Psychopharmacology

overview synapse

1. Strong stimulation → impulse (action potential)

2. action often tidal is propagated further down the axon

3. Axonal propagation (conduction)

4. when action potential reaches the axon terminal it imitates synaptic transmission 

5. when the action potential reaches the axon terminal → interacts with neurotransmitter vesicles pushing towards membrane 

6. Once the vesicles containing the neurotransmitter reach membrane → open up & neurotransmitter is released end into the synaptic cleft

7. neurotransmitter then binds to its receptors in the postsynaptic neuron → this open channel 

8. Ions enter the postsynaptic, resulting in a post-synaptic potential

substances can influence/interfere

• different phases of the synaptic sequence

• with signals going through axon 

• with the release of the transmitter

• with the release of the transmitter

• can enhance the release of the transmitter

• different phases of synaptic sequence 

• alter how the transmitter interacts with its receptors 

Substances can influence different phases of the synaptic sequence

• Some act as early as the propagation of the action potential 

• others may influence the release of transmitter

• other modulate how the transmitter interacts with the postsynaptic challenges (receptors) 

• Some alter the presence of the transmitter in the synapse by modulating its inactivation & recycling 

• some alter the presence of the transmitter in the synapse by modulating its inactivation and recycling 

Some chemical interfere with signals going through axon

• By blocking sodium channels in the axon’s membrane 

  • e.g tetrodotoxin TTX (toxin found in certain species of fish)

• TTX can produce paralysis of the diaphragm & death due to respiratory failure (over 10,000x deadlier than cyanide) 

Substances can interfere with the release of the transmitter

• tetanospasmin toxin interferes with the vesicles of the neurotransmitter GABA fusing with the cell membrane 

  • reduces amount of GABA released into the synapse 

    • GABA = inhibitory neurotransmitter 

    • results in an imbalance between excitation & inhibition of neural signals 

• leads to strong uncontrollable muscle contractions (tetanus)

• Neurotransmitters can be classified by chemical structure

  • e.g adrenaline, noradrenaline, serotonin, dopamine histamine and melatonin

    • called monoamines because contain a single amino group 

Substances can interfere with the releases of the transmitter 

• Acetylcholine is a neurotranmistter that has 2 types of receptors

  • nicotinic (excitatory)

  • muscarinic (inhibitory)

• botulinum toxin (formed by bacteria in improperly canned) interferes with the release of acetylcholine at nicotinic synapses, by preventing the vesicles from fusing with the cell membrane 

• this toxin is used in the cosmetic agent BOTOX

  • used to treat wrinkles by reducing synaptic effectiveness at the neuromuscular function in facial muscles 

Substances can enhance the release of the transmitter

• Amphetamine has a similar structure to neurotransmitter dopamine 

• similarity = amphetamine can enter dopamine-releasing neurons either directly through membrane or by binding to the dopamine or dopamine transporter (molecule that recycles dopamine back into the cells from the synaptic cleft)

• once inside the cell, amphetamine facilitates release of dopamine from the vesicles when these fuse with the membrane 

• amphetamine & other drugs have a profound on dopaminergic pathways in the brain

  • one pathways is seen as crucial in explaining the potent effects of theses drugs 

    • the projections from the ventral regimental area (VTA, group of cells in brain stem) to nucleus accumbens (group of cells in basal ganglia)

    • VTA & nucleus accumbens are thought to be involved in pleasure, reward and motivation 

Substances can influence different phases of synaptic sequence

• Some act as early as the propagation of the action potential (e.g blocking sodium channels)

• other modulate how the transmitter interacts with the post-synaptic channels (rec peters)

• finally some alter the presence of the neurotransmitter in the synapse by modulating its inactivation and recycling 

Substances can alter how the transmitter interacts with its receptors 

• Antagonists

• Agonists imitate the behaviour of the neruotransmitter thus increasing it effect

Antagonists

• Certain substances simply bind to receptors (blocking the way of the neurotransmitter) but without opening the channel 

  • E.g plant toxin curare in South America occupies acetylcholine’s receptor in excitatory (in tonic) synapses, blocking them & causing paralysis 

    • curare here acts as an antagonist (occupies channel, but does not open it)

    • curare is used in surgery as an anesthetic agent

Agonists

• Heroin

  • artificially modified form of morphine (contained in opium)

  • Agonist of endorphins 

    • a natural body chemical that binds to opiate receptors & reduces pain & induces relaxation 

• Marijuana (cannabis)

  • contains THC agonists of anandamide (a natural body chemical which binds to cannabinoid receptors)

  • anandamide involved in emotion, pain, appetite and memory

• Nicotine

  • stimulates nicotinic receptors

  • has a short-lived generalised excitatory effect

some alter the presence of the transmitter in the synapse by modulating its inactivation and recycling 

1. Diffusion: the transmitter is “lost” in the inter-cellular space

2. Enzymatic degradation: enzymes break down the transmitter

3. Re-uptake (uptake): the transmitter is recycled either in the pre-synaptic or the post-synaptic neuron. This is the most economical way to inactivate the transmitter: saves synthesis resources

Drugs can influence transmitter inactivation and recycling

• The reuptake of neurotransmitters into the original cell is done by specialised proteins: transporters

• Cocaine blocks the transporter of noradrenaline and dopamine, thus interfering with their re-uptake and boosting their effect

Psychoactive substances

• chocolate

• coffee

• alcohol

psychoactive substance → chocolate

• Chocolate contains several psychoactive compounds

• One of them is anandamide → neurotransmitter produced naturally by the brain, whose agonist is THC (contained in cannabis)

• Another is phenylethylamine – a compound closely related to amphetamine

• However, chocolate contains these in such small amounts that it would not cause a noticeable effect (e.g. to obtain an effect similar to that of marijuana, one would have to consume half of their body weight in chocolate!)

