The Minds Machine Foundations of Brain and Behavior 3rd by Neil V Watson S Marc Breedlove ch4-6

The Chemistry of Behavior: Neurotransmitters and Neuropharmacology

A Dream of Soups and Sparks

  • People have experimented with exogenous substances to change body and brain functions throughout history.
  • Modern scientists study the physiological actions of these substances to unlock brain function mysteries.
  • The brain is an electrochemical system.
  • Neurons electrically process information through synapses and release chemicals to pass information to the next cell.
  • A presynaptic neuron releases neurotransmitters, endogenous substances, to communicate with the postsynaptic cell.
  • Most drugs that affect behavior do so by affecting this chemical communication process at synapses.
  • There was controversy about how neurons communicated; some believed it was electrical signals ("sparks"), others believed it was chemical substances ("soups").
  • Otto Loewi's experiment with frog hearts demonstrated chemical neurotransmission.
  • Loewi electrically stimulated the vagus nerve of a frog, causing its heart to slow down.
  • He collected the fluid surrounding the slowing heart and applied it to another frog's heart.
  • The second heart also slowed, providing conclusive evidence of chemical neurotransmission.
  • The neurotransmitter was later identified as acetylcholine (ACh).

Chemical Neurotransmission

  • Synaptic transmission involves electrochemical events.
  • Receptors capture, recognize, and respond to neurotransmitter molecules.
  • Neurotransmitters share general properties, and there are major chemical families of transmitters.
  • Major neurotransmitters have distinct neuroanatomical distributions and functional roles.
  • Neurotransmitter action is rapidly reversed through reuptake and enzymatic breakdown.

Synaptic Transmission: A Detailed View

  • An action potential arrives and spreads over the presynaptic membrane, causing voltage-gated Ca2+Ca^{2+} channels to open.
  • The influx of Ca2+Ca^{2+} causes synaptic vesicles to migrate to the presynaptic membrane, fuse, and rupture, releasing neurotransmitter molecules into the synaptic cleft.
  • Neurotransmitter molecules briefly bind to postsynaptic receptors, changing the function of the postsynaptic cell.
  • Some receptors open ion channels, resulting in a flow of ions that initiate an inhibitory or excitatory postsynaptic potential.
  • Other receptors are linked to second messengers that trigger changes in excitability or metabolism in the postsynaptic cell.

Neurotransmitter Versatility

  • A given neurotransmitter may interact with many different receptors in different brain parts.
  • A neurotransmitter may activate an ionotropic receptor (ligand-gated ion channel), opening an ion channel to affect the postsynaptic cell's membrane potential.
  • The same neurotransmitter may activate a metabotropic receptor, activating second messengers (via G proteins) that open other ion channels and/or cause other changes in the cell.

Synaptic Transmission: Electrochemical Process

  • A neuron integrates inputs; if sufficiently excited, it fires an action potential down the axon toward axon terminals.
  • The action potential induces voltage-gated calcium (Ca2+Ca^{2+}) channels in the terminal membrane to open.
  • The inflow of calcium ions drives synaptic vesicles to the presynaptic membrane.
  • Proteins on vesicle walls and synaptic membrane interact, causing vesicles to release neurotransmitter molecules into the synaptic cleft (exocytosis).
  • Neurotransmitter molecules diffuse across the cleft and briefly bind to neurotransmitter receptors.
  • Receptors mediate a response on the postsynaptic side.
  • Transmitter molecules are either broken down by enzymes or brought back into the presynaptic terminal (reuptake).
  • Reuptake relies on transporters that bind and conduct neurotransmitter molecules back inside the presynaptic terminal.
  • Neurotransmitter receptors are selective about substances they respond to, likened to a key opening a lock.
  • Receptors are categorized as ionotropic or metabotropic.

