Psych Actions of Drugs- Ch.1

How many nerve cells (neurons/gray matter) in the brain?

86 billion

How many glial cells (support cells/white matter) in the brain?

85 billion

How many synapses in the brain?

100 trillion

Only place in brain where nerve cells can regenerate

hippocampus

label 8 things

label 8 things

Myelin

fatty deposits that provide support and efficiency for neurons

Action Potential

Function of glial cells

surround/insulates neurons, prevents NT from spreading to other synapses, absorb NT and recycle, can release NT (GLUTAMATE)

Dale’s Principle

Neurons release only one type of NT (false)

Oligodendrocytes

Creates myelin sheath around neuron cell axons in the CNS. Makes up most of white matter in the brain

Astrocytes

Anchors neurons to blood supply. Provides scaffolding to hold synapses together in CNS. Remove excess ions and recycle NT

Microglia

Macrophage cells that scavenge for waste- main CNS immune function

3 types of chemical synapses that increase/decrease NT release:

axodendritic (targets dendrites), axosomatic (targets soma), axoaxonic (targets axons)

2 types of receptors and where they’re typical

Inhibitory (presynaptic) & Excitatory (Postsynaptic)

2 types of Receptor mechanisms

Ionic (“ligand-gated”) & Metabolic (“G-Protein”)

2 Types of changes in receptors

Up (increase # of receptors) & Down (decrease # of receptors) regulation

Which Receptor Mechanism is this?

Ionic

Which Receptor Mechanism is this?

Metabolic (G-Protein)

Autoreceptor Activity

On presynaptic neuron detect amount of NT in cleft; regulate REUPTAKE. If not enough, release more NT. If too much, release less NT.

Reuptake Transporters

Reuptake Channels. Removal of NT from synapse. Metabolized for resynthesis or Metabolized and eliminated (Ex. SERT, DAT, NET)

NT Metabolism

Breakdown or waste removal by enzymes like Monoamine oxidase (MOA-A/B), Catechol-O-Methyltransferase (COMT), and Acetylcholinesterase (AChE)

Excitatory Receptor

Agonist (increase action) & antagonist (decrease action)

Inhibitory Receptor

Agonist (decrease action) & Antagonist (increases action)

Primary excitatory NT?

Glutamate

Primary inhibitory NT?

GABA

Monoamine

One amino group

Catecholamine

Monoamine that also has catechol group and arise from tyrosine (epinephrine, norepinephrine, dopamine)

Norepinephrine (NE)

Arousal, reward, Vasoconstriction/Vasodilation, Blood pressure, SNS

Dopamine (DA)

Motor function, reward, cognition/learning, impulse control, endocrine function, addiction

5-Hydroxytryptamine (5HT)- SEROTONIN

Mood, Anxiety, Aggression, Satiety and food motility, Sleep, Pain reduction, Sexual functioning

Acetylcholine (ACh)

A NT that deals with Cognition/Learning, Memory, Arousal, Muscle activation, PNS

Allosteric binding

Binding on a receptor near the NT’s binding site but not at the actual NT binding site

Glutamate

Receptors 9NMDA & AMPA) are ligand-gated

GABA

Neurotransmitter that plays role in calming and relaxing body. GABA(A) receptor is ionic, GABA(B) receptor is g-protein. Drugs like benzos and alcohol act allosterically on GABA receptors

Norepinephrine (NE)

A neurotransmitter and hormone that plays a vital role in the body's response to stress and other situations. Binds to adrenergic receptors: Alpha (a1 and a2) and Beta (b1, b2, and b3)

Andrenergic Alpha-1

most important NE receptor for reward in nucleus accumbens

• Vasoconstriction, increased blood pressure, mydriasis (dilate pupils), bladder sphincter closyre

Andrenergic alpha 2

inhibits NE release and may be important in decreasing anxiety

• Inhibit NE, ACh, and insulin release

Beta 1

Andrenergic receptor that affects tachycardia, increased lipolysis, increased heart contractions, increase4 release of renin

b2

Andrenergic receptor involved in vasodilation, bronchodilation, increasead glucose utilization, relaxed uterine smooth muscle. Binds to NE & E

Dopamine

d1, d2, d3, d4

d1

Most numerous DA receptor in the brain. Most numerous in caudate, putamen, substantia nigra, amygdala, frontal cortex.

