys local tissue, vasoconstriction

  • results in perforated septum

  • IV gives a more intense ‘ high ‘

metabolism of cocaine

• rapidly metabolised in the liver

• metabolites are measurable in human hair

toxic side effects of cocaine

• acute or chronic cardiovascular effects

  • systolic and diastolic dysfunction, arrythmias, atherosclerosis

Describe the dependence seen with cocaine

• substance dependence - not true addiction, mostly psychological

• associated with rapid routes of administration

cocaine use in pregnancy to foetus impact

• foetal malformation

• microcephaly

• abnormal neural differentiation and proliferation

caffeine found where

• methylxanthine

• nuts of coca plants

mechanism of caffeine

• mild cns stimulant

• diuretic

• antagnosim to adenosine receptor 1 and 2

• inhibits phosphodiesterases

antagonism of adenosine receptors impact with caffeine

• adenosine and atp are modulatory

• fine tunes actions of other neurotransmitters

• dec in cns activity

• caffeine disinhibits it, stimulating the cns

effects of caffeine on the CNS

• mental functions improved at moderate dose 200mg

• tolerance/habituation but not severe, rodents wont self administer

• neuroprotective

neuroprotective effect of caffeine

• protective management of parkinsons disease

• mechanisms for caffeine neuroprotection in parkinsons

  • adenosine 2a receptor antagonists

  • modulates VMAT-2 expression