Handout for Biology of Mental Disorders (BCS 246)
Lecture 13

• Chemical synapse
• Main synapse of human brain (synaptic cleft)
• Distance across synapse is much greater than for electrical synapse
• Vesicles for neurochemicals present in presynaptic terminals
• Time to affect next neuron longer than for electrical but more "flexible"
• Electrical synapse
• Fewer of these in brain
• Much shorter distance from pre to post synaptic neuron
• Faster than chemical synapse but less "flexible" in the information transferred
• Transmission over the synapse results in either excitatory post synaptic potentials (EPSPs) or inhibitory post synaptic potentials (IPSPs). Note: in book called EPPS and IPPS respectively
• Inputs from one synapse not critical
• Summation of all synaptic inputs on a target neuron is what is critical, with predominantly EPSP activity causing greater depolarization (i.e. positivity inside), possibly reaching the CFL, and resulting in the firing of the neuron (or increased rate for spontaneously firing cell); vs. overall IPSP predominance and greater polarization and negativity in the cell, and no firing or decreased cell firing
• Calcium very important in cell firing and synaptic release
• Despite firing, there is room for modulation of transmitter release through a number of mechanisms, including calcium content and presynaptic enzyme activity (that produces the transmitter)
• Presynaptic function can also be affected by "autoreceptors" that are stimulated by the released transmitter and "turn down" the neuron as well as other messengers such as nitrous oxide (diffuses back from post synaptic receptor area), which may affect the presynaptic neuron through calcium channel changes (local feedback)
• Classical neurotransmission
• Release of transmitter has rapid action on very small area postsynaptically (motor neurons and much of brain neuronal transmission)
• Diffuse neurotransmission
• Transmitter release affects larger area of neurons and for longer time (ex. amines, opiates)

• General characteristics
• Proteins to which neurotransmitters bind, located on outer surface of cell membrane
• Genes that dictate structure of many receptors have been cloned and many have very similar structure (? common evolutionary precursor)
• Receptors linked to intracellular G proteins have very similar structure
• Seven transmembrane (lipophilic, hydrophobic) segments joined by intracellular and extracellular loops
• Thought that the transmitter substance links to the extra cellular portion and causes either changes in conformation and ionophore opening/closing, or change in intracellular metabolism through "2nd messengers"
• Some receptors are intracellular and take the transmitter substance to nucleus of cell (steroids)
• Substances other than "natural" transmitter can interact with receptors
• Agonists mimic the natural transmitter substance (excite or inhibit depending on what the natural transmitter does)
• Antagonists block the receptor thereby blocking the effect of natural transmitter and agonists
• Receptor/transmitter interaction can stimulate production of intracellular "second messengers" substances within the cell which activate protein kinase and which leads to phosphorylation of proteins (this causing the physiologic response)
• G proteins involved as intermediaries in the adenylate cyclase/cAMP 2nd messenger system
• Another system involves phospholipase C, protein kinase C, and a calmodulin-dependent protein kinase
• Calcium is very important in 2nd messenger systems, and can change the degree of cell reactivity when a transmitter substance links to a receptor (depolarization vs.hyperpolarization)
• Studies of receptors typically report:
• Receptor affinity (Kd), or the "stickiness" of the receptor
• Receptor density (Bmax), or the number of receptors
• Receptor reactivity, the "robustness" of a receptor's effect on the neuron is not reported in human studies due to our current inability to test this in vivo (can in animal tissue after sacrifice)
  
  
• Dopamine (DA) receptors
• Five types of DA (D₁, D₂, D₃, D₄, D₅)
• Two sub-families (D₁, D₅ and D₂, D₃, D₄)
• D₁ and D₅ are linked to adenylate cyclase (2nd messenger system)
• D₂, D₃, and D₄ are linked with phospholipase C (2nd messenger system)
• Some cells have both D₁ and D₂ receptors, with D₁ activation enhancing intracellular activity induced by D₂ agonists as well as enhancing behavioral effects of D₂ agonists
• Research examples of DA receptor findings and use of Bmax and Kd:
• Clinical efficacy of antipsychotic medication is highly correlated with the affinity (Kd or "stickiness") of these agents to the D₂ dopamine receptor (higher affinity, lower dose needed for efficacy; low affinity, higher dose needed to be effective)
• Many studies show increases in D₂ dopamine receptor density in the basal ganglia of patients with schizophrenia, but unfortunately antipsychotics cause increases, and most of these studies did not have drug naive patients (some did!)
  
