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65 Cards in this Set
- Front
- Back
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Electrical synapse
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-AKA gap junctions
-channels made by protein subunits called connexons -large pores that allow ions and larger molecules such as ATP to pass -electrical activity passivly spreads, thus "coupling" neurons -hormone secreting cells in hypothalamus and glia linked by gap junctions |
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Chemical synapse
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-synaptic cleft between neurons composed of extracellular fluid
-presynaptic terminal and postsynaptic membrane -neurotransmitters are released and diffuse across synaptic cleft |
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Neurotransmitter definition
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1) A chemical substance released by synaptic terminals that triggers an excitatory or
inhibitory response in a postsynaptic neuron or tissue. It may also: 2) Cause changes in the postsynaptic partner that do not directly affect cell excitability (for example, gene transcription); 3) Regulate its own release via feedback mechanisms that are local to the synapse (for example, through autoreceptors positioned on the synaptic terminal). |
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Neurotransmitter criteria (5Rs)
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1) Resides in the presynaptic neuron. This means that the neurons should contain the
transmitter and the appropriate enzymes to synthesize it. 2) Released in response to presynaptic activity. 3) Receptors present postsynaptically. This is usually demonstrated through pharmacological blockade of the putative receptor with known antagonists. Receptors may also be immunocytochemically detected. 4) Removal - Termination of the transmitter action occurs via active mechanisms such as enzymes, reuptake by presynaptic terminals and uptake by postsynaptic neurons. 5) Reproduction – The application of the substance at concentrations near that of the endogenously available substance reproduces the physiological effects achieved with pathway stimulation. |
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Steps in synaptic transmission
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1) Invasion - Action potential invades the synaptic terminal
2) Activation - Depolarization of terminal activates voltage-dependent calcium channels - calcium enters the terminal, yielding a net concentration increase of nearly 1000 fold near the active zones. 3) Vesicle Binding - Calcium binds to proteins 4) Vesicle Fusion – The calcium binding to vesicle proteins induces the vesicles to fuse with the presynaptic membrane (exocytosis) 5) Diffusion - Neurotransmitter diffuses across synaptic cleft 6) Receptor Binding- Neurotransmitter binds to a postsynaptic receptor (either on target muscle, vasculature, or neuron). Receptor binding may also occur onto presynaptic autoreceptors that modulate transmitter release. 7) Postsynaptic response. This is classically in the form of a postsynaptic potential (PSP). 8) Spread of postsynaptic potential. In postsynaptic neurons, this spread can be passive or active in some systems, but in either case serves to excite (EPSP) or inhibit (IPSP) the neuron, making it more or less likely that the next neuron in the chain will generate an action potential. In muscle, contraction results. 9) Deactivation – neurotransmitter action is terminated 10) Recycling – Vesicle membrane that fused with presynaptic terminal is recycled, reused. If it was not recycled, nerve terminal would continuously grow! 3-6 and 9-10 are chemically mediated |
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Frequency and autoreceptor feedback control
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Frequency (The number of action potentials invading the terminal per unit time)
determines the degree of neurotransmitter release, because at higher frequencies more calcium enters the presynaptic terminal due to opening of voltage-gated calcium channels. Feedback control of the synapse via autoreceptors helps to keep activity from becoming too high. |
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Vesicles and role of calcium
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-Ca concentrations must reach 100microM to produce vesicle fusion
-Only occurs in close proximity to voltage gated Ca channels -synaptotagmin |
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Synaptotagmin
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One
possible target of Ca2+ is thought to be synaptotagmin, which is a vesicle protein that becomes involved in a vesicle-docking complex that brings the synaptic vesicle membrane and the presynaptic membranes into close apposition. Calcium is thought to induce a conformational change in synaptotagmin that leads to the formation of a fusion pore, through which the neurotransmitter is released from the presynaptic terminal. |
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Ionotropic receptors
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Ionotropic receptors are relatively large, multi-subunit complexes that combine in the
membrane to form an ion channel. These channels will not pass ions in the absence of neurotransmitter. Binding of neurotransmitter induces conformational changes in the channels that opens them and permits ion flow down electrochemical gradients. Ion flow ceases when the transmitter disengages, or if the receptor becomes desensitized |
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Metabotropic receptors
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G-protein coupled receptors (GPCRs) composed of a
single polypeptide. They possess numerous membrane spanning regions. Binding of neurotransmitter induces a conformational change that is permissive for interaction with G-proteins in the neural membrane. They may affect ion channels laterally through the membrane, or through second-messenger coupling. |
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Metabotropic receptor effects
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tend to be slow effects, some of which are classically
considered to be neuromodulatory, such as modifying the electrical activity of other inputs. They may even alter gene transcription in neurons. |
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Neurotransmitter effects
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Many neurotransmitters activate both ionotropic and metabotropic receptors.
