psychotropics and psychostimulants: use and abuse (adrenergic pharmacology)

The monoamines are noradrenaline, dopamine (catecholamines - catechol group) and serotonin (tryptamine - indol group)

Noradrenaline

There are two main nuclei in the brain that produce noradrenergic fibres:

  • locus coeruleus which has projectrions throughout the brain

  • lateral tegmental area which has projections and signals through the spinal cord

Activation of the noradrenergic fibres result in different behaviours such as alertness, arousal (forebrain - fight or flight) as well as regulating mood , pain and blood pressure

Dopamine

there are a few nuclei where dopaminergic fibres arise from:

  • ventra tegmental area - projections to the forebrain

    • important for decision making

    • affected by addiction - drug target

  • substantia nigra - projections to the middle brain

    • dopaminergic neurons degenerate in parkinson’s diseases

activation of dopaminergic fibers result in control in motor, behaviour, mood and endocrine function

ALL DOPAMINERGIC RECEPTORS AND G PROTEIN COUPLED

There are two major dopamine receptors: D1 and D2 like each of which can be broken down into groups

D1-LIKE

These can be broken down into D1 and D5 subgroups which are coupled to the g protein subgroup Gas. The second messengers for this include increased cAMP and PKA activity

D2 LIKE

These have the subgroups D2,D3 and D4 subgroups that are coupled to Gai g proteins. The second messengers to the activation of these are reduced cAMP and PKA activity. the gby subgroup also reduces the activity of VG Ca2+ channels and opens K+ channels

Activation of any receptors leads physiological responses such as voluntary movements, reward, sleep, mood/cognition/attention, hormonal activity, nausea and sympathetic activity

Serotonin

Serotonin has very extensive projections through the brain with the primary nucleus being the Raphe nucleus. It extends all the way through the brain meaning it is involved in many different behaviors such as:

  • sleep, wakefulness and mood

  • feeding behaviour

  • control of pain and sensory transmission

There are many receptors for serotonin ( 5-HT1-7)

  • 5-HT1 is coupled to a gai receptor

  • 5-HT2 is coupled to a gaq receptor

    • second messenger include PKC and Ca2+

  • 5-HT3 is an ion channel for Na+ and Ca2+

  • 5-HT4,5,6,7 are coupled to Gas

Monoamine uptake and inhibition

Monoamine uptake into vesicles happens via the same mechanism as the uptake of ACh into vesicles. Many psychoactive drugs target and inhibit the uptake of monoamines at the plasma membrane or the synaptic vesicles and lead to monoamine accumulation in the cleft

Cocaine and dopamine

Cocaine inhibits dopamine uptake by blocking the transporter which allows the reuptake of it into the presynaptic terminal. This leads to accumulation of dopamine in the cleft which is responsible for the immediate rush felt after

MDMA and serotonin

MDMA is taken up the serotonin transporter which allows the accumulation of serotonin in the cleft. It also competes for the vesicle which means more secretion of it

Amphetamine and noradrenaline

Amphetamines are taken up by the noradrenaline transporter and also compete for the vesicle with it however they also inhibit MAO enzymes so noradrenaline in the cleft is not broken down

Stimulant properties of amphetamines

The main effects of amphetamines are:

  • increased motor activity

  • euphoria and excitement

  • insomnia

  • anorexia <3

The effects are due mainly to increased levels of monoamines in the synaptic cleft. They were used at stimulants during WW2 due to these effects

They can also induce strong psychological dependance and psychosis can occur with prolonged use which resemble schizophrenia

Clinically, they can be used to read ADHD or narcolepsy as low doses help to focus attention. Obesity can also be treated in severe cases

Stimulant properties of cocaine

The main effects of cocaine are:

  • increased motor activity

  • euphoria, excitement and garrulousness

  • increased peripheral sympathetic NS activity

They cause strong psychological dependance and the effects are mainly due to the increased levels of monoamines. Cocaine has shorter lasting effects compared with amphetamines

Modafinil

Modafinil is thought to affect the dopamine transporter. When a PET scan was taken with labelled cocaine, it bound very strongly however with modafinil, cocaine did not bind as strongly.

The main effects are:

  • increased wakefulness and vigilance

  • suggested to improve cognitive performance

Modafinil binds with low affinity to DAT and to NET and has additional actions at a variety of NT systems as well as a low abuse potential

Cognitive enhancers are hoped to:

  • reduce mental fatigue

  • maintain attention and concentration

  • increase motivation

  • normalise behaviour

    • schizophrenia

    • autism disorders

    • addiction

ampakines

ampakines enhance the activation of glutamate AMPA receptors. They promote the release of brain derived neurotrophic factor and show evidence of enhancing cognition in a range of tests (the rat one)

The monoamine theory for depression was first proposed by Jow Schildkraut in 1965 and it is based on the theory that drugs that enhance monoamine levels improve mood and symptoms of depression

There are various signs of depression that clinicians use in the diagnosis of depression which could be caused by messed up monoamine levels. Antidepressants essentially normalise the levels of the neurotransmitters which can be used to alleviate some of the symptoms

Dopamine and schizophrenia

Schizophrenia is a condition that displays positive, negative and cognitive symptoms.

Positive symptoms relate to over activity in the mesolimbic dopaminergic pathway activating dopamine D2 receptors

Negative symptoms relate to decreased activity in the mesocortical dopaminergic pathway in D1 receptors

Cognitive receptors relate to attention and memory - mesocortical pathway

Therapies

There are two generations of antipsychotics

The first generation target D1 and D2 receptors while the second generation has some activity in D1 but more in D2

Dopamine and Parkinson’s disease

Parkinson’s disease is a neurodegenerative disorder in which patients display a profound motor impairment

It has a suppression of voluntary movements with a tremor at rest and increased resistance in passive limb movement with a variable degree of cognitive impairment