  
• Excitatory amino acid receptors (EAA receptors)
• Glutamate and aspartate are the main excitatory amino acids of the CNS, with the majority of CNS activation due to the release of these substances
• Glutamate receptors are of two main types, AMPA and NMDA receptors
• Also kainate receptor and trans-ACPD receptors
• NMDA receptor activation results in longer neural activity (changes in Ca⁺⁺ permeability) than AMPA receptor stimulation (coupled to Na⁺ channel)
• Excessive NMDA receptor activity results in excess calcium influx and neuronal death (NMDA antagonists can be protective during times of excess activity, ex. hypoxia)
• NMDA channel normally "blocked" by magnesium (Mg⁺⁺), which is removed on depolarization
• Many NMDA receptors have within them a glycine binding site (need binding here for opening of Ca⁺⁺ channel)
• NMDA receptors involved in learning in simple animals and are very dense in hippocampus, a structure very important in memory function in humans
• Phencyclidine (PCP, angel dust, etc.) blocks NMDA receptors, as does ketamine (anesthetic) and MK 801 (laboratory drug blocks NMDA without activating DA receptors)
• CNS changes similar to those in psychosis seen in patients with PCP toxicity (some feel this is better than excess dopamine model of psychosis)
• Adrenoreceptors
• alpha-1, 2, beta-1, 2, and 3
• Alpha-1 are postsynaptic and excitatory
• Alpha-2 are both pre- and postsynaptic, with presynaptics involved in noradrenaline release
• Alpha-1 blockers are potent blood pressure lowering agents
• Serotonin (5-HT) receptors
• Three subtypes depending on their second messenger system (with further subdivisions)
• Receptors linked to adenyl cyclase
• Those linked to phosphatydal inositol system
• One linked directly to channel receptor
• 5-HT receptors are involved in regulation of dopamine (DA) and acetyl choline release (ex. 5-HT₃ stimulation results in DA release and decreased Acetyl Choline release in striatum and mesolimbic regions)
• GABA and benzodiazepine receptors
• GABA is most ubiquitous of neurotransmitters and is the major inhibitory transmitter of the brain (30% of all synapses have GABA receptors)
• GABA_a receptors linked to chloride channel and if opened, result in hyperpolarization
• GABA_a sites are linked to benzodiazepine receptors, with benzos (Valium, Xanax, etc.) increasing the efficacy of GABA at this site (i.e. enhance inhibition)
• Other receptors
• Acetyl choline, muscarinic, nicotinic, opiate, enkephalin, histamine, and numerous peptides
• Transporters
• These sites are where transmitter substance is collected after being released and brought back into the presynaptic cell terminal
• Gives neurons ability to reuse the transmitter that is released
• Many medications, including most antidepressants, are very potent blockers of the reuptake sites for norepinephrine (Desipramine), serotonin (Prosac, Zoloft), or both (Imipramine, Effexor)
• Many drugs of abuse are also reuptake inhibitors, particularly of dopamine (DA), such as amphetamine and cocaine
  
  

• Glia
• "Supportive" cells that also are involved in myelin formation and beginning to be seen as involved in neurotransmitter functions (i.e. transporters found on some, other receptors also)
• Astrocytes, oligodendrocytes, microglia, Schwann cells, and ependyma cells
• Vast majority of the cells of the nervous system are glia
• Neurones
• Dendrites
• Cell body (Soma) with nucleus, where essential metabolic molecules synthesized, then transported to other parts of neuron
• Axon (long tubular part of neuron, some with myelin sheath)
• Terminals (sites for synapses)
• Specialized for storage and release of transmitter substances
• Synaptic contacts can be axo-somatic, axo-dendritic, axo-axonic; the closer the synapse is to the axon hillock of the target neuron, the greater the effect
  
  

• Acetylcholine
• GABA
• Glycine
• Serotonin (5-HT)
• Catecholamines (including norepinephrine and dopamine in brain)
• Peptides
• Enkephalins, neurotensin, Substance P, cholecystokinin (CCK), vasoactive intestinal protein (VIP), angiotensin, releasing hormones of the hypothalamus (ACTH, CRH, TSH etc.)
• One neuron does not only produce one transmitter, with multiple seen in one cell; as well as peptides affecting neurons of another system (ex. DA neurons)
• Neuronal interactions due to large numbers of axonal connections on single neurons as well as different transmitters affecting one neuron and one neuron producing a number of effector substances with potentially opposing actions!!
• Transmitter substance can be broken down enzymatically in the synapse, taken up by presynaptic transporter for either intracellular breakdown (ex. monoamine oxidase [MAO] or catechol-O- methyl transferase [COMT]), or more distant metabolism by glia