-Most important excititory NT in brain

-primary NT for fast chemical signaling between cells

-ALL NEURONS have receptors for it

-Changes in signalling major mechanism for learning and memory

-if too excessive can cause exitotoxicity

enzyme that transorms glutamine into glutamate

-Located mainly on astrocytes

-rapidly remove glutamate molecules from the synapse

-Glutamate receptors

-allow NA+ passage

-gluatamate receptor

-not only allows Na+ flow, but Ca++ as well (which functions as a 2nd messenger)

Gi/o - coupled, reduce cAMP production

(various roles - modulation of other receptors, participation in synaptic plasticity, act as presynaptic autoreceptors to inhibit glutamate release)

agonist: supress transmission

1. glutamate binding site occupied

2. glycine binding site occupied (by glycine or d-serine)

3.  Depolarization of the membrane allows for magnesium ions to dissociate and stop blocking the channel 

(also, special binding site for PCP that can block the opening of this channel if bound)

-tetanic stimulus causes prolonged activation of AMPA receptors and a greater postsynaptic deplorization, which permits NMDA channels to open

-Influx of Ca ions through the NMDA receptor activates several protein kinases (inlcuding CaMKII)

-CaMKII and other kinases phosphorylate AMPA receptors, which 1. increases sensitivity of AMPA receptors to glutamate and 2. causes more AMPA receptors to be inserted into the postsynaptic membrane

These mechanisms enhance the strength of signaling at the potentiated synapses. 

LTP Induction

and 

LTP expression

takes place during an dimmediately after the tetanic situation

 (NDMA plays critical role, but AMPA too)

represents the enhanced synaptic strength measured at a later time

(AMPA receptors play critical role, because it is an AMPA receptor-mediated EPSP that is facilitated in LTP)

effects produced by excessive exposure to glutamate and related excitatory amino acids are caused by a prolonged depolarization of hte receptive neurons that in some way leads to their eventual damage or death (kills nerve cells but spares fibers of passage)

most strongly triggered by activation of NDMA receptors

-most important inhibitory NT

-found throughout brain in high concentrations

-synethesized from glutamate by GAD

vGAT

ionotropic ligand-gated Cl- channel (GABA binds, Cl channel open, hyperpolarize neuron)

consists of 5 subunits (usually 2a, 2b, and a Y)

(even on the same neuron, different subunit combinations are found in different locations)

-metabotropic

-heterodimers (require both GABAb1 and GABAb2 to function)

-G protein coupled, Gby modulates K and Ca ion channels, Gai inhibits adenylate cyclase

-excititory vs. inhibitory

-80% of cortical neurons are glutamatergic, 20% are GABAergic

-more glutamate, but more different kinds of GABA

-Glutamate are projectory (spiny), GABA are mostly interneurons (aspiny)

-GABA can be broken down into succinate and glutamate, glutamate gets converted to glutamine

sculpts when neuronal populations can fire

constrains timing of projectoin cell, interneurons can force groups to fire synchronously, acts as an ensemble or assembly, a goup or neurons that fire together

makes GABA bind more readily to receptor

formed by combination of a and y subunits (but only a1, 2, 3 and 5 subunits participate)

responsible for anxiolytic effects of benzodiazepines

known by: knock-in mice that were insensitive to diazepam, anxiolytic action was absent in mice with a2 point mutation, but present in ones with a3 point mutation

without a2, no anxiolytic effects

green liquor, popular by end of 19th century, popular now, wormwood macerated in alcohol, then redistilled

-produces a more "lucid" clear-headed form of intoxication

GABAa receptor antagonist (key component of absinthe)

reversibly binds to GABAa and blocks opening of Cl channels

absinthe is a paradoxical mix of actions to enhance GABAa cl currents with alcohol and reduce them with thujone

G protein activated by GABAb receptors

-inhibits adenylate cyclase, reduces cAMP production

modulate ability of Gby to activate GIRKs, determines how effectivel Gby opens K channels

"regulators of G-protein signaling"

primary metabolic product of THC, equally or more potent than THC itself

-causes delay between peak THC levels and subjective high

-THC in pill form

-Schedule III drug

-approved for treatment of nausea and anorexia in AIDS and cancer patients

-little abuse so far

-not sure if it provides all of the beneficial effects of cannabis

-hard for patients to regulate dose (you can't change the pill)

present in higher brain concentrations than anandamine

Full CB1 agonist

regulators of synaptic transmission for excititory and inhibitory synapses

synthesized in post-synaptic side and serve as retrograde messengers to alter physiology of pre-synaptic terminal

involved in both short term and long term synaptic change, including spike-timing dependent plasticity

*too lipid soluble to be stored in vesicles, synthesized as needed, structures unrelated to THC and most have little selectivity for CB1 vs. CB2

-injected into NAc cause pleasurable reactions, enhances DA release in NAc (could be abused by some people)

short-term decrease in presynaptic glutamate release

(occurs when presynaptic [glutamate] cell releases too much glutamate, and then it causes retrograde tranmitter in post-synaptic cell to tell it to stop firing)

-especially in hippocampus

short-term decrease in presynaptic GABA

endogenous opiates (peptides)

-several larger peptides (precursor peptides) that are broken down into smaller active opioids

-inhibition of adenylate cyclase (less cAMP production)

-shutdown of voltage-gated Ca channels (prevents NT release)

-enhancement of GIRKS (hyperpolarizes cell by opening K channels)

periaqueductal grey, spinal cord

FUNCTION: analgesia