• Locomotion, reward/reinforcement/addiction, learning/memory, impulse control, affect, attention

d2

highest concentration in caudate, putamen, nucleus accumbens, substantia nigra, and ventral tegmental area.

• Locomotion, reward/reinforcemnt, addiction, learning/memory, impulse control, affect, attention, psychosis

d3

Mainly in nucleus accumbens and limbic system

• Locomotion, reward/reinforcemnt, addiction, cognition

d4

Least numerous DA receptor in brain. Moderately in hippocampus, substantia nigra, nucleus accumbens, amygdala, and frontal cortex

• Locomotion, cognition

d5

Less numerous than d1 located mainly in prefrontal cortex, premotor cortex, substantia nigra, hypothalamus, hippocampus

• Locomotion, cognition

4 Main DA Pathways

Mesolimbic, Mesocortical, Nigrostriatal, Tuberoinfundibular

Mesolimbic

Hyperactivity leads to Hallucinations, Delusions, Euphoria

• Primarily lined with d2 receptors

• Positive Dopamine Theory of Schizophrenia

• Tegmentum to nucleus accumbens, part of ventral striatum

Mesocortical

Hyperactivity leads to Cognitive and affective NEGATIVE symptoms of schizophrenia

• d1 & d2 receptors

• Tegmentum to dorsolateral prefrontal cortex and ventromedial prefrontal cortex

Nigrostriatal

Extrapyrimidal Motor System

• Substantia nigra to striatum

• Controls involuntary movements

Tuberoinfundibular

Prolactin secretion (lactation and mammary gland growth)

• Hypothalamus to pituitary

5-HT1a

Found in: CNS & blood vessels

Function: Addiction, Aggression, Anxiety, Sexual Functioning, Mood, Nausea, Pupil Dilation, Sleep, Detection of pain

• Inhibitory nature

5-HT2a

Found in: CNS, blood vessels, smooth muscle, peripheral nervous system, GI tract

Function: Addiction, Anxiety, Appetite, Cognition, Learning, Memory, Sleep, Vasoconstriction, Sexual behavior

Acetylcholine (Ach) 2 types of receptors

• Nicotinic

• Muscarinic

Nicotinic Receptors

• N1 or Nm- found in neuromuscular junctions

• N2 or Nn- found in CNS, ANS, Adrenal Medulla

Prefrontal Cortex

allows functional planning, daily coordination, functionality

Frontal Lobe

Reasoning, planning, problem solving, regualting emotions, regulating sexual urges, impulse control, speech (movement), motor movement

Parietal Lobe

Sensation (regulating senses), perception of stimuli (pressure, pain, touch), movement (orientation), visual recognition

Temporal Lobe

Perception and recognition of auditory stimuli, interpretation of smells and sounds, formation of memory, speech (understanding)

Occipital Lobe

Visual Processing, movement recognition, color recognition

Executive Functions

Controlled in the prefrontal cortex (anterior portion of frontal love) = reasoning, planning, problem solving, impulse control

Go Systems

Structure: Anterior Cingulate Cortex (gyrus)

Function: Maintain attention on desired activities, planning, self-initiation, goal-directed

Structure: Dorsolateral Prefrontal Cortex

Function: Working memory, planning, strategy

Stop Systems

Structure: Ventromedial Prefrontal Cortex

Function: Response inhibition, sustained attention, memory retrieval, shifting

Structure: Orbitofrontal Prefrontal Cortex

Function: Assigning value of stimulus, integrating reward and punishment

Limbic System

emotion system

Cingulate Cortex (gyrus)

Connect limbic system and prefrontal cortex; affect regulation

• OCD & anxiety

Septum Pellucidum and Nuclei

Part of pleasure center (w/ nucleus accumbens, medial hypothalamus, subthalamic nuclei)

• Schizophrenia, impulse control disorders, addiction

Fornix

Carries signals from hippocampus to septal nuclei and mammillary bodies

• memory and emotion

Mammilary Bodies

Relays from the amygdala and hippocampus

• recognition & smell memory

Hippocampus

Transfer short-term memory into long-term memory, new learning, spatial recognition, impulse and emotion control

• Alzheimer’s, other dementias, memory deficits, depression

Amygdala

Elicits and control aggression, threat appraisal

• Impulse control disorders, conduct disorders, depression, anxiety, personality disorders (antisocial, borderline)

Basal Ganglia

Striatum, Nucleus Accumbens, Globus Pallidus, Substantia Nigra

a cluster of nuclei found deep to the neocortex of the brain. It has a multitude of functions associated with reward and cognition but is primarily involved in motor control.