A given neurotransmitter may be excitatory or inhibitory, rapid or slow acting depending on the activated receptor. The degree of excitation or inhibition depends on the reversal potential of the ion charge carrier, and the voltage difference between resting potential and spike threshold. |
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Desensitization
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Two known mechanisms account for receptor desensitization:
1) Rapid - (Seconds to minutes) Phosphorylation of metabotropic receptors causes conformational change that impedes G-protein binding. 2) Slow- (Minutes to hours) Phosphorylation causes removal of receptors from plasma membrane. A) Sequestration - reversible endocytosis of receptors. B) Down-regulation – irreversible endocytosis caused by entry of receptors into protein degradation pathways. |
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Acetylcholine projection system
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1) Reticular activating system – Cholinergic cell bodies are present in the
pedunculopontine tegmental region of the brainstem. These send an extensive and diffuse projection to the thalamus. This system is intimately involved in modulating sleep/wake states. 2) Basal forebrain – Originating in the nucleus basalis, this system projects to cortical areas. These neurons, along with cells of the diagonal band, are the neurons that undergo degeneration in Alzheimer’s disease. In addition to these projection systems, there is a group of cholinergic interneurons in the striatum. While Dopamine is implicated in Parkinson disease, part of the motor symptoms derives from loss of dopaminergic regulation of these cholinergic cells. Treatment with cholinergic receptor antagonists can reduce the motor symptoms of Parkinsonism. |
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Acetylcholine synthesis
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The synthesis of acetylcholine occurs in a single step. The acetyl group
from acetyl-coenzyme A (AcoA) is transferred to choline by the enzyme choline acetyltransferase (ChAT). Presence of this enzyme (immunocytochemically determined) is the definitive evidence for cholinergic neurons and terminals. ACoA is a byproduct of glucose metabolism, and must exit the mitochondria to donate the acetyl group. Choline is abundant in blood plasma, but choline donors such as lecithin have been used to treat Alzheimer’s disease with little positive effect. It turns out that the PNS and CNS use two different choline transporters. The CNS transporter is saturated at plasma level choline concentrations, perhaps underlying the difficulty of choline “loading” as a treatment strategy. |
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Acetylcholine release
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Botulinum toxin blocks cholinergic release, causing paralysis.
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Acetylcholine receptors
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Decreasing cholinergic transmission is achieved through blocking the
postsynaptic receptors with cholinergic antagonists. Curare causes paralysis by blocking nicotinic receptors |
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Acetylcholine breakdown
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The most effective means of increasing cholinergic neurotransmission is
through control of the breakdown (or hydrolysis) of acetylcholine by acetylcholinesterase. |
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Myasthenia Gravis
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-autoimmune, body makes antibodies to acetylcholine receptor
-cause lysis of junctional folds in the target muscle, endocytosis of AChRs, or steric hindrance of binding -diminished amplitude of miniarture end-plate potential |
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Eaton-Lambert myasthenic syndrome
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-autoimmune attack of voltage dependent calcium channels necessary for release of ACh
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Alzheimer's disease
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-characterized by degeneration of cholinergic neurons in the basal forbrain
-involves multiple brain regions and noradrenergic and serotonergic systems can be affected -pathological sign: plaques containing amyloid and neurofibrillary tangles (microtubule associated protein tau) |
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Catecholamines overview
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-dopamine, norepinephrine, epinephrine
-act only at metabotropic receptors -phenylalanine and tyrosine are precursors for synethesis |
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Phenylketonuria
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Phenylalanine hydroxylase, a liver enzyme, converts phenylalanine to tyrosine.
