SUBMH Neurobiology
NEUROBIOLOGY OF DRUG DEPENDENCE
THE NERVOUS SYSTEM
Psychoactive substances produce their effects by changing the activity of the nervous system.
Nervous System Components
Divisions of the Nervous System:
Central Nervous System (CNS):
Comprises the brain and spinal cord, known as the "control center".
Area most affected by psychoactive substances.
Peripheral Nervous System (PNS):
Includes all other nerve elements.
Functions of the Nervous System
Sensory Function:
Senses changes both in and outside the body.
Integrative Function:
Interprets and explains the changes sensed.
Motor Function:
Responds to the interpretations made by activating muscles and glands to secrete hormones or chemicals into the circulatory system.
Within the CNS, nerve cells (neurons) facilitate communication that allows for feeling, thinking, learning, and behaving.
NEURONS AND NEUROTRANSMITTERS
Structure of Neurons:
Axon: Carries electrical signals to synaptic knobs.
Myelin Sheath: Protects axon and facilitates conduction of electrical signals.
Synaptic Knob: Releases neurotransmitters to cross the synapse and activate receptor cells.
Key Neurotransmitters
Dopamine (DA):
Functions: Movement, motivation, emotional response, desire, ability to experience pleasure and pain.
Conditions Related to Dopamine:
High levels: Linked to schizophrenia and psychosis.
Low levels: Associated with Parkinson’s Disease.
Serotonin (5-HT):
Functions: Mood control, sensory perception, temperature regulation, satiety, inhibition.
Conditions Related to Serotonin:
Low levels: Linked to depression and anxiety; deficiency can lead to aggression.
High levels: Associated with positive energy and will power, known as the “happy hormone”.
Norepinephrine:
Functions: Arousal to the environment, mood regulation, dreaming.
Conditions Related to Norepinephrine:
Low levels: Linked to depression.
High levels: Associated with anxiety.
Acetylcholine:
Excites neurons in brain, muscles, tissues, and glands.
Condition Related to Acetylcholine:
Low levels: Linked to Alzheimer’s Disease.
Endorphins:
Functions: Pain regulation, inducing dreaminess and calmness.
Endocannabinoids:
Functions: Mood regulation, pain control.
Glutamate (GLU) and GABA:
Amino acids that act as neurotransmitters.
Glutamate: Exciting effect on neurons.
GABA: Inhibitory effect on neurons.
Effects on Emotions:
Increased glutamate: Linked to aggression, anxiety, mood swings, hyperactivity, confusion.
NEUROTRANSMISSION
Components of Neurotransmission:
Terminal button, autoreceptors, axons, vesicles (contain neurotransmitters), reuptake transporters, enzymes, synaptic clefts, receptors on receiving neurons.
DRUGS AND THEIR NATURAL COUNTERPARTS
Main Categories of Drugs and Counterparts:
Opioids: Mimic endorphins.
Cocaine: Mimics or increases dopamine.
Prozac (SSRI): Increases serotonin levels.
Nicotine: Mimics acetylcholine.
Cannabis: Mimics endocannabinoids.
PSYCHOACTIVE SUBSTANCES AND NEUROTRANSMISSION
Psychoactive substances affect the brain through:
Directly: Mimicking a neurotransmitter and stimulating a receptor site.
Indirectly: Influencing interactions of naturally produced neurotransmitters with receptor sites.
Types of Drug Actions
Agonists:
Definition: Chemicals that bind to receptors and mimic or facilitate the effects of neurotransmitters.
Partial Agonists:
Partially mimic neurotransmitter effects.
Antagonists:
Inhibit neurotransmitter action, typically by blocking receptor sites.
AGONIST ACTIONS
How Agonists Work:
Imitates aspects of neurotransmitters fooling receptor sites.
Prevent neurotransmitter absorption into the sending neuron (e.g., SSRIs).
Inhibits enzymes that metabolize neurotransmitters.
Forces the release of neurotransmitters by invading vesicles, displacing natural transmitters.
UP REGULATION / DOWN REGULATION
Down Regulation:
Definition: The cell decreases the number of receptor sites when too many neurotransmitters are sensed, slowing message transmission (linked to tolerance).