Striatum

Planning and modulation of movement. NMDA (glutamate) receptors modulating dopamine activity

• Parkinsons, Huntingtons, Other Choreas, Tourettes, OCD, Schizophrenia, ADHD

Nucleus Accumbens

Dopamine innervation for reward, pleasure, addiction, aggression, fear, impulsivity

• Substance abuse, addictive disorders, OCD, anxiety, mood disorders, ADHD

Globus Pallidus

Relay from Striatum to thalamus. Inhibits excitatory input from cerebellum, NMDA (glutatmate) receptors modulating dopamine activity

• Tremors, jerks, spasmodic movement, schizophrenia, ADHD

Substantia Nigra

Reward, addiction, motor planning, learning

• Parkinsons, addiction, schizophrenia

Autonomic Nervous System

Automatic functions such as heart rate, breathing, sweating, digestion, excretion. Two complementary systems make up the ANS

Parasympathetic Nervous System

Energy Conservation

Sympathetic Nervous System

Fight or flight

Neural Response to trauma and stress

HPA Axis and SNS

Pharmacokinetics

What the body does to the drug

• Absorption

• Distribution

• Metabolism

• Elimination

Pharmacokinetics: Absorption

Drug associated factors:

• Molecular weight (size to pass the blood brain barrier)

• Degree of ionization

• Lipophilic/Lipophobic

• Formulation

Patient Associated Factors:

• Route of admission

• Presence of food in stomach

• Stomach acidity and gastric mobility

Bioavailability

Amount of active drug in system

Pharmacokinetics: Distribution

• Membrane Permeability

• Membrane Barriers- all drugs passing blood brain barrier must be lipophilic

• Reservoir storage- Lipophilic drugs stored in body fat

• Protein Binding- usually bind to albumin, but also to red blood cells and a acid glycoprotein

Pharmacokinetics: Metabolism

(Biotransformation)

• Most psychotropics are metabolized hepatically (liver), not lithium

  • Phase 1 Reaction- degradation by cytochrome P450 enzymes

  • Phase 2 Reaction- Conjugation

Enzyme Inhibition

Increases drug levels

Enzyme Induction

Decreases drug levels

Cytochrome P450 (+ inducers)

Enzymes which reduce drugs to a more water soluble (polar) form

• Smoking

• Alcohol

• Carbamazepine (Tegretol)

• Phenobarbital

• Chlorpromazine

Pharmacokinetics: Elimination

Primarily via kidneys

Half Life (T1/2)

Distribution and/or elimination half life

Steady State

Amount administered is = to the amount eliminated. It takes 4-5 T1/2 to reach steady state

Loading Dose

Initial high does to rapidly achieve therapeutic concentrations

Onset

First clinical effects

Duration

Length of time drug works

Titration

Balancing drug dose against symptoms

Pharmacodynamics: What the drug does to the body

• Alter rate of synthesis: more/less NT

• Alter storage rate: more/less NT (leaky vesicles)

• Alter release: more/less release of NT

• Alter reuptake: more/less (Ex. SSRI’s block reuptake = more NT in synapse)

• Alter deactivation by enzymes: reduce action of enzymes that break down NT so there is more NT in synapse

• Block or mimic receptor site attachment: block and prevent attachment to receptors, mimic NT at the receptor site, may be allosteric regulation

Up and Down Regulation

Drug causes body to change # of receptor sites

• Up: increase # of receptors, most commonly due to decreased stimulation (E.g. receptors are blocked) or decreases in NT

• Down: decrease # of receptors, most commonly due to increased stimulation due to increased NT

Effects of drugs on receptors:

• Agonists

• Partial agonists

• antagonist

• partial inverse agonist

• inverse agonist

• Mimics NT by stimulating postsynaptic receptors

• Partially mimics NT

• Blocks receptor site

• Partially causes opposite reaction of NT

• Causes opposite reaction of NT

Efficacy

Degree to which drug works as intended

Potency

Amount of drug necessary to produce 50% of maximal response

ED 50

Effective dose 50; dose that produces desired effect in 50% of subjects

LD 50

lethal dose 50; dose that is lethal to 50% of subjects (animal studies)