Psychopharmacology - Get as PowerPoint by cuiliqing



Interaction of ligands and

   Administration
    – Oral
    – Parenteral: IV, IM, sub-Q
    – Sublingual
    – Suppositories and pessaries
    – Inhalation
    – Topical
    – Transdermal
    – Intracerebral: cannulae

   Administration
   Distribution
    – Depot injection
    – Protein binding
    – Ion trapping
            » Metabolization and elimination
Drug effects

   Dose-response curve
   Therapeutic index
   Tolerance and sensitization
   Withdrawal effects
   Placebo effects

   Neurotransmitter availability
   Neurotransmitter release
   Postsynaptic events
   Presynaptic events
   Termination events

   Neurotransmitter availability effects:
    – Production effects
       • Facilitate with precursors: L-DOPA
       • Inhibit precursor availability: hemicholinium
       • Inhibit enzymes: PCPA
    – Storage effects
       • Block transporter proteins: reserpine
       • Make vesicles leaky: amphetamine?
Neurotransmitter release effects

   Block release by blocking docking:
    botulinum toxin
   Cause continuous release: venom of
    the black widow spider
   Block release by stimulating
    autoreceptors: apomorphine, clonidine
   Stimulate release by blocking
    autoreceptors: idazoxan
Postsynaptic effects

   Direct agonist mimics: nicotine,
   Direct antagonist blockers: curare,
   Noncompetitive binding
    – Indirect agonist: diazepam
    – Indirect antagonist: flumazenil
Presynaptic effects: Axoaxonic
   Presynaptic heteroreceptors
    – Block presynaptic facilitation
    – Stimulate presynaptic facilitation
    – Block presynaptic inhibition
    – Stimulate presynaptic inhibition
Presynaptic effects: Dendritic
   In some neurons, dendrites emulate the
    terminal buttons of the same neuron.
   Thus, dendritic autoreceptors sense
    released neurotransmitter and produce
    – Drugs that stimulate dendritic
      autoreceptors are antagonists
    – Drugs that block dendritic autoreceptors
      are agonists.
Neurotransmitter termination
   Block AChE: physostigmine
   Block MAO or COMT: tranylcypromine
   Block reuptake:cocaine, fluoxetine

   Criteria for neurotransmitter status
    – What would you expect?
    – Based on synaptic transmission events
    – Over 50 putative neurotransmitters
    – Very few meet all of the criteria so far
   Transmission effects (glutamate, GABA,
    and glycine)
   Modulating effects (All other
Specific neurotransmitter
   Acetylcholine
   Monoamines: DA, NE, E, 5-HT
   Amino acids: Glutamate, GABA, glycine
   Peptides: Endorphins and enkephalins
   Lipids: Anandamide
   Nucleosides: Adenosine
   Soluble gases: Nitric oxide
Understanding neurotransmitters

   Loci of action and receptor types
   Types of action
   Synthesis and metabolism
   Representative drug interactions

   Acts on
    – Neuromuscular junction (n)
    – ANS ganglia (preganglionic synapses) (n)
    – Parasympathetic postganglionic synapses,
      on the target organs (m)
    – Brain: dorsolateral pons, basal forebrain,
      medial septum (m + n)
    – Nicotinic ionotropic receptors and
      muscarinic metabotropic receptors
Synthesis of acetylcholine

Acetyl-CoA + Choline

            Acetylcholine + CoA
Metabolism of acetylcholine

 ACh          Acetic acid + free choline
Drug interactions for ACh

   Inhibit synthesis: hemicholinium
   Block release: botulinum toxin
   Cause continuous release: Black widow
    spider venom
   Block receptor sites: Atropine (m), d-
    tubocurarine (n)
   Mimic ACh: muscarine and nicotine
   Block AChE: DDT, malathion,

   Catecholamines: Dopamine (DA),
    norepinephrine (NE), epinephrine (E)
   Indole amines: Serotonin (5-HT)

