PSYC 304 - 2.21

Ways drugs effect behaviour

Altering Presynaptic Effects

Modify behaviour of presynaptic neuron 

• Effects NT production, release, and clearance

Effects on NT Production

• Inhibition of Synthesis: 

  • Blocking enzymes that convert precursor molecules into the NT 

• Blockade of axonal transport: 

  • Prevents movement of enzymes/precursors that are made in cell body + need to travel to the terminal to make the NT

    • Still works, just at the wrong place so NT is disrupted

• Interference with storage

  • Disrupts packaging of NT in synaptic vesicles, leaving them vulnerable to breakdown

Effects on NT release

• Prevention of synaptic transmission: 

  • Blocking of sodium channels (AP cannot be initiated) → signal does not reach terminal (no depolarizing signals entering neuron bc Na+ cant help) 

• Alteration of NT release: 

  • Blocking of Ca2+ channels (opens after AP reaches terminal), decreasing NT release

• Alteration of autoreceptors:

  • Feedback loop doesn't work

  • Caffeine prevents inhibition, increased release of excitatory NT 

  • Also block adenosine postsynaptic receptors, leads to increased alertness

• Alteration of synaptic transmitter release through other mechanisms

  • Botox + tetanus break down SNARE proteins (allow vesicles to dock onto membrane), preventing vesicle fusion + acetylcholine release at neuromuscular junctions 

  • Less NT going around!

Deactivation of NT

• Reuptake: 

  • Most common mechanism 

  • Once released, NT almost immediately drawn back into presynaptic buttons by transporter mechanisms 

• Enzymatic Degradation: 

  • NT broken down in synapse by action of enzymes

Effects on NT Clearance

• Inactivation of NT uptake 

  • Prevents reuptake of NT from synaptic cleft back into presynaptic neuron → prolongs action at postsynaptic receptor 

  • Ex. cocaine blocks dopamine transporter (DAT) 

  • SSRIs (selective serotonin reuptake inhibitors) block serotonin transporter

• Blockade of NT degradation 

  • Inhibits enzymes that normally break down neurotransmitters in the presynaptic terminal/synapse

  • Increase amount of NT available for signaling 

  • Ex. Monoamine oxidase (MAO) inhibitors block breakdown of monoamines (ex. Dopamine, norepinephrine, serotonin)

Altering Postsynaptic Effects

• Direct effects on transmitter receptors

  • Postsynaptic receptors can be directly blocked/activated by drugs 

• Effects on cellular processes in postsynaptic neuron: regulation of number of receptors 

  • Ex. modulation of intracellular signalling: drugs can affect second messengers/intracellular pathways → change neuronal excitability/gene expressions

  • Ex. lithium modulated intracellular signaling pathways, influencing mood regulation 

Half-Life of a Drug

Time needed for drug’s active substance in body to reduce by half

Caffeine’s Rebound Effect

• Adenosine is continuously produced as a byproduct of ATP breakdown (energy) 

• While caffeine is present, adenosine continues to accumulate

• Once caffeine wears off, previously blocked receptors become available + accumulated adenosine can now bind!

  • Up-regulation of adenosine receptors to maintain homeostasis → more receptors, that means person has more places for adenosine to bind at once

How to prove a molecule is a NT?

• Present in presynaptic axon terminals

• Presynaptic cell contains appropriate enzymes for synthesize substance 

• Released in significant amounts when AP reach terminals 

• Has specific receptors on postsynaptic membrane 

• Molecule must produce same changes in postsynaptic cell when apple experimentally, as it does when released naturally from presynaptic neuron 

• Blocking release of substance prevents presynaptic activity from affecting postsynaptic cell 

Techniques for Studying NT Systems

• Localization of transmitters + transmitter-synthesizing enzymes 

• Immunohistochemistry

Immunohistochemistry

Used to anatomically localize specific molecules (NTs) in specific cells 

1. Candidate molecule in injected, causing immune response + generation of antibodies

2. Blood is withdrawn and antibodies are isolated 

3. Antibodies are tagged with marker + applied to brian tissues

4. Only cells containing target molecules are labelled 

• Using different markers allows visualization of multiple cell types in the same tissue 

• Can also identity synthesizing enzymes 

Studying Transmitter Release - PNS

Easier to stipulate specific sites of cells/axons + take sample of the fluid surrounding their synapses

• Easier to demonstrate chemical signalling (ex. Loewi’s heart study → Ach discovery)

Studying Transmitter Release - CNS

Most regions contain mix of synapses using different NT → challenging ti isolate one

• Opogenetics allow specific neurons to be stimulated using light 

• Difficulties to confirm that NT candidate is released by presynaptic axon terminal upon stimulation (not from other neurons/glial cells) 

Studying Synaptic Mimicry

• Confirm that exogenous application of NT produces same response than naturally (endogenous) released NT 

• Microiontophoresis: allows application of candidate molecule directly onto postsynaptic membrane using fine-tipped pipette

Studying Receptors

• Pharmacological analysis: exploring how receptors respond to different substances 

• Finding agonist + antagonists 

• Molecular analysis: establishing structure of receptor 

Designer Receptors Exclusively Activated by Designer Drugs (DREADDS)

• Custom-designed G-protein coupled receptors that respond only to custom-made drugs

• Receptors expressed only by neurons of interest 

• Drugs designed to selectively activate/inhibit only targeted cells 

• Used in research to determine function of targeted neurons