Up Regulation:
Definition: The receiving neuron increases the number of receptor sites when too few neurotransmitters are present to trigger messages, enhancing effectiveness over time.
Concepts of Homeostasis and Allostasis:
Homeostasis refers to maintaining function within a normal range, leading to allostasis, which allows for stability through change and adjustments in the set point of stability.
HOW DO PSYCHOACTIVE SUBSTANCES ALTER NEUROTRANSMITTER EFFECTS
Psychoactive substances can:
Block neurotransmitter release from vesicles.
Force neurotransmitter release by entering presynaptic neurons.
Prevent reabsorption of neurotransmitters.
Inhibit enzymes that synthesize neurotransmitters.
Inhibit enzymes that metabolize neurotransmitters.
Interfere with neurotransmitter storage.
TOLERANCE
Definition of Tolerance:
The phenomenon where a user requires increasing amounts of psychoactive substances to achieve the same effects due to homeostasis and metabolic adaptation.
Types of Tolerance:
Dispositional Tolerance:
The body accelerates the breakdown (metabolism) of the drug; more enzymes are present to eliminate the drug.
Pharmacodynamic Tolerance:
Nerve cells become less sensitive to the drug’s effects, often producing antagonists to counteract the drug.
Behavioral Tolerance:
Adaptation by the brain allows individuals to function despite drug effects by using unaffected brain regions.
Reverse Tolerance:
Increased sensitivity results in less tolerance due to potential brain tissue damage (e.g., with MDMA).
Acute Tolerance:
Rapid adaptation to the toxic effects of drugs (e.g., hallucinogens like LSD).
Select Tolerance:
Different rates of tolerance development for mental and physical effects; can lead to fatal overdoses (e.g., barbiturates).
Inverse Tolerance (Kindling):
Increased sensitivity to drug effects as brain chemistry adapts, allowing responses to even placebo effects.
DEPENDENCE
Definition of Dependence:
The body's biological adaptation to prolonged drug use, leading to tissue dependence.
Psychological Dependence:
Behavioral compulsion to use a substance due to perceived benefits or avoidance of negative effects.
Drug Automatism:
A state induced by sedatives and opiates that results in aimless, repetitive substance use.
Reinforcements:
Positive Reinforcement: Desire to experience a substance's positive effects.
Negative Reinforcement: Desire to avoid negative effects or emotions.
Social Reinforcement: Social factors that encourage continued use of psychoactive substances.
REWARD PATHWAY
Anatomy of the Reward Pathway:
Involves brain areas such as the Frontal Cortex, Nucleus Accumbens (NAc), Ventral Tegmental Area (VTA), Amygdala, and Hippocampus.
MESOLIMBIC DOPAMINERGIC REWARD PATHWAY
Discovery and Implications:
Discovered accidentally in 1953; altered understanding of how the brain processes pleasure and pain.
Demonstrated that the desire for pleasure does not compete with basic drives (e.g., food, procreation) but overrides them.
Connects older brain structures with newer brain regions (neocortex).
FUNCTIONS OF THE REWARD PATHWAY
Specific Roles of Structures:
Ventral Tegmental Area (VTA):
Rich in dopamine and serotonin neurons; projects to NAc and Prefrontal Cortex.
Nucleus Accumbens (NAc):
Processes natural rewards such as food and sex.
Locus Ceruleus (LC):
Manages physiological responses to stress and panic.
Amygdala:
Involved in forming and storing memories of emotional events.
Hippocampus:
Plays a role in memory storage.
Prefrontal Cortex (PFC):
Responsible for executive functions, including aligning actions with goals.
LEVELS OF USE
Stages of Substance Use:
Abstinence: No use of psychoactive substances.
Experimentation: Initial trial of substances.
Social/Recreational Use: Occasional use in social settings.
Habituation: Regular use without significant consequences.
Abuse: Use that leads to negative outcomes and issues.
Addiction: Compulsive need to consume substances despite harmful consequences.
