Introduction to CNS Pharmacology

Introduction to CNS Pharmacology Section A-1 Introduction to CNS Drugs Among the first discovered by primitive humans Most widely used group of pharmacologic agents Treats neurologic and psychiatric conditions Manages pain, nausea, fever, and other symptoms Most CNS drugs act on sp...

Introduction to CNS Pharmacology Section A-1 Introduction to CNS Drugs Among the first discovered by primitive humans Most widely used group of pharmacologic agents Treats neurologic and psychiatric conditions Manages pain, nausea, fever, and other symptoms Most CNS drugs act on specific receptors Modulate synaptic transmission Impact on Disease Understanding Drug studies led to disease mechanism hypotheses Antipsychotic drugs → schizophrenia pathophysiology GABA receptor studies → anxiety and epilepsy insights Central Nervous System Overview Composed of brain and spinal cord Integrates sensory information and generates motor output Contains approximately 100 billion interconnected neurons Neurons are organized in nuclei or layered structures Forms circuits that regulate information flow through the CNS Neuron Structure and Function Electrically excitable cells that process and transmit information Main components: cell body (soma), dendrites, and axons Dendrites: Branched structures receiving input from other neurons Axons: Carry output signals, usually one per neuron Synapses: Specialized junctions where neurotransmitters are released Blood-Brain Barrier (BBB) Protective barrier between blood and CNS extracellular fluid Formed by tight junctions between capillary endothelial cells Surrounded by astrocyte end-feet Drugs must be hydrophobic or use specific transporters to cross Specific transporters exist for nutrients like glucose Some regions (circumventricular organs) lack normal BBB BBB characteristics influence drug development strategies Types of Neuronal Membrane Channels Two main types based on gating mechanisms: 1. Voltage-gated channels: Respond to membrane potential changes 2. Ligand-gated channels: Respond to neurotransmitter binding Both types crucial for neuronal function and signaling Synaptic Communication in CNS Chemical synapses are the primary means of neuronal communication Limited electrical coupling exists but rarely targeted by drugs Synaptic transmission delay is approximately 0.5 milliseconds Most delay occurs during the release process and calcium channel opening Synaptic Transmission Process 1. Action potential reaches synaptic terminal 2. Activates voltage-gated calcium channels 3. Calcium influx promotes synaptic vesicle fusion 4. Neurotransmitter release into synaptic cleft 5. Binding to postsynaptic receptors causes ion channel changes Synaptic transmission Excitatory Postsynaptic Potentials (EPSPs) Results from excitatory transmitter activation Causes increased cation permeability Creates depolarization of membrane Can undergo spatial summation (multiple synapses) Can undergo temporal summation (repeated firing) Action Potential Generation EPSPs can summate to reach threshold Spatial summation: Multiple synapses activate simultaneously Temporal summation: Repeated firing of same input When threshold reached, generates all-or-none action potential Resting membrane potential typically around -60 mV Inhibitory Postsynaptic Potentials (IPSPs) Caused by opening of chloride channels Creates hyperpolarization of membrane Equilibrium potential near -65 mV Makes neuron 'leaky' through shunting effect Decreases effectiveness of EPSPs Types of Inhibition 1. Postsynaptic inhibition via IPSPs 2. Presynaptic inhibition through autoreceptors 3. Spillover inhibition affecting nearby synapses IPSPs can prevent action potentials even with normal EPSP input Multiple inhibitory mechanisms provide precise control Overview of CNS Drug Action Most CNS drugs modify chemical synaptic transmission Actions divided into presynaptic and postsynaptic categories Drug selectivity based on neurotransmitter systems and receptor types Multiple receptor subtypes allow targeted therapeutic approaches Presynaptic Drug Actions Modification of neurotransmitter synthesis (production) Interference with storage (e.g., reserpine depletes monoamines) Alteration of metabolism inside nerve terminals Changes in release mechanisms (e.g., amphetamine for catecholamines) Effects on transmitter reuptake (e.g., cocaine blocks catecholamine uptake) Neurotransmitter Clearance Two main mechanisms of transmitter removal: 1. Reuptake into presynaptic terminals and surrounding glia 2. Enzymatic degradation (e.g., acetylcholinesterase for acetylcholine) Peptide transmitters: No known uptake mechanisms Drugs can target both clearance mechanisms Postsynaptic Drug Actions Primary site: Transmitter receptors Can act as agonists (e.g., opioids mimicking enkephalin) Can act as antagonists (e.g., strychnine blocking glycine receptors) Direct ion channel effects (e.g., ketamine blocking NMDA receptors) Modification of second messenger systems (e.g., methylxanthines affecting cAMP) Different neurotransmitters in distinct neuronal systems Systems often control different CNS functions Multiple receptor subtypes for each neurotransmitter Brain Organization Overview CNS neuronal systems divided into two broad categories: 1. Hierarchical Systems: Direct sensory perception and motor control 2. Nonspecific/Diffuse Systems: Global brain state regulation Each system has distinct characteristics and functions Hierarchical Systems: Structure Composed of large myelinated fibers Fast conduction rates (>50 meters/second) Information transmitted in phasic action potential bursts Sequential processing through relay nuclei System failure occurs if any link is damaged Neurotransmitter Identification Criteria Three key criteria for identifying CNS neurotransmitters: 1. Localization: Must be present in presynaptic terminals 2. Release: Must be released by neuronal activity in Ca²⁺-dependent manner 3. Synaptic Mimicry: Application should mimic natural transmission Amino Acid Neurotransmitters: Glutamate Primary excitatory neurotransmitter in CNS High concentration in synaptic vesicles (~100 mM) Three ionotropic receptor types: AMPA, Kainate, NMDA Metabotropic receptors (mGluR1-8) in three groups Critical role in learning and memory through NMDA receptors Inhibitory Amino Acids: GABA and Glycine GABA: Primary inhibitory transmitter throughout CNS Two main receptor types: GABAA (ionotropic) and GABAB (metabotropic) Glycine: Major inhibitor in spinal cord and brain stem Both open chloride channels to inhibit neurons Key targets for many therapeutic drugs Acetylcholine Systems First identified CNS neurotransmitter Two receptor types: Nicotinic (ionotropic) and Muscarinic (metabotropic) Eight major nuclei with diffuse projections Important role in cognitive functions and memory Implicated in Alzheimer's disease pathology Monoamine Neurotransmitters Include dopamine, norepinephrine, and serotonin Present in small amounts but wide-reaching effects Primarily act through metabotropic receptors Target of many therapeutic drugs Regulate mood, attention, arousal, and reward Neuropeptides Packaged in large dense core vesicles Often coexist with classical neurotransmitters Can act locally or diffuse long distances Primarily serve modulatory roles Involved in pain, reward, appetite, and social behaviors Neurotransmitters & their functions