L1: Intro to CNS Drugs

NMDA receptor antagonists Ischemia:

- inotropic glutamate - excitotoxic damage occurs in people who experience brain ischemia  due to stroke or MI
receptor = excitatory - ischemia  massive glutamate release in area  prolonged NMDA receptor activation
- high levels of - antagonists MAY be helpful  to reduce ischemic cells loss, but adverse SE
glutamate toxic to - Glycine site antaonists may be more promising
neurons!
- Domoic acid  Motor movement disorders:
produced by marine
algae, CNS effects ALS  abnormalities in EEAT2 in afected areas of CNS
include headache, - Riluzole  blocks glutamatergic neurotransmission (NMDA antagonist)
dizziness, mental
confusion, muscle Parkinson’s disease:
weakness, and possible - amantadine  weak noncompetitive, low affinity antagonist of NMDA
short term memory - has dopamine releasing properties
loss - also for adjunctive therapy in tx of catatonic syndromes

Learning and memory:

- NMDA receptor activation necessary for induction of hippocampal memory formation LTP; Ca
- LTP: process of synaptic strengthening  learning/memory
- Memantine  noncompetitive, low affinity NMDA antagonist for Alzherimer’s disease  reduces
excitotoxicity

Anesthesia:
- Ketamine  NDMA receptor noncompetitive antagonist
- A dissociative anesthetic: peds and vets
- Also abused as recreational drug (PCP too)

GABA A receptor agonists Muscimol

- A: inotropic - classic agonist
- B: metabotropic - found in mushroom: amanita muscaria
- Inhibitory - sedative-hypnotic and psychoactive hallucinogen
- hyperthermia, mydriasis, mood elevation, anorexia, ataxia, hallucinations
 Barbiturates:
- bind to barb. Site of GABA A receptor complex and faciliate actions of GABA
- can activate GABA a receptor directly at high doses  increased duraiton of ion channel openings

Benzodiazepines:
- bind to benzo site on GABA A receptor (alpha 1, gamma 2) & facilitate action of GABA
- do NOT activate it directly  allosteric modulation  increase frequency of ion channel opening
GABA A receptor agonists
Cont’d Ethanol
- enhances GABA a receptor activity in addition to other NTs/receptors
- mechanism not entirely clear

Neuroactive steroids:
- made in brain
- act as lcoal signaling mechanisms rather than hormones
- ex: allopregnanolone, pregnenolone, DHEA
- can enhance or inhibit GABA
- involved in: mood, learning/memory, stress, seizures, sleep

Convulsants
- both competitive and noncomp. Antagonists
- NO therapeutic use
- Example: bicuculline, picrotoxin, pentlenetetrazol

Antiseizure/epilepsy:
- Tigabine
- Selective inhibitors of GAT -1  elevates extracellular GABA and potentiates transmission
- Protects against seizures
- Vigabatrin
- Irreversible inhibitor of GABA – T  prevent GABS metabolism
- Indicated for infantile spasms (monotherapy) and as adjunctive for adults with refractory complex partial
seizures with no response to other drugs
GABA B receptor agonists Baclofen:
Coupled to Ca++ or K+ via - agonist
second messenger systems - centrally acting muscle relaxant/antispasmodic
- tx for alcoholism?

GHB:
- sodium oxybate
- weak agonist, made from GABA
Activation of receptor  ↓ in - indicated for narcolepsy
Ca++ conductance, activates K+ - a date rape drug
channels (hyperpolarization
 neuronal inhibition)

Serotonin 5-HT1A receptors

- agonists here will:
- induce hyperphagia  stimulation of autoreceptors  inhibits activity of 5-HT ergic neurons  decrease
in 5-HT release in forebrain  reduced appetitie and food intake
- reduce anxiet  Buspirone
- reduce alcohol intake in rats
- induce hypothermia

5-HT 1B/1D receptors

- agonists: tx of migraine headaches
- activation of receptors  cranial VC, inhibited release of proinflammatory neuropeptides  reduced
transmission in pain pathway (trigeminal)
- Triptans: sumatriptan, frovatiptan, naratiptan, rizatriptan, almotriptan, zolmitriptan, eletriptan

5-HT 2A receptors:
- located in cerebral cortex, striatum, nucleus accumbens, etc
- agonists are hallucinogenic (LSD?)
- antagonists at these receptors  treatment of Schizophrenia  Ritanserin, clozapine, risperidone

5-HT 3 receptors:
- antagonists used to prevent or reduce nausea/vomiting due to surgery, chemo, etc
- example: granisetron, odansetron, dolsaetron, palonsetron
Dopamine: Involved in reward, addiction, and movement/motor

Endocannabinoids GPCRs
2 primary endogenous cannabinoids:
- anandamide & 2arachidonylglyercol
- made from arachidonic acid
- involved in memory, cognition, immunomodulation, appetite, and pain perception

Orexin/hypocretin Produced in lateral/posterior hypothalamus

Also release glutamate  excitotoxic

Involved in sleep/wake cycle, metabolism, food intake, mood, reward

Narcolepsy with cataplexy often due to lack of it

Suvorexant:
- antagonist at OX1 and 2 for inomnia