unit 9 Flashcards
glutamate
ubiquitous excitatory neurotransmitter - causes EPSPs
- involved in every behavior and cognitive process
- why? because nearly every, if not every, neuron in the CNS has glutamate receptors
- Glutamate is by a wide margin the most abundant neurotransmitter in the vertebrate nervous system that causes excitation . It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain.
glutamate receptors
- NMDA – ionotropic
- AMPA – ionotropic
- Kainate - ionotropic
- Metabotropic glutamate receptors – G-protein coupled receptors (AKA metabotropic receptors; there are 8 subtypes )
- the most important are ionotropic
glutamatergic synapse
processes of glutamate synthesis and metabolism, neuronal and glial glutamate uptake, and vesicular glutamate uptake and release. Pre- and postsynaptic excitatory amino acid receptors are also shown. The table lists important glutamatergic receptor agonists and antagonists. Note the interesting property that not only can the neuron use re-uptake of glutamate for repackaging, but glial cells can also take in glutamate. The glial cells then metabolize the glutamate (via glutamine synthetase) to glutamine, release the glutamine, and neurons take up the glutamine for synthesis (via glutaminase) back into glutamate for repackaging.
criteria glutamate has met to be considered a neurotransmitter
It is localized presynaptically in specific neurons where it is stored and released from synaptic vesicles.
It is released by a calcium-dependent mechanism by physiologically relevant stimuli in amounts sufficient to elicit postsynaptic responses.
A mechanism (reuptake) exits that will rapidly terminate its transmitter action.
It demonstrates pharmacological identity with the naturally occurring transmitter.
Receptors
pathways using excitatory amino acid neurotransmitters
There is no need to know the location of all of these glutamatergic/aspartaminergic neurotransmitter pathways. Just be aware that these excitatory neurotransmitters, especially glutamate are very widely distributed throughout the brain.
structural and functional properties of glutamate receptors
It is only necessary to know that there are 3 types of ionic glutamate receptors – AMPA, Kainate, and NMDA and that there are metabotropic receptors.
- AMPA - ligand gated channel superfamily => cation selectivity = Na+, K+
- Kainate - ligand-gated channel superfamily => cation selectivity = Na+, K+
- NMDA - ligand-gated channel => cation selectivity => Na+, K+, Ca2+
schematic representation of NMDA receptor complex
The NMDA receptor is very important for controlling synaptic plasticity and memory function. It has some unique features.
1) The NMDAR selectively binds the molecule N-methyl-D-aspartate (NMDA).
2) The ligand gating requires co-activation by two ligands: glutamate plus glycine or D-serine (possibly two molecules of each!)
3) The channel can be blocked by Mg2+ under resting conditions.
4) Depolarization dislodges the Mg2+ allowing Na+ and Ca2+ to enter and K+ to exit.
The NMDA receptor complex possesses a glutamate recognition site to which receptor agonists and competitive antagonists bind, as well as other binding sites for glycine, polyamines such as spermine and spermidine, phencyclidine (PCP) and related drugs, Mg2+, and Zn2+. Channel opening permits an influx of Na+ and Ca2+ ions, and efflux of K+ ions.
biochemical processes hypothesized to underlie ischemic neuronal injury and death
Overactivation of NMDA receptors can lead to neuroexcitotoxicity. This happens by relieving the Mg2+ block and causing excessive influx of Ca2+. Excitotoxicity is implied to be involved in some neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.
Ischemia is a restriction in blood supply to tissues, causing a shortage of oxygen that is needed for cellular metabolism. Reduced cellular energy metabolism during ischemia causes increased release and decreased reuptake of glutamate, as well as increased extracellular K+ concentrations due to inhibition of the Na+-K+ ATPase.
Neurons are strongly depolarized by glutamate stimulation of AMPA and kainate receptors and by exposure to the elevated extracellular K+ levels. Persistent glutamate activation of NMDA receptors with simultaneous membrane depolarization leads to a prolonged opening of NMDA receptor channels, permitting massive Ca2+ influx across the membrane. Depolarization is also thought to cause additional Ca2+ entry into the cell through voltage-operated Ca2+ channels (VOCC). Elevated intracellular Ca2+ levels activate a variety of Ca2+-dependent processes, including specific proteases and endonucleases; phospholipase A2 (PLA2), which liberates arachidonic acid (AA) from membrane lipids; nitric oxide synthase (NOS), which catalyzes the formation of nitric oxide (NO); and ornithine decarboxylase (ODC), which mediates polyamine biosynthesis. Ca2+ accumulation in mitochondria can also lead to severe damage to these organelles.