   Soma in substantia nigra and ventral
    tegmental area (VTA)
   Nigrostriatal system to caudate nucleus
    and putamen
   Mesolimbic system to nucleus
    accumbens, amygdala, and
   Mesocortical system to prefrontal cortex
Receptor types

   All metabotropic
   D1 are postsynaptic and increase cAMP
   D2 are presynaptic and postsynaptic
    and decrease cAMP
   D3 , D4 , and D5 also exist.
 Synthesis of catecholamines
       tyrosine hydroxylase

Tyrosine                      l-DOPA
DOPA decarboxylase
Dopamine b-hydroxylase
phenylethanolamine N-methyl transferase
Metabolism of catecholamines

   MAO-A, MAO-B, and COMT
Representative drug interactions

   L-DOPA increases synthesis
   AMPT deactivates tyrosine hydroxylase,
    lowering production of dopamine
   Reserpine blocks storage transport
   Apomorphine mimics dopamine at D2
    autoreceptors, inhibiting tyrosine
   At higher doses, apomorphine mimics
    dopamine at postsynaptic D2 receptors
More drug effects

   Amphetamine, cocaine, and
    methylphenidate (Ritalin) inhibit
    dopamine reuptake
   Amphetamine also reverses the
    reuptake transport proteins, dumping
    both dopamine and norepinephrine into
    the cleft.
   Cocaine also blocks voltage-dependent
    Na+ channels: Eye surgery
And still more…

   Deprenyl destroys MAO-B
   Chlorpromazine blocks D2 receptors
   Clozapine may block D4 receptors

   Soma in sympathetic chain ganglia,
    axons to target organs
   In CNS, soma in pons (locus ceruleus),
    medulla, and thalamus
   Axonal varicosities release NE in most
    brain areas
NE receptors

   All are metabotropic
   a1, a2 , b 1 , and b 2 receptors in CNS
    and target organs
   b 3 receptors in adipose tissue
   Mostly slow excitatory effects, although
    a2 receptors are inhibitory autoreceptors
Drug interactions

   Fusaric acid inhibits dopamine b-
    hydroxylase in terminal button
   Moclebimide blocks MAO-A
   Pseudephedrine and phenylephrine
    mimic NE at a1 receptors
   b- blockers like atenolol or Inderal lower
    blood pressure
   Desipramine inhibits NE reuptake, and
    combats depression
Serotonin, 5-HT or
   Soma in raphe nuclei of pons and
   Axons to cortex, cerebellum, basal
    ganglia, midbrain, and dentate gyrus of
    the hippocampal formation
Two serotonin systems

   From the dorsal raphe, D system axons
    have spindle-shaped varicosities that
    release 5-HT as a neuromodulator
   From the median raphe, M system
    axons have bead-shaped varicosities
    that form synapses
5-HT receptor types

   Nine types, subscripted 1A, 1B, 1D, 1E,
    1F, 2A, 2B, 2C, and 3
   All are metabotropic except 5-HT3,
    which controls a Cl- channel
   1B and 1A are presynaptic
   1A are dendritic and somatic
 Synthesis and metabolism
               Tryptophan hydroxylase

                      5-HTP decarboxylase
5-hydroxytryptophan (5-HTP)

Drug interactions

   PCPA blocks trypotophan hydroxylase
   SSRIs like fluoxetine (Prozac) and Paxil
   Fenfluramine causes release and
    inhibits reuptake
   Many hallucinogens, like LSD, mimic

   Loci: Everywhere
   Ionotropic receptors:
    – NMDA controls sodium-calcium channels
    – The NMDA receptor complex is both
      voltage- and neurotransmitter-dependent
    – AMPA and kainate control sodium
   Metabotropic glutamate receptors
Synthesis and metabolism

   Dietary and cellular
   Drug interactions
    – NMDA, AMPA, kainate/kainic acid
    – PCP
    – Zinc

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