• So, why does one become “addicted” to chocolate? This may be down to its taste!

psychoactive substance → coffee

• Caffeine (effective ingredient)

• Many of the neurons that release substances like dopamine and adrenaline (catecholamines) also release a self-inhibiting transmitter- adenosine

• Adenosine binds to its receptors in the pre-synaptic neuron and inhibits the release of catecholamines 

• Caffeine competes with adenosine for its receptors (it is an antagonist), blocking adenosine and thus reducing its inhibitory effect.

• Caffeine also has a non-synaptic effect in neurons

• It acts on cyclic adenosine monophosphate (cAMP)

• cAMP controls the energy levels in the cell via the regulation of glucose metabolism

• Caffeine inhibits the enzyme that breaks down cAMP, thus increasing glucose metabolism in cells 

psychoactive substance → alcohol

• Low doses: Alcohol is an agonist of the neurotransmitter GABA. GABA is typically found in inhibitory synapses. Thus, alcohol increases the effectiveness of these synapses, leading to a feeling of relaxation.

• Alcohol indirectly stimulates dopamine release. Dopaminergic synapses in certain parts of the brain are associated with reward pleasure and positive motivation (nucleus accumbens and other structures in basal ganglia), hence the euphoria when alcohol is consumed in small to moderate doses.

• In moderate amounts, alcohol also indirectly increases the release of endorphines

  • In high doses, the binding of alcohol to GABA channels leads to powerful inhibition and sedation

  • In very high doses alcohol leads to the destruction of cell membranes and, hence, to brain cell death

Psychoactive substances used to treat psychiatric conditions

• anxiety & GABA

• depression & serotonin

• schizophrenia & dopamine

• cocaine

• methamphetamine & amphetamine

• Parkinsons

anxiety & GABA

• Anxiety disorders are in part characterised by deficits in GABA-ergic transmission

• Benzodiazepines (valium) are GABA agonists used to treat anxiety disorders

• Although their effect may seem similar to that of alcohol, they bind to different sites on GABA receptors

• They also do not bind to the same receptor sites as GABA itself: such an action is one of a non-competitive agonist

Depression

• Depression is associated with reduced monoamine (serotonin, dopamine, noradrenaline) transmission

• MAO Inhibitors

  • interfere with the enzyme MAO, which breaks down serotonin, dopamine and noradrenaline

• Tricyclic Antidepressants

  • inhibit the transporter of serotonin,  dopamine and noradrenaline (prevent reuptake)

depression drug side effects

• The drugs affect lots of systems because the neurotransmitters are involved in loads of function.

• This means they can have unwanted effects 

depression & serotonin

• However, it has been found that serotonin is in fact the neurotransmitter closely linked to depression and less so dopamine and noradrenaline

• Selective Serotonine Reuptake Inhibitors (SSRI, Prozac, Citalopram etc.): inhibit the transporter of serotonin without affecting other neurotransmitters (e.g. dopamine)

schizophrenia & dopamine

• Schizophrenia is associated with a surplus of dopamine

• Its symptoms include paranoia and hallucinations

• Neuroleptics (e.g. Haldol): anti-psychotic drugs that block the transmission of dopamine by binding to dopamine receptors without opening ion channels. 

• They are dopamine antagonists.

cocaine acting as a blocker

• Cocaine blocks the transporter of noradrenaline and dopamine, thus interfering with their re-uptake and boosting their effect

Methamphetamine & Amphetamine derivatives

• As Cocaine, these substances reduce the reuptake transport of monoamine neurotransmitters (dopamine, noradrenaline, serotonin)

• In addition, they also attach to enzymes that break down these neurotransmitters

• The overall effect is a boost in neurotransmitter transmission

• by increasing dopaminergic transmission, they can induce schizophrenia-like symptoms in high doses

Parkisons

• The medication for Parkinson’s and schizophrenia push dopamine in the opposite direction and can cause each others' symptoms in high doses

conclusions (psychopharmacology)

• Psychoactive substances act at different stages of the synapse

• They can affect pre-synaptic processes:

  • Axonal conduction (TTX), 

  • Release (botulinum, tetanospasmin)

• As well as post-synaptic processes:

  • Binding to receptors (nicotine), 

  • Transmitter break-down (MAO inhibitors) 

  • Transmitter re-uptake (cocaine)

• Psychoactive substances that bind to receptors, imitate the molecular structure of some endogenous substances in order to fit the receptor like a key fits the lock

Agonist/antagonist:

substances that bind to receptors and either imitate the action of the transmitter (enhancing it) or preclude it

Competitive/Non-competitive

agonists or antagonists that bind to the same (competitive) or different (non-competitive) sites on the ion channel (or receptor) as the transmitter