Neuropharm - Second Exam Outline

Second Exam Outline

Definitions / Extra Information

• Neurotransmitter: A chemical substance that transmits signals across a synapse from one neuron to another, fundamentally playing a key role in communicating information throughout the brain and body. It includes various types such as amino acids, peptides, and monoamines.

• Dynamic: Refers to the interactive and ever-evolving relationship between a neurotransmitter and its receptor, which can be influenced by various factors including the presence of drugs or ligands.

Clinical Actions of Drugs Affect Neuronal Plasticity:

• Long-term potentiation (LTP): A persistent strengthening of synapses based on recent patterns of activity. It is a prime example where drug activation influences neuronal adaptation over time, enhancing synaptic efficacy and facilitating learning and memory.

Factors Influencing Drug Effects:

• Absorption: Relates to the percentage of the administered drug that reaches the central nervous system (CNS), commonly described by the term bioavailability which is crucial for effective pharmacological action.

• Stability: Refers to the duration for which the drug remains biochemically active in the body, impacting its overall effectiveness and the timing of therapeutic effects.

• Elimination: The metabolic process primarily executed by the liver, where the drug is broken down and removed from the body, significantly affecting the drug's duration of action and potential toxicity.

• Inert Drugs: Some pharmaceutical agents may bind non-specifically within the bloodstream, limiting their effectiveness at target sites and diminishing overall therapeutic benefit.

Allosteric Modulators

• Allosteric Modulator: A substance that binds to a receptor at a distinct site from the active site, perpetually functioning in a non-competitive manner, resulting in altered receptor activity.

• Allosteric Inhibition: Occurs when the inhibitor binds to the allosteric site, inducing conformational changes that obstruct the binding of endogenous ligands, leading to decreased receptor activity.

• Allosteric Activation: When an activator binds at the allosteric site, it enhances ligand binding at the active site, thereby promoting increased receptor efficacy and output.

Drug Binding

• Good interactions include saturated ligand-receptor binding, characterized by competitive and reversible mechanisms. Some drugs may exhibit greater efficacy than the endogenous ligand, translating to a more substantial effect.

• Binding Reversibility: Binding is not always reversible, particularly with certain synthetic drugs that covalently bond to receptors, potentially leading to prolonged pharmacological effects.

Quantification of Binding

• Affinity: Represented as Kd, which is the concentration of a ligand at which 50% of the receptors are occupied. A lower Kd indicates higher affinity between the ligand and receptor.

• Total Binding (Bmax): Denotes the maximum level of drug binding attained and typically represents a plateau in binding capacity.

• Potency: While related to affinity, potency reflects the specific amount of drug required to produce a defined biological effect. A lower Kd also indicates increased potency.

• Efficacy: Refers to the actual biological result produced by the drug, irrespective of its affinity for the receptor.

• Agonists: Drugs that mimic the action of endogenous ligands and can vary in efficacy, influencing therapeutic outcomes.

• Partial Agonists: Have high affinity but produce partial effects, potentially acting as antagonists in the presence of a full agonist. This unique property can modulate overall receptor activity based on presence and concentration.

• Full Agonists: Create effects closely resembling those of endogenous ligands, fully activating the receptor and eliciting maximum biological response.

• Inverse Agonists: Contrast the effects of agonists by inducing an opposite effect and reducing constitutive activity of receptors.

• Antagonists: Compounds that can be competitive or non-competitive; they bind to receptors and hinder activation without generating a biological response.

Competition Curves

• Competitive Binding: Occurs when drugs compete for the same binding site as endogenous ligands, where the drug concentrations achieving displacement are denoted by Ki (the inverse of Kd).

• Non-competitive Binding: Involves drug binding at a site distinct from that of endogenous ligands, leading to decreased maximal response regardless of ligand concentration.

Signal Transduction

• First Messenger: The ligand that triggers an extracellular signaling cascade, initiating biological responses in the nervous system. This involves various forms of neurotransmission and biological outcomes.

• Second Messenger Systems: Include molecules such as cAMP, cGMP, Ca2+, NO, and DAG, which play a crucial role in amplifying the first-messenger signal and mediating downstream effects related to protein phosphorylation.

G-Protein Coupled Receptors (GPCRs)

• G-Protein Coupled Receptors serve as critical mediators to link extracellular ligands with intracellular effector systems through the binding and activation of G proteins (GDP and GTP).

• GPCRs are typically found as heterotrimers in cell membranes and require GTP for their functional activity.

Types of G Proteins:

• Gs: Facilitates an increase in cAMP levels through the activation of adenylyl cyclase (AC), resulting in diverse physiological responses via ion channels and PKA.