THE NERVOUS SYSTEM
Psychoactive substances produce their effects by changing the activity of the nervous system, which is the body's complex network for communication and control.
Nervous System Components
Divisions of the Nervous System:
Central Nervous System (CNS):
Comprises the brain and spinal cord, acting as the "control center" for all mental processes and bodily functions.
It integrates received information and coordinates all voluntary and involuntary activity.
This is the primary area most profoundly affected by psychoactive substances, leading to alterations in thought, emotion, and behavior.
Peripheral Nervous System (PNS):
Includes all other nerve elements outside the CNS, extending throughout the body.
It acts as a communication highway, relaying information between the CNS and the rest of the body, including organs, muscles, and glands.
The PNS is further divided into the Somatic Nervous System (voluntary movements) and the Autonomic Nervous System (involuntary functions).
Functions of the Nervous System
Sensory Function:
Detects and senses changes both in and outside the body through specialized sensory receptors (e.g., touch, sight, temperature, internal organ states).
This information is then transmitted to the CNS for processing.
Integrative Function:
Interprets and explains the changes sensed by processing sensory information, assessing its significance, and storing it in memory.
This function involves complex cognitive processes like thinking, learning, decision-making, and emotional processing.
Motor Function:
Responds to the interpretations made by activating muscles and glands to secrete hormones or chemicals into the circulatory system.
This can result in voluntary movements (like moving a limb) or involuntary responses (like changes in heart rate or hormone release).
Within the CNS, nerve cells (neurons) facilitate intricate communication through electrical and chemical signals, forming neural circuits that allow for feeling, thinking, learning, and behaving.
NEURONS AND NEUROTRANSMITTERS
Neurons are the fundamental units of the nervous system, specialized for transmitting information. Each neuron typically consists of a cell body (soma), dendrites, an axon, and synaptic terminals.
Structure of Neurons:
Dendrites: Branch-like projections that receive incoming electrical and chemical signals from other neurons.
Cell Body (Soma): Contains the nucleus and cellular machinery, integrating incoming signals.
Axon: A long, slender projection that carries electrical signals (action potentials) away from the cell body towards other neurons, muscles, or glands.
Myelin Sheath: A fatty insulating layer that surrounds and protects many axons, significantly increasing the speed and efficiency of electrical signal conduction.
Synaptic Knob (Axon Terminal/Terminal Button): The specialized end of the axon where electrical signals are converted into chemical signals (neurotransmitters) that are then released to cross the synapse and activate receptor cells on a receiving neuron.
Synapse: The tiny gap between the synaptic knob of a sending neuron and the dendrite or cell body of a receiving neuron, across which neurotransmitters diffuse.
Key Neurotransmitters
Neurotransmitters are chemical messengers that transmit signals across a chemical synapse, from one neuron to another target neuron, muscle cell, or gland cell.
Dopamine (DA):
Functions: Crucial for voluntary movement control, motivation, pleasure, reward, emotional response, and the ability to experience desire, pleasure, and pain. It plays a central role in the brain's reward system.
Conditions Related to Dopamine:
High levels: Implicated in psychotic disorders like schizophrenia, characterized by hallucinations and delusions.
Low levels: Strongly associated with Parkinson’s Disease, leading to motor symptoms such as tremors and difficulty with movement.
Serotonin (5-HT):
Functions: Widely distributed, influencing mood control, sensory perception, temperature regulation, sleep-wake cycles, appetite regulation (satiety), impulse control, and inhibition. It contributes to feelings of well-being and happiness.
Conditions Related to Serotonin:
Low levels: Strongly linked to depression, anxiety disorders, obsessive-compulsive disorder (OCD), and can contribute to aggression and impulsivity.
High levels: May contribute to conditions like serotonin syndrome in excessive amounts, but generally associated with positive energy, emotional stability, and willpower.
Norepinephrine (NE):
Functions: Also known as noradrenaline, it acts as both a neurotransmitter and a hormone. Involved in arousal to the environment, vigilance, alertness, mood regulation, attention, and the stress response (fight or flight). It plays a role in dreaming and learning.
