CNS Pharmacology

1. Why CNS Pharmacology is Unique

2. Organization of the CNS

Neurons

• Dendrites - receive and integrate inputs from other neurons
• Cell body (soma) - integrates dendritic signals
• Axon - carries output signal, sometimes over long distances
• Axon terminal - forms the synapse, releases neurotransmitter

Glia (Supporting Cells)

3. The Blood-Brain Barrier (BBB)

• Tight junctions between capillary endothelial cells
• Surrounding astrocyte end-feet

• Drugs must be highly lipophilic OR use specific transport mechanisms to enter the CNS
• Second-generation antihistamines (e.g., cetirizine) were made more polar to limit BBB crossing and reduce sedation
• L-DOPA (not dopamine itself) crosses the BBB via an amino acid transporter, which is why it is used in Parkinson disease instead of dopamine directly
• Circumventricular organs (area postrema, neurohypophysis) lack a BBB - the antiemetic action of many drugs targets the area postrema

4. Ion Channels and Receptor Types

A. Ionotropic Receptors (Ligand-Gated Ion Channels)

• Directly coupled to an ion channel
• Fast responses (milliseconds)
• Examples: NMDA, AMPA (glutamate), GABA-A, nicotinic ACh, 5-HT3
• Drugs: benzodiazepines (potentiate GABA-A), ketamine (NMDA antagonist)

B. Metabotropic Receptors (G Protein-Coupled)

• Act through second messengers (cAMP, IP3/DAG, or K+/Ca2+ channel modulation)
• Slower, longer-lasting effects
• Examples: dopamine D1/D2, norepinephrine α/β, serotonin 5-HT1/2, muscarinic ACh, most GABA-B
• Most CNS drugs act here

5. Synaptic Transmission

1. Action potential arrives at axon terminal
2. Voltage-gated Ca2+ channels open → Ca2+ influx
3. Synaptic vesicles fuse with presynaptic membrane
4. Neurotransmitter released into synaptic cleft
5. Binds postsynaptic receptors → changes membrane conductance
6. Produces EPSP (excitatory) or IPSP (inhibitory)
7. Summation of multiple EPSPs → action potential threshold → firing

• Block vesicle release (e.g., botulinum toxin in periphery)
• Block reuptake (e.g., SSRIs, cocaine, tricyclics)
• Block degradation (e.g., MAO inhibitors)
• Receptor agonism/antagonism

6. Central Neurotransmitters and Their Pharmacology

Acetylcholine (ACh)

• Cell bodies at all CNS levels; also motoneuron-Renshaw cell synapse
• Muscarinic (M1, M2): Pirenzepine, atropine are antagonists; modulate K+ and IP3/DAG
• Nicotinic: blocked by α-bungarotoxin, dihydro-β-erythroidine
• Role: attention, memory, arousal; deficiency in Alzheimer disease

Dopamine

• D1-like (D1, D5): increase cAMP; blocked by phenothiazines
• D2-like (D2, D3, D4): decrease cAMP, open K+ channels; blocked by phenothiazines, butyrophenones
• Generally inhibitory; slow-acting

Norepinephrine (NE)

• Located primarily in locus coeruleus and lateral tegmental areas
• All receptor subtypes are metabotropic (α1, α2, β)
• α2 activation hyperpolarizes neurons (opens K+ channels) - basis of clonidine action
• α1/β activation blocks K+ conductances → enhanced excitatory transmission
• Role: attention, arousal, mood; target of antidepressants (SNRIs, TCAs)

Serotonin (5-HT)

• Originates in raphe nuclei (pons/upper brain stem)
• Diffusely innervates almost all CNS regions
• Over a dozen receptor subtypes:
  • 5-HT1A: inhibitory via K+ channel opening (anxiolytic target - buspirone)
  • 5-HT2: slow excitatory via K+ channel blockade
  • 5-HT3: only ionotropic subtype; fast excitation at limited sites; target of ondansetron (antiemetic)
• Regulates: mood, anxiety, pain, sleep, appetite, temperature, aggression
• Target of SSRIs, SNRIs, triptans, and many antipsychotics

GABA (γ-Aminobutyric Acid)

• Primary inhibitory neurotransmitter in the CNS
• GABA-A (ionotropic): Cl- channel; benzodiazepines (positive allosteric modulators), barbiturates, alcohol, and general anesthetics act here
• GABA-B (metabotropic): opens K+ channels; target of baclofen (muscle relaxant)
• Target of: benzodiazepines, barbiturates, anticonvulsants (valproate, vigabatrin)

Glutamate

• Primary excitatory neurotransmitter in the CNS
• AMPA receptors: fast, Na+/K+ permeant; main mediator of fast excitatory transmission
• NMDA receptors: slow, Ca2+ permeant; require both glutamate AND glycine AND membrane depolarization (Mg2+ block); key in long-term potentiation (LTP), memory
• Metabotropic glutamate receptors (mGluR): modulate synaptic strength
• NMDA antagonists: ketamine (anesthetic/antidepressant), memantine (Alzheimer disease)
• Excessive NMDA activation → excitotoxicity (relevant in stroke, trauma)

Monoamines: Other Notes

• Histamine: CNS histamine from hypothalamic neurons; modulates arousal, appetite; H1 antagonists = sedation (first-generation antihistamines)
• Endocannabinoids (anandamide, 2-AG): retrograde messengers; suppress presynaptic release via CB1 receptors; target of cannabis/THC
• Nitric oxide (NO): synthesized by neuronal NOS activated via NMDA-Ca2+-calmodulin; possible retrograde messenger; role in cerebellar long-term depression
• Purines (ATP, adenosine): adenosine acts on A1 (inhibitory) and A2A (mildly excitatory) receptors; rising adenosine promotes sleep; caffeine antagonizes adenosine A2A receptors to promote wakefulness

7. Major Drug Classes Acting on the CNS

8. Key Principles of CNS Drug Action

1. Selectivity depends on receptor distribution - drugs targeting D2 in the mesolimbic system for psychosis also hit D2 in the nigrostriatal pathway (causing extrapyramidal side effects) and tuberoinfundibular system (causing hyperprolactinemia)
2. Presynaptic vs. postsynaptic - Many receptors are also found presynaptically as autoreceptors that inhibit further neurotransmitter release (e.g., D2 autoreceptors, α2 autoreceptors)
3. Tolerance and dependence - Prolonged receptor activation leads to downregulation and desensitization; basis for withdrawal syndromes
4. Multiple receptor subtypes - Drug specificity for receptor subtypes determines therapeutic vs. adverse effect profiles (e.g., atypical antipsychotics with 5-HT2 + D2 blockade have fewer EPS)
5. Signal amplification - Metabotropic receptors amplify signals through second-messenger cascades (cAMP, PKA, CREB) affecting gene expression - relevant to long-term antidepressant effects

Summary Diagram of Neurotransmitter Balance

Excitatory ←————————————————————→ Inhibitory
  GLUTAMATE                           GABA
  (AMPA, NMDA)                   (GABA-A, GABA-B)
  
Monoamines (modulatory):
  Dopamine  → Reward, movement, cognition
  NE        → Arousal, attention, mood
  5-HT      → Mood, sleep, appetite
  ACh       → Memory, arousal (muscarinic/nicotinic)
  Histamine → Wakefulness

• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 21: Introduction to the Pharmacology of CNS Drugs, pp. 577-596