GABA
Ubiquitous inhibitory neurotransmitter
- Involved in every behavior
GABAa – Ionotrophic (chloride ion influx)
GABAb – Metabotropic
GABA essentially acts as a “brake” in the central nervous system
Drugs that promote GABA activity have been used to treat anxiety and sleep disordersgamma-Aminobutyric acid, or GABA is the chief “inhibitory neurotransmitter” in the mammalian central nervous system.
Two general classes of GABA receptor are known:
1) GABAA in which the receptor is part of a ligand-gated ion channel (permitting Cl- ion influx)
2) GABAB metabotropic receptors, which are G protein-coupled receptors.
Its principal role is reducing neuronal excitability throughout the nervous system.
In humans, GABA is also directly responsible for the regulation of muscle tone.
GABA synthesis
Note that the most important so-called “excitatory” neurotransmitter in the brain is the precursor molecule to the most important “inhibitory” neurotransmitter in the brain with the use of the appropriate enzyme.
GABA synapse
, illustrating the processes of -aminobutyric acid (GABA) synthesis and metabolism, neuronal and glial GABA uptake, and vesicular GABA uptake and release. Pre- and post-synaptic GABA receptors and sites of action of some GABAergic drugs are also shown. The table lists important GABAergic receptor agonists and antagonists.
the interplay between neurons and glia in GABA metabolism
Glial cells play an important role in controlling the amount of GABA in neurons and in the extracellular space.
techniques used to localize GABA pathways
Immunohistochemical localization of glutamic acid decarboxylase (GAD).
Immunohistochemical localization of GABA itself.
Histochemical localization of the GABA-destroying enzyme GABA aminotransferase (GABA-T).
Uptake of labeled GABA followed by autoradiography.
GABAa receptor complex
is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is GABA, and its activation inhibits neurotransmission. Upon activation, the GABAA receptor selectively conducts Cl- through its pore and hyperpolarizing the cell. The figure shows the different sites of action where neural depressants bind to activate the GABAA receptor.
therapeutic uses of sedative-hypnotics and anxiolytics
Insomnia
Anxiety
Epilepsy
Muscle spasticity
Induction of amnesia
As preanesthetic medication
Adjunct in alcohol withdrawal
classifications of sedative-hypnotics and anxiolytics
barbiturates, benzodiazepines, non-barbiturates/non-benzodiazepines
barbiturates
- Thiopental
- Secobarbital
- Pentobarbital
- Phenobarbital
benzodiazepines
- Chlordiazepoxide (Librium)
- Diazepam (Valium)
- Oxazepam
- Others
non-barbiturates/non-benzodiazepines
- Chloral hydrate
- Carbamates (e.g., meprobamate)
- Buspirone
- beta-blockers (propranolol); alpha2-adrenergic receptor agonist (clonidine)]
characteristics of barbituates
*all general, non-selective CNS depressants
*relatively low therapeutic indices
*drug interactions – induce liver enzymes(involved in metabolizing drugs)
*all derived from barbituric acid
absorption and distribution of barbituates
*administered as water-soluble free acid
*oral – when used to treat anxiety or sleep disorders
*intravenously – when used as adjuncts to general anesthesia
*thiobarbiturates are very lipid soluble and have a very rapid onset of action because of high rate of entry into CNS; but they also rapidly redistribute from CNS to highly perfused tissues and then to fat thus rapidly terminating their CNS effects.