• Gi/o: Functions to inhibit AC, limiting cAMP production and subsequent opening of ion channels, playing a crucial role in dampening neuronal activity.

• Gq: Activates phospholipase C (PLC), leading to an increase in intracellular calcium release from the endoplasmic reticulum (ER), significantly impacting cellular excitability and signaling pathways.

Calcium Regulation

• Activation of receptors may modulate calcium ion entry into neurons, notably through direct passage via ligand-gated channels such as NMDA receptors and the inhibition of specific voltage-gated calcium channels by Gi proteins.

• Calcium changes may also occur as a consequence of phosphatidylinositol system regulation via PLC, contributing to dynamic neuronal signaling processes.

Excitatory and Inhibitory Amino Acids

• Amino Acids: Vital for the synthesis of neurotransmitters; key players include glutamate (excitatory) and GABA (inhibitory), which are essential for proper neuronal function.

Glutamate Synthesis and Degradation:

• Glutamate is synthesized from glucose in presynaptic terminals and is subsequently degraded and recycled through EEAT transporters to maintain synaptic homeostasis.

Receptors Types

Ionotropic Receptors:

• NMDA: Requires a depolarization event and the binding of two agonists (glutamate and glycine) for full activation, critical for synaptic plasticity and memory formation.

• AMPA/Kainate: Cation-selective receptors that mediate fast synaptic responses and undergo rapid desensitization, localized in presynaptic terminals to facilitate neurotransmitter release.

Metabotropic Receptors:

• Glutamate mGluRs: G-protein coupled receptors that modulate ion channel activity and are categorized into three groups, each having distinct effects on neuronal excitability and neurotransmitter release.

GABA Receptors:

• GABAa: An ionotropic receptor facilitating Cl- channel opening, leading to hyperpolarization and decreased neuronal excitability.

• GABAb: A metabotropic receptor involved in inhibitory mechanisms, regulating postsynaptic responses to GABA.

Monoamines, Acetylcholine, and Orexin

• Monoamines: These neurotransmitters are synthesized from amino acids and are targeted by monoamine oxidase (MAO) inhibitors, a class of antidepressants designed to prolong neurotransmitter actions and improve mood.

• Acetylcholine (ACh): Plays a critical role in cognitive functions such as memory and attention; it is synthesized and released via the enzyme choline acetyltransferase (ChAT) and acts on two types of receptors: muscarinic (GPCRs) and nicotinic (ligand-gated).

• Orexin (hypocretin): A neuropeptide involved in regulating arousal, wakefulness, and appetite, synthesized in the hypothalamus and influencing various monoaminergic pathways impacting alertness and energy levels.

Catecholamine Synthesis:

• Tyrosine Hydroxylase (TH): This enzyme serves as the rate-limiting step in catecholamine synthesis, with its activity influenced by environmental conditions and various drug interactions.

• Dopamine (DA): Integral to reward pathways and cognitive controls; its reuptake is managed primarily via dopamine transporters (DAT), and storage is influenced by vesicular monoamine transporter 2 (VMAT2).

• Norepinephrine (NE): Shares a similar biosynthetic pathway with dopamine, with distinct physiological roles in arousal and focus, regulated by specific receptor types affecting neurotransmitter release.

• Serotonin (5-HT): Synthesized from tryptophan, this neurotransmitter modulates mood, emotions, and diverse behaviors while interacting with numerous receptor subtypes, including both GPCRs and ionotropic receptors.

Histamine and Neuropeptides

• Histamine: Functions primarily in arousal through GPCRs and is involved in modulating various neural pathways that influence alertness, response to injury, and immune function.

• Neuropeptides: Slow-acting neurotransmitters synthesized from precursor proteins in DNA, often functioning as hormones. They differ from classical neurotransmitters in their storage, release patterns, and effects on synaptic activity based on stimulation intensity and duration, thus playing crucial roles in modulatory functions within neurocircuitry.

Opioid Receptor Subtypes

• Mu, Kappa, Delta: Each opioid receptor subtype exhibits unique roles in the modulation of analgesia, emotional responses, and neurotransmitter dynamics, with differing affinities affecting various behaviors and experiential outcomes.

Oxytocin and Vasopressin

• Both peptides are synthesized and released through specific neuroanatomical pathways and are pivotal in governing social behaviors and emotional responses, particularly showcased in the regulation of anxiety and stress responses.

Neuropeptide Y

• Abundantly localized in brain regions associated with feeding and appetite regulation, neuropeptide Y also influences anxiety and metabolic processes, highlighting its significance in maintaining physiological and psychological homeostasis.