Conditions Related to Norepinephrine:
Low levels: Frequently associated with depression, fatigue, and lack of focus.
High levels: Linked to anxiety, panic attacks, hypertension, and hyper-vigilance.
Acetylcholine (ACh):
Functions: A primary excitatory neurotransmitter in the CNS, PNS, and neuromuscular junctions. It excites neurons in the brain, facilitates muscle contraction, and is vital for learning, memory, and attention.
Condition Related to Acetylcholine:
Low levels: A hallmark of Alzheimer’s Disease, impacting memory formation and cognitive function.
Endorphins:
Functions: Naturally occurring opioid peptides that act as natural pain relievers (analgesics) and induce feelings of euphoria, dreaminess, and calmness. Released during exercise, excitement, pain, and sexual activity.
Endocannabinoids:
Functions: Endogenous lipids that modulate mood regulation, appetite, pain control, memory, and sleep. They play a crucial role in maintaining homeostasis within the nervous system.
Glutamate (GLU) and GABA (Gamma-aminobutyric acid):
Amino acids that are the primary excitatory and inhibitory neurotransmitters in the CNS respectively.
Glutamate: The most abundant excitatory neurotransmitter in the brain, crucial for learning, memory, and synaptic plasticity.
GABA: The primary inhibitory neurotransmitter, reducing neuronal excitability throughout the nervous system, helping to regulate anxiety and promote relaxation.
Effects on Emotions:
Increased glutamate (imbalance with GABA): Linked to aggression, anxiety, mood swings, hyperactivity, confusion, and can contribute to excitotoxicity (neuronal damage).
NEUROTRANSMISSION
Neurotransmission is the process by which neurons communicate via chemical signals. This complex process involves several key components:
Terminal button (axon terminal): Where neurotransmitters are stored and released.
Autoreceptors: Receptors on the presynaptic neuron that detect the amount of neurotransmitter released, providing feedback to regulate further release.
Axons: Conduct electrical signals to the terminal buttons.
Vesicles: Small sacs within the terminal button that contain and store neurotransmitters.
Reuptake transporters: Proteins on the presynaptic neuron that reabsorb neurotransmitters from the synaptic cleft, terminating their action and recycling them.
Enzymes: Proteins in the synaptic cleft or neuronal cytoplasm that metabolize and break down neurotransmitters, effectively inactivating them.
Synaptic clefts: The microscopic space between the presynaptic and postsynaptic neurons where neurotransmitters are released.
Receptors on receiving neurons (postsynaptic receptors): Specialized proteins on the dendrites or cell body of the postsynaptic neuron that bind to neurotransmitters, causing a biological response (excitation or inhibition).
DRUGS AND THEIR NATURAL COUNTERPARTS
Many psychoactive drugs exert their effects by interacting with the body's natural neurotransmitter systems, often by mimicking or altering the actions of endogenous ligands.
Main Categories of Drugs and Counterparts:
Opioids (e.g., morphine, heroin): Mimic the effects of natural endorphins by binding to opioid receptors, producing pain relief and euphoria.
Cocaine: Primarily acts by blocking the reuptake of dopamine, norepinephrine, and serotonin, leading to increased levels of these neurotransmitters in the synaptic cleft, resulting in enhanced pleasure, energy, and alertness.
Prozac (SSRI - Selective Serotonin Reuptake Inhibitor): Increases serotonin levels in the synaptic cleft by blocking its reuptake, used to treat depression and anxiety.
Nicotine: Acts as an agonist for acetylcholine receptors (nicotinic receptors), leading to enhanced alertness, focus, and pleasure.
Cannabis (THC): Mimics the effects of natural endocannabinoids by binding to cannabinoid receptors (CB1 and CB2 receptors) in the brain and body, influencing mood, pain, appetite, and memory.
PSYCHOACTIVE SUBSTANCES AND NEUROTRANSMISSION
Psychoactive substances alter brain function and behavior by directly or indirectly interfering with the normal processes of neurotransmission.
Psychoactive substances affect the brain through two main mechanisms:
Directly: By mimicking a naturally occurring neurotransmitter and directly binding to and stimulating a specific receptor site (e.g., opioids mimicking endorphins).