CNS actions of barbituates
*decrease the amount of neurotransmitter released in excitatory neurons
*barbiturates interact with GABA to enhance postsynaptic inhibition
*increases the duration of GABA-Cl channel opening
*depresses the reticular activating system and excitability of cortical cells
*sedation – drowsy, aroused by external stimuli
*hypnosis – sleep, aroused by external stimuli
*coma – not aroused by external stimuli
*death – not aroused by external stimuli
*anticonvulsant action: best anti-epileptics are phenobarbital, mephobarbital and metharbital; they have rather selective actions as patient can be seizure-free and functional
*analgesia – very weak or none
respiratory, cardiovascular, and autonomic effects of barbituates
*depress respiratory drive and rhythm
*cross placental membrane and may depress fetal respiration
*at sedative-hypnotic doses, there is only a slight fall in blood pressure and heart rate
*blockade of sympathetic ganglionic transmission
cautions, side effects and contraindications of barbituates
*spatial judgment impaired
*drug interactions – augmentation of CNS depressive effects of ethyl alcohol; phenothiazine (antipsychotics); antihistamines; and antihypertensives
*contraindicated in certain pathological states (e.g., pulmonary insufficiency and emphysema)
*contraindicated in patients with previous allergic reactions
*drug interactions - enzymes
tolerance of barbituates
tolerance develops to the sedative-hypnotic effects of barbiturates
*metabolic tolerance – enzyme induction
*pharmacodynamic tolerance – adaptation of nervous tissue to drug presence
physical dependence of barbituates
*large problem!!
*withdrawal symptoms may be severe (e.g., seizures)
barbiturate poisoning
*moderate intoxication similar to alcoholic inebriation
*symptoms of severe intoxication: coma – can last up to five days with phenobarbital; constricted pupils dilation due to hypoxia; breathing slow or rapid and shallow; shock syndrome may develop (fall in blood pressure)
*death may be due to respiratory depression or complications of prolonged coma (pulmonary edema)
*treatment – charcoal lavage; intensive support therapy (respiratory); no stimulants; hemodialysis
duration of action of barbiturates
uses boil down to some basic pharmacokinetics: their lipid solubility. The higher the lipid solubility, the quicker the onset of action and shorter the duration of effect.
Thiopental is used to help you relax before you receive general anesthesia with an inhaled medication. It was once thought to be “truth serum”.
Secobarbital and Pentobarbital are used short-term to treat insomnia, an emergency treatment for seizures, or as a sedative before surgery.
Phenobarbital is a treatment of certain types of epilepsy in developing countries and commonly used to treat seizures in young children.
Secobarbital, Pentobarbital and Phenobarbital used in the US for physician-assisted suicide and executions of criminals.
tolerance and therapeutic index
Metabolic tolerance is an issue with barbiturates. With repeated use there is substantial increase in liver microsomal enzymes which increases drug metabolism and thus requiring more drug to give the desired effect. Note here that, while more drug is required to get the desired effect, the dose for respiratory depression does not change! Thus, the therapeutic index and margin of safety shrinks.
The above are theoretical dose-response curves for the barbiturate-induced desired effect (e.g., mood change or sedation) and lethal respiratory depression. The top panel shows that with early drug use (non-tolerant) the individual experiences mood effects without significant respiratory depression. However, as tolerance develops with repeated use (bottom panel), larger amounts of drug are needed to experience the mood change (the curve shifts to the right) but no change in the dose causing depression of respiration occurs. The margin of safety (i.e., therapeutic index) shrinks dramatically in the tolerant individual.
effects of acute and chronic barbiturate administration on sleep architecture
Another problem with barbiturates is that they promote sleep, but not normal, restful sleep. They disrupt typical sleep architecture.
Recall that sleep stages are cycled-through about 4-5 times per night with several bouts of REM sleep.
The left panel shows the initial effects of pentobarbital, which include a short onset of sleep and few spontaneous awakenings. The right panel shows the changes after chronic nightly use of the drug. Tolerance is shown by the long onset of sleep (1 hour) and the 12 spontaneously awakenings during the night. Both REM and stages 3 and 4 sleep are suppressed
blood levels of secobarbital in mothers and newborn infants
Effect of barbiturate on mothers in labor. Blood levels of secobarbital in mothers and their newborn infants after intravenous administration of the drug to the mothers. Each point represents one subject (circles, mothers; asterisks, infants).
characteristics of benzodiazepines
*today, the most commonly used sedative - hypnotics
mechanism of action for benzodiazepines
*preferentially act on the limbic system (septum, amygdala and hippocampus) where they potentiate GABAergic inhibitory neurotransmission
*increases the frequency of GABA-Cl channel opening
absorption and distribution of benzodiazepines
- benzodiazepines are weakly basic (therefore absorbed better in duodenum)
- several are metabolized to active forms
- the more lipophilic benzodiazepines have shorter onset and duration of action