Receptor Types: Ionotropic vs Metabotropic

  • Ionotropic receptors are ion channels; neurotransmitter binding changes their shape to open or close the channel.
  • Opening the channel allows ions to flow into or out of the postsynaptic neuron, changing the local membrane potential.
  • Depolarization has an excitatory effect; hyperpolarization has an inhibitory effect.
  • Metabotropic receptors don't contain ion channels; they link to chemical machinery inside the postsynaptic neuron.
  • Activation alters the inner workings of the postsynaptic cell, using second messengers to cause changes in excitability or larger-scale responses.
  • Metabotropic receptors may kick off a chain of chemical reactions that affect gene expression.
  • Changes in gene expression can have lasting effects, such as changes in excitability, connections, or production of receptors and signaling chemicals.
  • Transmitter receptors allow rapid responses (ionotropic) and complex, integrative behaviors (metabotropic).
  • Diversity of receptor subtypes is true for both metabotropic and ionotropic receptors.
  • The response of a postsynaptic neuron is determined by the types of receptors present on the postsynaptic membrane.

Neurotransmitter Identification Criteria

  • A candidate substance is a transmitter if:
    • It can be synthesized by presynaptic neurons and stored in axon terminals.
    • It is released when action potentials reach the terminals.
    • It is recognized by specific receptors on the postsynaptic membrane.
    • It causes changes in the postsynaptic cell.
    • Blocking its release interferes with the presynaptic cell's ability to affect the postsynaptic cell.

Major Categories of Neurotransmitters

  • Amino acid neurotransmitters: Based on single amino acid molecules (e.g., GABA, glutamate, glycine).
  • Peptide neurotransmitters (neuropeptides): Based on short chains of amino acids (peptides).
  • Amine neurotransmitters: Include acetylcholine, dopamine, and serotonin.
  • Gas neurotransmitters: Soluble gases that diffuse between neurons (e.g., nitric oxide, carbon monoxide).

Neurotransmitter Distribution

  • Each neurotransmitter has a unique pattern across brain regions.

Acetylcholine (ACh) - The First Neurotransmitter

  • Loewi's experiment in 1936 led to the discovery of Acetylcholine

Neurotransmitter Types

  • Amino acid neurotransmitters: GABA, glycine, and glutamate.
  • Peptide neurotransmitters: Short chains of amino acids (neuropeptides).
  • Amine neurotransmitters: Acetylcholine, serotonin, and dopamine.
  • Gas neurotransmitters: Nitric oxide and carbon monoxide.

Neurotransmitter Systems in the Brain

  • Amino acids are the most common transmitters.

    • Glutamate: Widespread excitatory transmitter.
    • GABA: Widespread inhibitory transmitter.

  • Glutamate interacts with subtypes of receptors:

    • AMPA receptors: Ionotropic, rapid excitatory effects.
    • NMDA receptors: Ionotropic, central role in memory formation.
    • Metabotropic glutamate receptors (mGluRs): Act slowly through second messengers.

  • GABA receptors:

    • GABAA receptors: Ionotropic, allow Cl- ions to flow into the postsynaptic cell, inhibiting activity.
    • GABAB receptors: Metabotropic, also inhibitory.

  • Benzodiazepines (e.g., Xanax, Ativan): Activate GABAA receptors, used to treat anxiety and panic attacks.

Amine Neurotransmitters

  • Modulate brain activity and are a major target for drug development.
  • Each is carried by a different set of axons projecting to different brain regions.
  • There may be overlap as two different transmitters arrive at the same target.
  • How targets respond depends on the neurotransmitter and receptors present.
  • Some neurons make and release more than one type of transmitter (co-localization).