Indirectly: By influencing the synthesis, storage, release, reuptake, or metabolism of naturally produced neurotransmitters, thereby altering their interactions with receptor sites (e.g., cocaine blocking dopamine reuptake).
Types of Drug Actions
Agonists:
Definition: Chemicals or drugs that bind to receptor sites and mimic or facilitate the effects of a neurotransmitter. They activate the receptor and produce a biological response, acting quite like the natural ligand.
Full Agonists: Bind to a receptor and produce a maximal response, fully mimicking the natural neurotransmitter (e.g., morphine).
Partial Agonists: Bind to a receptor and produce a sub-maximal response, even when all receptors are occupied. They have less intrinsic activity than full agonists (e.g., buprenorphine).
Antagonists:
Definition: Chemicals or drugs that inhibit or block the action of a neurotransmitter, typically by binding to and blocking receptor sites without activating them. They prevent the natural neurotransmitter or other agonists from binding and producing a response.
Competitive Antagonists: Bind reversibly to the same receptor site as the neurotransmitter, competing for binding (e.g., naloxone reverses opioid overdose).
Non-competitive Antagonists: Bind to a different site on the receptor or to a separate receptor, altering the receptor's shape or function so that the neurotransmitter cannot bind or activate it effectively.
AGONIST ACTIONS
Agonists interact with neurotransmitter systems through various mechanisms to enhance or mimic natural signaling:
Imitates aspects of neurotransmitters fooling receptor sites: The agonist has a molecular structure similar enough to the natural neurotransmitter that it can bind to the receptor and activate it, producing a response (e.g., nicotine acting like acetylcholine).
Prevent neurotransmitter absorption into the sending neuron (reuptake inhibition): Agonists can block the reuptake transporters on the presynaptic neuron, leaving more neurotransmitter in the synaptic cleft to bind to postsynaptic receptors and prolonging its effect (e.g., SSRIs increasing serotonin levels).
Inhibits enzymes that metabolize neurotransmitters: By blocking enzymes responsible for breaking down neurotransmitters in the synaptic cleft, agonists can increase the concentration and duration of action of the natural neurotransmitter (e.g., MAOIs inhibiting monoamine oxidase).
Forces the release of neurotransmitters by invading vesicles, displacing natural transmitters: Some drugs enter the presynaptic neuron and cause vesicles to release neurotransmitters independently of nerve impulses, leading to a surge of neurotransmitter in the synapse (e.g., amphetamines forcing dopamine release).
UP REGULATION / DOWN REGULATION
These are homeostatic cellular mechanisms that regulate the sensitivity of neurons to neurotransmitters or drugs, playing a critical role in tolerance and dependence development.
Down Regulation:
Definition: A process by which the receiving cell decreases the number or sensitivity of its receptor sites in response to prolonged overstimulation by neurotransmitters or agonists. If too many neurotransmitters are sensed, the cell internalizes or inactivates receptors, effectively slowing message transmission and reducing the cell's responsiveness (linked to the development of tolerance).
Mechanism: Chronic exposure to an agonist or high levels of a neurotransmitter leads to fewer functional receptors available on the cell surface.
Up Regulation:
Definition: A process where the receiving neuron increases the number or sensitivity of its receptor sites when too few neurotransmitters are present or when receptors are chronically blocked by antagonists. This enhances the cell's ability to trigger messages in response to limited stimulation, increasing effectiveness over time.
Mechanism: Chronic exposure to an antagonist or low levels of a neurotransmitter leads to more functional receptors available on the cell surface, making the cell more sensitive.
Concepts of Homeostasis and Allostasis:
Homeostasis refers to the body's inherent drive to maintain physiological stability and function within a normal, narrow range (e.g., stable body temperature, blood pH). It represents adaptive regulation around a set point.
Allostasis extends this concept, allowing for stability through change. It describes the process by which the body achieves stability (or allostasis) through physiological or behavioral adjustments, particularly in response to chronic or significant stressors, including drug exposure.
In drug dependence, prolonged exposure forces the body to create a new