Phenylketonuria is a disorder caused by insufficient phenylalanine hydroxylase. If people suffering from this disorder do not restrict dietary intake of phenylalanine, severe intellectual impairment can be the result |
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Noradrenergic neurons location
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-locus coeruleus, part of the reticular activating system
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Dopamine projections
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Dopamine cell bodies are present in the midbrain, including the substantia
nigra, ventral tegmental area, and retrorubral field. These give rise to forebrain projections, including the amygdala, ventral hippocampus, and the striatum. Degeneration of the neurons projecting to the striatum is implicated in Parkinson disease. |
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Dopamine synthesis
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Enzymes that control synthesis of DA can be regulated at the
transcriptional and posttranslational level. L-DOPA (which crosses the blood brain barrier) can be peripherally administered with a decarboxylase inhibitor (which doesn’t cross the blood brain barrier), thus preserving the L-DOPA until it reaches the CNS. |
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Dopamine release
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The vesicular monoamine transporter packages dopamine into terminals
for subsequent release. Reserpine, an antipsychotic, blocks the transporter. The D2 family of autoreceptors can have effects on synthesis, release, or overall neural activity. Synthesis is reduced upon agonist stimulation of the autoreceptors. |
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Dopamine breakdown
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Two enzymes catabolize catecholamines: monoamine oxidase (MAO),
and catechol-o-methyltransferase (COMT). There are two MAOs. MAOA has higher affinity for NE and serotonin; MAOB has higher affinity for dopamine. Transporter proteins mediate reuptake of catecholamines (in addition to the dopamine transporter, there is also a norepinephrine transporter). Psychostimulants such as cocaine and amphetamine exert their effects through blockade of the dopamine transporter. Tricyclic antidepressants inhibit the norepinephrine transporter and are used in the treatment of depression. |
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Mesolimbic dopaminergic system
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implicated in addictions to stimulants,
opiates, nicotine and ethanol. |
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Serotonin projections
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There are nine serotonergic cell groups in the brainstem (designated B1-B9).
The dorsal pontine and median raphe groups project to virtually the entire brain. Groups of the ventral medulla and caudal pons provide descending projections to the spinal cord, and are involved critically in pain sensation. Melatonin is made from serotonin in the pineal gland, and affects sleep and sexual behavior |
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Serotonin synthesis
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Serotonin is made from tryptophan, and increasing plasma levels of
tryptophan can increase precursor levels in the brain, but only if levels of other aromatic amino acids are controlled. Reason: They compete for the same uptake mechanism. 5-HTP is rapidly converted to serotonin and can also be administered. Unlike catecholamines whose synthesis is sensitive to local catecholamine concentrations, intracellular levels of serotonin do not affect synthesis of serotonin. |
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Serotonin release
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An autoreceptor, called the 5-HT1a receptor, modulates release from the
presynaptic terminal |
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Serotonin breakdown
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The serotonin transporter controls inactivation of the neurotransmitter.
Prozac inhibits the reuptake of serotonin into the synaptic terminal by the serotonin transporter, and is widely used as an antidepressant. Breakdown. MAOA performs the enzymatic oxidative deamination of serotonin, and is also the target of some antidepressants. |
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Serotonin clinical implications
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Like dopamine, serotonin is part of the brain’s reward system. Clinical depression is
thought to result from dysregulation of serotonergic transmission |
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Glutamate projections
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Glutamatergic neurons are located throughout the brain, in projection
neurons. The only regions that do not have glutamate-containing neurons are neurotransmitter-specific nuclei such as the thalamic reticular nucleus, which is exclusively GABAergic. Pyramidal cells of the cerebral cortex are among the bestcharacterized glutamatergic cells of the CNS. |
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Glutamate and GABA formation
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formed as an offshoot of the Krebs cycle. Thus, attempts
to alter levels of these neurotransmitters through this route would be potentially devastating. |
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Glutamate release
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An emerging area of research is that of the metabotropic glutamate
receptors, which can perform autoreceptor functions similar to those of the catecholamines. Development of specific agonists and antagonists may make this a means of control of glutamatergic transmission in the future. Another type of modulator is called an “allosteric” modulator. “Allosteric refers to the drug acting only when the natural agonist is bound to the receptor. These compounds can be “positive”(increasing activity of the receptor) or “negative” (reducing) modulators. |
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Glutamate receptors
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Antagonist pharmacology of the ionotropic glutamate receptors is
currently the most important means of controlling postsynaptic glutamate effects |
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Glutamate clinical implications
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Glutamate-mediated excitotoxicity. If abnormally high concentrations of glutamate
accumulate in the extracellular space, neurons that contain glutamate receptors can be excited to death. Stroke or other ischemic injury produces this effect. Injections of glutamate antagonists into experimental animals (particularly antagonists to N-methyl- D-aspartate (NMDA) receptors are neuroprotective. The excitotoxicity hypothesis holds that low oxygen interferes with energy-dependent uptake of glutamate at synapses. Clinical trials are now focused on administration of glutamate antagonists after the onset of brain insult to protect dying neurons. |
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NMDA receptors
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ionotropic glutamate receptors involved in a process called long
term potentiation (LTP), which is associated with selective strengthening of active synapses. It is thought to be the cellular underpining of learning and memory. The synaptic strengthening is in the form of a potentiated, or larger amplitude EPSP. In LTP, Ca2+ flowing into the cell through NMDA receptors activates CaM kinase II, leading to increased AMPA receptor function and larger EPSPs. |
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GABA projections
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GABAergic interneurons are extensively distributed throughout the brain.
