Precursors (getting the raw materials)

Precursors (getting the raw materials)

• Precursors (getting the raw materials)

• Biosynthesis (making the NTs)

• Storage (vesicles - Golgi bodies)

• Transport (neurofilaments and microtubules)

• Docking

• Influx of Ca++

• Vesicle movement

• Exocytosis— (fusion and release)

• Crossing synaptic gap

• Binding postsynaptic receptors

• Reuptake mechanisms to recover NTs

• Deactivation

Amino Acids

• Amino Acids

• Glutamate (Glu)
• GABA

• Biogenic Amines

• Quaternary Amines
• Acetylcholine (Ach)
• Monoamines
• Catecholamines
• Dopamine (DA)
• Norepinephrine (NE)
• Indolamines
• Serotonin (5-HT)

• Neuropeptides

• Opioid Peptides
• Enkephalins
• Endorphins
• Dynorphins

• Others (e.g. lipids, nucleosides)

Genetically-coded proteins embedded in cell membrane

• Genetically-coded proteins embedded in cell membrane

• Gating

• Ligand-gated - Stretch-gated
• Voltage-gated

• Effects

• Ionotropic
• Metabotropic

• Location

• Postsynaptic
• Presynaptic
• Heteroreceptor
• Autoreceptor

Probable functional dysregulation:

• Probable functional dysregulation:

• Dopamine (DA)

• Serotonin (SER)

• Acetylcholine (ACh)

• Endorphins (END)

• Gamma-aminobutyric acid (GABA)

• Glutamate (GLU)

Why do people have “drugs of choice”?

• Why do people have “drugs of choice”?

• • Dopamine - amphetamines, cocaine, ETOH

• • Serotonin - LSD, ETOH

• • Endorphins - opioids, ETOH

• • GABA - benzodiazepines, ETOH

• • Glutamate –ETOH

• • Acetylcholine - nicotine, ETOH

• Anandamide – Marijuana

High concentration in brain (micromolar)

• High concentration in brain (micromolar)

• Circuits

• Cortico-cortical
• Sensory-motor

• Point-to-point communication

• Consistently excitatory or inhibitory

• Mainly ionotropic receptors but do have metabotropic receptors

• Fast acting, short duration (1-5 ms)

• Examples: Glutamate, Aspartate, GABA, Glycine

.

• .

• Because they are structurally very similar, various drugs affect the presence of GLU and GABA in the synaptic gap and increase or decrease action potentials.

Principal excitatory NT

• Principal excitatory NT

• Biosynthesized as byproduct of cell metabolism

• Removed by reuptake

• Elevated levels  neurotoxic

• 4 receptor types

• NMDA
• AMPA
• Kainate
• mGluR - Metabotropic

4 outside cell

• 4 outside cell

• Glutamate
• Glycine
• Obligatory co-agonist
• Inhibitory NT at its “own” receptor
• Zinc (inverse agonist)
• Polyamine (indirect agonist)

• 2 inside cell

• Magnesium (inverse agonist)
• PCP (inverse agonist)

GABA

• GABA

• Benzodiazepine (indirect agonist)

• Probably also site for alcohol
• Endogenous inverse agonist binds here

• Barbiturate (indirect agonist)

• Steroid (indirect agonist)

• Picrotoxin (inverse agonist)

Medium concentration in brain (nanomolar)

• Medium concentration in brain (nanomolar)

• Circuits

• Single-source divergent projections
• Mainly midbrain to cortex

• Modulatory functions

• Excitatory or inhibitory as a function of receptor

• More metabotropic receptors than ionotropic, but plenty of both

• Slow acting, long duration (10-1000 ms)

• Examples: Acetylcholine, Epinephrine, Norepinephrine, Dopamine, Serotonin

Mostly excitatory effects

• Mostly excitatory effects

Dorsolateral Pons  mid/hindbrain [REM sleep]

• Dorsolateral Pons  mid/hindbrain [REM sleep]

• Basal Forebrain  cortex [Learning (esp. perceptual), Attention]

• Medial Septum  Hippocampus [Memory]

Catecholamines

• Catecholamines

• Dopamine - DA

• Dopaminergic

• Norepinephrine - NE

• Noradrenergic

• Epinephrine - E

• Adrenergic ~

Modulatory (can have both excitatory and inhibitory effects- varies by receptor)

• Modulatory (can have both excitatory and inhibitory effects- varies by receptor)

• Recycled by reuptake transporter

• Excess NT in terminal broken down by

• monoamine oxidase (MAOA/B)
• catechol-O-methyltranferase - COMT

• Axonal varicosities (bead-like swellings) with both targeted and diffuse release

