Glutamate, opiates, neuropeptides, anandimide, and neuromodulators

Question 1

Glutamate and aspartate

Answer 1

• Glu is major excitatory NT, both are implicated in excitotoxicity and have high-affinity reuptake systems
• Reuptake can be to glial cells, and uses Na/K gradients to facilitate reuptake
• Glutamate receptors: both gated ion channels (fast, ionotropic) and GPCR (slow, second messengers)
• All are excitatory: AMPA, Kainate, NMDA
• Selective agonists of metabotropic glu receptors (GPCRs) may be useful in Rx anxiety and schizophrenia

Question 2

AMPA and Kainate receptors

Answer 2

• AMPA: various forms of 16 different subunits, activation cause depolarization via outward flow of K and inward flow of Na (also permeable to Ca)
• AMPA found largely in striatum, hippocampus and cerebellum
• Influx of Ca can trigger apoptosis
• Kainate receptors: binds kainic acid better than glutamate, excessive excitation can lead to seizures and kill neurons
• Neuro-active steroids can protect against the seizures/toxicity

Question 3

NMDA receptors

Answer 3

• NMDA receptors: voltage sensitive (regulated by Mg) ad requires glycine as co-agonist along w/ Glu binding
• PCP (phencyclidine) compete w/ Mg for NMDA channel binding but are not removed w/ depolarization
• PCP produces delusions, hallucinations, and cognitive defects (high doses of etoh can produce similar effects)
• MSG also binds to these receptors

Question 4

Opiates

Answer 4

• Opiates are exogenous (morphine and codeine) and endogenous (endorphins, enkephalins, dynorphins) that bind to opioid receptors to produce analgesic effects
• Most potent compound is morphine and its antagonist is naloxone
• Morphine and endogenous opiates bind to the same receptors
• All endogenous opiates are made from a pro-peptide (POMC, pro-opiomelanocortin, makes beta-endorphin) by proteases to make pro-opioids (neuron specific)

Question 5

Opioid receptors

Answer 5

• 3 classes: mu, kappa, and delta
• Most significant is mu, since it binds most to morphine-like derivatives (naloxone, endorphins)
• Mu is a GPCR that activates cAMP in presynaptic cells to decrease NT release
• Also increases K efflux in postsynaptic cell to hyperpolarize neurons, which decreases the firing of pain neurons in the SC
• They inhibit pain pathways including presynaptic release of substance P (pain-causing neuro-peptide) which is released onto efferent neurons of STT tract to convey pain to the brain
• Capsaicin produces rapid release of substance P
• Other neuropeptides: nociceptin and nocistatin (regulate pain perception)

Question 6

Anandamide

Answer 6

• Derivative of arachidonic acid, actives cannabioid receptors (CB), same receptors THC activates
• CB1 found in CNS, CB2 has peripheral distribution (in leukocytes and testicles)
• CB1 acts via GPCR to reduce the presynaptic cell’s ability to conduct Ca and thus lowers NT release from presynaptic cell
• Most complicated effects of long term THC use are cognitive

Question 7

Neuromodulators

Answer 7

• In general are not release via synaptic vessels
• May not change the membrane potential of postsynaptic cell but changes the membrane’s capacity to respond to further signals
• Ex: protaglandins act on NE neurons to reduce NE release
• NO is also a neuromodulator that influences the levels of cGMP (released from postsynaptic cell to act on presynaptic cell like anandamide)