Specific Amine Neurotransmitters

  • Acetylcholine (ACh):
    • Cholinergic neurons in the basal forebrain project widely to the cortex, amygdala, and hippocampus.
    • Involved in learning and memory; loss of cholinergic neurons is associated with Alzheimer's disease.
  • Dopamine (DA):
    • Mesostriatal pathway (substantia nigra to basal ganglia): Crucial for motor control.
      • Loss of dopaminergic neurons leads to Parkinson's disease (tremors).
    • Mesolimbocortical pathway (VTA to limbic system and cortex): Important for reward processing.
      • Involved in learning shaped by positive reinforcement and is associated with some symptoms of schizophrenia.
  • Serotonin (5-HT):
    • Serotonergic neurons originate in the raphe nuclei and innervate vast expanses of the brain.
    • Participates in the control of mood, vision, anxiety, sleep, and sexual behavior.
      • Drugs that increase serotonergic activity are prescribed for depression and anxiety. actions depend on the 5-HT receptor subtypes affected.
  • Norepinephrine (NE):
    • Noradrenergic neurons have cell bodies in the locus coeruleus and lateral tegmental area.
    • Axons project to the cerebrum (cortex, limbic system, thalamic nuclei).
    • Participates in the control of alertness, mood, and sexual behavior, among others.

Peptide Neurotransmitters

  • Important signaling chemicals in the brain and body.
  • Opioid peptides (e.g., enkephalins, endorphins, dynorphins): Reduce pain perception and have rewarding properties.
  • Peptides originally discovered in the gut (e.g., substance P, cholecystokinin): Act as synaptic transmitters, often co-localized with classical transmitters.
  • Peptide hormones (e.g., oxytocin, vasopressin): Involved in various functions, such as memory and pair-bonding.

Gas Neurotransmitters

  • Nitric oxide and carbon monoxide.
    • Produced in cellular locations other than axon terminals (e.g., dendrites) and not held in vesicles.
    • Diffuse out of the neuron as produced.
    • No receptors in the target cell membrane involved.
    • Diffuse into the target cell to trigger second messengers.
    • Can function as retrograde transmitters (diffuse from postsynaptic to presynaptic neuron).
    • Convey information used to physically change the synapse, crucial for memory formation.

Drug Actions in the Brain

  • Drugs and toxins affect brain function.
  • Can alter transmission by interacting with presynaptic and postsynaptic mechanisms.

Ligands and Receptors

  • Drug: Medicine used in the treatment of a disease.
  • Psychoactive drugs: Alter brain function and affect conscious experiences.
  • Drugs of abuse: Psychoactive drugs used recreationally with varying risk levels.
  • Most drugs of interest to neuroscience act via receptors.
  • Ligand: Substance that binds to a receptor.
  • Natural ligands: Neurotransmitters.
  • Agonists: Mimic or potentiate a transmitter's actions.
  • Receptor agonist: Mimics the normal action of a neurotransmitter by binding to the receptor and activating it.
  • Antagonists: Reduce the normal actions of a neurotransmitter system.
  • Receptor antagonists: Bind to receptors, block them from being activated by their normal neurotransmitter.
  • Partial agonists: Produce only a middling response.

Origins of Drugs

  • Caffeine, opium, nicotine, and cocaine originally evolved in plants as a defense.
  • Modern drugs are synthetic and target specific transmitter systems.

Examples of Drugs and Their Actions

  • Benzodiazepine antianxiety drugs (e.g., lorazepam): Enhance GABA neurotransmission.
  • Classic antipsychotics (e.g., haloperidol): Block dopamine receptors.
  • Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine): Antidepressants.

Receptor Subtypes and Drug Design

  • A given neurotransmitter interacts with a variety of different subtypes of receptors.
  • The transmitter receptor subtypes present an opportunity as humans can craftily design drugs that single out just one or a few subtypes of receptors.
  • Selectively activating or blocking specific subtypes of receptors can produce diverse effects.

Drug Specificity

  • A particular drug will generally bind strongly to one kind of receptor, more weakly to a few other types, and not at all to many others.
  • This chemical attraction is known as binding affinity (or simply affinity).
  • At low doses, drugs preferentially bind to their highest-affinity receptors.

Neurotransmitter Molecules

  • Neurotransmitter molecules are low-affinity ligands; they bind only comparatively weakly to their receptors, so they can rapidly detach, allowing the synapse to reset.
  • The extent to which a drug molecule activates the receptor is termed its efficacy (or intrinsic activity).
    • Agonists have high efficacy; antagonists have low or no efficacy; partial agonists have appreciable but submaximal efficacy.