Rewarding/motivating effects

• Rewarding/motivating effects

• Biosynthesis:

Nigrostriatral (Substantia Nigra  Striatum) [Motor movement]

• Nigrostriatral (Substantia Nigra  Striatum) [Motor movement]

• Mesolimbic (VTA  limbic system) [Reinforcement and Addiction]

• Mesocortical (VTA  prefrontal cortex) [Working memory and planning]

• Tuberoinfundibular tract (hypothalamus  pituitary) [neuroendocrine regulation]

Generally excitatory behavioral effects

• Generally excitatory behavioral effects

• Biosynthesis:

Locus Coeruleus  throughout brain [vigilance and attentiveness]

• Locus Coeruleus  throughout brain [vigilance and attentiveness]

Varying excitatory and inhibitory behavioral effects

• Varying excitatory and inhibitory behavioral effects

• Biosynthesis:

Dorsal Raphe Nuclei  cortex, striatum

• Dorsal Raphe Nuclei  cortex, striatum

• Medial Raphe Nuclei  cortex, hippocampus

MAOIs

• MAOIs

• Iproniazid

• Reuptake blockers

• Tricyclic antidepressants
• Imipramine
• Desipramine
• - SSRIs
• Cocaine & Amphetamine ~

Low concentration in brain (picomolar)

• Low concentration in brain (picomolar)

• Large vesicles

• Co-localized with other transmitters

• Circuits

• Interneuronal

• Modulatory functions

• Mostly inhibitory

• Virtually all metabotropic

• Slow acting, long duration (10-1000 ms)

• Examples: Enkephalins, Endorphins, Oxytocin, Vasopressin, Opioids

-endorphin

• -endorphin

• made from proopiomelanocortin (POMC)
• produced in pituitary gland, hypothalamus, brain stem

• Enkephalin

• made from proenkephalin (PENK)
• produced throughout brain and spinal cord

• Dynorphin

• made from prodynorphin (PDYN)
• produced throughout brain and spinal cord

Receptor High affinity ligands

• Receptor High affinity ligands

• mu -endorphin, enkephalins

• delta enkephalins

• kappa dynorphins

Metabotropic, with either

• Metabotropic, with either

• moderately fast indirect action on ion channels
• long-term action via changes in gene expression

• Most analgesic effects from mu receptor action

• Some analgesic effects from delta

• Many negative side effects from kappa

Morphine and heroin are agonists that bind to receptor sites, thereby increasing endorphin activity

• Morphine and heroin are agonists that bind to receptor sites, thereby increasing endorphin activity

An electrochemical brain

• An electrochemical brain

• Neurotransmitters have retained function for millions of years and are found in many species - from invertebrates to humans

• Maximization of Darwinian fitness

• Evolution created many chemically-mediated adaptive and self-regulatory mechanisms to control emotion and behavior

• Mismatch between ancient chemical mechanisms and modern environments

DA and opioids are part of chemically-mediated incentive mechanisms that act as signals (motivation/reward) for a fitness benefit

• DA and opioids are part of chemically-mediated incentive mechanisms that act as signals (motivation/reward) for a fitness benefit
• you “like” something (opioids) or
• you “want” something (dopamine)
• Furthermore, DA plays a role in drawing attention/highlighting significant or surprising stimuli
• Mechanisms for greater control? As a means to prioritize likes? for anticipatory processing? facilitates learning?
• These functions become susceptible to disruption and addiction from external chemical signals

Technological inventions such as the hypodermic needle, synthetic psychoactive drugs, video games, snacks etc are evolutionarily novel features that create specific ecological pressures

• Technological inventions such as the hypodermic needle, synthetic psychoactive drugs, video games, snacks etc are evolutionarily novel features that create specific ecological pressures
• They can be inherently pathogenic because they bypass the adaptive mechanisms and act directly on neurotransmitter systems
• positive emotions are signals to approach
• drugs that artificially induce positive emotions give a false signal of a fitness benefit
• under some circumstances this could be beneficial (increase empathy)
• negative emotions are signals to avoid
• drugs that block negative emotions can impair useful defenses
• is there utility to anxiety? jealousy? low mood and depression (decrease the tendency for behaviors that are dangerous or useless? embarrassment and guilt (regulating the individual’s hierarchical role in a group?

External drugs hijack these evolved incentive mechanisms and most likely impair adaptation

• External drugs hijack these evolved incentive mechanisms and most likely impair adaptation

• When exposed to drugs the wanting system motivates persistent pursuit of drugs that no longer give pleasure – a core feature of addiction.
• Drugs produce sensitization of incentive mechanisms