Projection systems using GABA include a projection from the striatum to the substantia nigra, one from the nigra to the superior colliculus and motor thalamus, and one from zona incerta to prefrontal cortex. An important GABAergic nucleus is the thalamic reticular nucleus, which engages in the generation of brain rhythms associated with sleep. |
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GABA receptor
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The major postsynaptic receptor is the GABAA receptor, an ionotropic
receptor. A metabotropic receptor, the GABAB receptor, can serve as an autoreceptor but is also present postsynaptically in some systems. Two substances act to potentiate the effect of released GABA. Barbiturates activate postsynaptic GABAA receptors. Benzodiazepines (e.g., Librium and Valium) are an effective treatment of generalized anxiety disorders |
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GABA breakdown
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Glutamic acid decarboxylase (GAD) synthesizes GABA from glutamate.
GABA-aminotransferase is a degradative enzyme for GABA. Sodium dipropylacetate inhibits this enzyme, and increases the level of GABA. Sodium dipropylacetate is an anticonvulsant. |
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Epileptic or seizure activities
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results from blockade of GABAA receptors. Evidence
suggests that reduction of inhibitory tone permits over-excitation of glutamatergic pathways. Conversely in some epilepsies hyperglutamatergic signaling is implicated. Penicillin binds within the GABAA receptor pore, and at sufficiently high concentrations can cause widespread seizures |
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Peptide neurotransmitter overview
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-synthesized in soma as propeptides, then cleaved into neuroactive peptides and transported in vesicles to site of release
-stored in large vesicles away from synaptic cleft |
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Peptide neurotransmitter control points
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-increased neuronal demand requires increasing gene expression of the prohormone
-receptors are metabotropic -termination of action at receptors through enzymatic inactivation or simple diffusion -degradation products may be biologically active |
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Nitric oxide synthesis and release
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Nitric oxide is synthesized rapidly by the enzyme, nitric oxide
synthase. In neural systems, the calcium–dependent form of this enzyme is implicated. NO has a half-life of less than 5 seconds, and unlike other neurotransmitters, it diffuses freely through neural membranes. This means that it cannot be stored in neurons, and is instead made on demand in response to increased calcium concentration. In some systems it is made in the postsynaptic neuron, and diffuses in a retrograde fashion to affect synaptic release |
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NO receptor
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NO interacts directly with cGMP, and does not, as far as is known, bind its own specific receptor
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NO location
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-cerebellum, cerebral cortex, hippocampus
-gut, erectile response |
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NO control points
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NO is also known as
endothelial-derived releasing factor, and is important in the vascular system for its relaxation effects on the smooth muscle lining blood vessels Specific inhibition or stimulation of the synthase, or selective action of a phosphodiesterase (the enzyme that breaks down cGMP) may offer the best chance of a pharmaceutical manipulation |
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NO clinical implications
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NO is implicated as an important agent in learning and memory. NMDA receptormedicated
stimulation of the synthase with calcium in the postsynaptic cell is hypothesized to lead to a burst of NO that diffuses in the retrograde direction, to one or many presynaptic terminals, where it affects the probability of synaptic release via cGMP coupled mechanisms. NO can assume anterograde roles like that of a classical neurotransmitter, for example in the penis. |
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Categorical vs Dimensional system
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Categorical System
Each Diagnosis is a discrete entity with absolute boundaries dividing it from other mental disorders or no mental disorder Dimensional System Classification is based on quantification of attributes Describes phenomena that are distributed continuously and don’t have clear boundaries |
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Criteria and modifiers
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“Criteria”
-Inclusion – Must have “X”, e.g. for Major Depression must have a depressed mood -Exclusion – Can’t have “Y”, e.g. for Major Depression can’t be directly due to substance use Modifiers -Course - Can indicate things like a single episode vs. recurrence -Severity (mild, moderate, severe) and specific features like with or without psychosis, and state like in full or partial remission -Often N.O.S. (Not Otherwise Specified) categories exist |
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Axis I-V
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Axis I Acute (State) Disorders
Axis II Personality Disorders; Mental Retardation (Trait) Axis III General Medical Conditions Axis IV Psychosocial and Environmental Stresses Axis V Global Assessment of Functioning |
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Hierarchy of Defense Mechanisms
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Psychotic defences - psychotic denial, delusional projection
Immature defences - fantasy, projection, passive aggression, acting out Neurotic defences - intellectualization, reaction formation, dissociation, displacement, repression Mature defences - humor, sublimation, suppression, altruism |
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Defense mechanisms definitions: denial, displacement, intellectualisation, projection
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Denial - An ego defence mechanism that operates unconsciously to resolve emotional conflict, and to reduce anxiety by refusing to perceive the more unpleasant aspects of external reality;
Displacement - Redirecting emotion from a ‘dangerous’ object to a ‘safe’ object. Intellectualisation - Concentrating on the intellectual components of the situations as to distance oneself from the anxiety provoking emotions associated with these situations; Projection - Attributing to others, one’s own unacceptable or unwanted thoughts and/or emotions |
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Defense mechanisms definitions: rationalization, reaction formation, regression, repression
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Rationalization - The process of constructing a logical justification for a decision that was originally arrived at through a different mental process;
Reaction formation - The converting of unconscious wishes or impulses that are perceived to be dangerous into their opposites; Regression - The reversion to an earlier stage of development in the face of unacceptable impulses; Repression - The process of pulling thoughts into the unconscious and preventing painful or dangerous thoughts from entering consciousness; |
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Defense mechanisms definitions: sublimation, undoing, suppression, dissociation
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Sublimation - The refocusing of psychic energy away from negative outlets to more positive outlets. Sublimation is the process of transforming libido into ‘socially useful’ achievements, mainly art. Psychoanalysts often refer to sublimation as the only truly successful defence mechanism.
Undoing - A person tries to 'undo' a negative or threatening thought by their actions. Suppression - The conscious process of pushing thoughts into the preconscious. Dissociation - Separation or postponement of a feeling that normally would accompany a situation or thought. |
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Defense mechanisms definitions: humor, idealisation, identification, splitting
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Humor - Refocuses attention on the somewhat comical side of the situation as to relieve negative tension.
Idealisation - Form of denial in which the object of attention is presented as "all good" masking true negative feelings towards the other. Identification - The unconscious modeling of one's self upon another person's behavior. Splitting. Primitive defence mechanism-when a person sees external objects or people as either "all good" or "all bad." |
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Freud's psychosexual stages
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Oral – Dependency Issues
-Associated defense mechanisms: projection, denial, identification -Associated Personality types: Dependent Anal – Control Issues -Associated defense mechanisms: Undoing, reaction formation, isolation regression -Associated Personality types: Obsessive Compulsive Phallic – Self-esteem issues -Associated defense mechanisms: Intellectualization, repression -Associated Personality types: Histrionic Narcissistic Latency/Adolescence -Associated defense mechanisms: Sublimation, Humor |
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Personality disorders definition
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-patterns of inflexible and maladaptive personality traits that cause subjective distress, significant impairment in social or occupational functioning, or both.
-These traits "deviate markedly" from the culturally expected and accepted range (or "norm") -must have been stably present and enduring since adolescence or early adulthood -pervasive (broad range of situations) -egosyntonic: non-distressing and not recognized as a problem by the patient |
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Cluster A personality disorders
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Schizotypal
-Discomfort in close relationships -Cognitive and perceptual distortions -Eccentricities of behavior Schizoid -Detachment from social relationship (comfortable loner) -Restricted range of emotional expression Paranoid -A pattern of distrust and suspiciousness -Tending to see others’ motives as malevolent |
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Cluster B personality disorders
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Borderline
-Instability in self-image and affect (primary affect of anger) -Unstable interpersonal relationships -Marked impulsivity Histrionic -Excessive emotionality and attention seeking Narcissistic -Grandiosity and excessive need for admiration -Lack of empathy Antisocial -Disregard for laws and violation of the rights of others |
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Cluster C personality disorders
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Avoidant
-Social inhibition -Feelings of inadequacy -Excessive sensitivity to negative evaluation Dependent -Submissive and clinging behavior -Excessive need to be taken care of Obsessive-Compulsive -Preoccupation with orderliness, perfectionism, and control |
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Axis II- Axis I Associations
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Avoidant – Social Phobia, Panic d.o.
Schizotypal, Paranoid, Schizoid – Schizophrenia or Delusional disorder Histrionic – Somatoform disorders Borderline – Bipolar Mood disorder Obsessive Compulsive - OCD |
