Chapter 4 Psychopharmacology

advertisement

Chapter 4

Psychopharmacology

Psychopharmacology

 The study of the effects of dugs on the nervous system and on behavior

 Q: What is a drug?

 A: “An exogenous chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses”

 Drug effect – the changes a drug produces in an animal’s physiological processes and behavior

 Sites of action – the locations at which molecules of drug interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells

Principles of Psychopharmacology

 Pharmacokinetics – the process by which drugs are absorbed, distributed within the body, metabolized, and excreted

 Routes of administration

 Intravenous (IV) injection

– directly into a vein; fastest route

Intraperitoneal (IP) injection

– into the peritoneal cavity – the space that surrounds the stomach, intestines, liver, and other abdominal organs

Intramuscluar (IM) injection

– into a muscle

 Subcutaneous (SC) injection – into the space beneath the skin

 Oral administration – admin into the mouth, so that it is swallowed; most common with humans

 Sublingual admin – placing substance beneath tongue

 Intrarectal admin

– into the rectum

Inhalation

– admin of a vaporous substance into lungs

 Topical admin – directly onto skin or mucous membrane

 Intracerebroventricular (ICV) admin – into one of the cerebral ventricles; to allow for widespread distribution in the brain

Principles of Psychopharmacology

 Distribution of drugs within the body

 Several factors determine the rate at which a drug in the bloodstream reaches sites of action within the brain:

Lipid solubility: BBB blocks only water-soluble molecules; thus, lipidsoluble molecules can pass into brain and distribute themselves

 Depot binding – binding of a drug with various tissues of the body or with proteins in the blood; causes drugs to not reach their site of action

 e.g. Albumin – a protein found in the blood that transports free fatty acids and can bind with some lipid-soluble drugs

 Can delay or prolong the effects of a drug

 Inactivation and Excretion

 Drugs do not remain in body indefinitely

 Most deactivated by enzymes

 Excreted by kidneys

Drug effectiveness

 The best way to measure the effectiveness of a drug is to plot a dose-response curve

 Do this by giving subjects various doses of a drug and plotting effects

 Increasingly stronger doses of a drug causes increasingly larger effects, until a maximum effect is reached

Drug effectiveness

 One measure of a drug’s margin of safety is its therapeutic index

 The ratio b/t the dose that produces the desired effect in 50% of the animals (ED 50) and the dose that produces toxic effects in

50% of the animals (LD 50)

 The lower the therapeutic dose is, the more care must be taken when prescribing the drug

 Why do drugs vary in effectiveness?

 Different drugs may have different sites of action

 Affinity – the readiness with which 2 molecules join together; drugs in

CNS produce effects by binding to receptors, transport molecules or enzymes

 The higher the affinity, the lower the concentration needed to produce effects

Effects of repeated administration

 In some cases, when a drug is administered repeatedly its effects will diminish, i.e. develop tolerance

 e.g. heroin, once taken regularly enough, individual will suffer withdrawal symptoms (opposite to those produced by a drug) when they stop taking it; caused by same mech as tolerance

 Tolerance is the body’s attempt to compensate for the effects of a drug

 In other cases, a drug will become more and more effective, sensitization

 Less common than tolerance

 Some drug effects show tolerance while others may show sensitization

 e.g. cocaine; repeated admin may causes more movement disorders, while euphoric effects may show tolerance

Placebo effects

 An innocuous substance that has no specific physiological effect

 Often used for control groups in clinical drug studies

Sites of drug action

 Most drugs affecting behavior do so by affecting synaptic transmission:

 Antagonist – a drug that opposes or inhibits the effects of a particular NT on the postsynaptic cell

 Agonist – a drug that facilitates the effects of a particular NT on the postsynaptic cell

Sites of drug action

 Effects on production of NT

 precursors can increase rate of NT synthesis and release; agonist

(Step 1)

 NT synthesis is controlled by enzymes; some drugs can inactive these enzymes, thus preventing NT production; antagonist (Step 2 in diagram)

 Effects of storage and release of NT

 transporter molecules that fill synaptic vesicles with molecules of NT can be blocked by a drug; thus, preventing NT to fill vesicles; antagonist (Step 3)

 Some drugs prevent release of NT from terminal button by deactivating proteins that help fuse vesicles to membrane; antagonist

(Step 5)

 some drugs can trigger release of NT; agonist (Step 4)

Sites of drug action

 Effects on receptors

 Some drugs can bind to postsynaptic receptors like NT

 Direct agonist – a drug that mimics the effects of a NT by binding with and acting on a receptor (Step 6)

Receptor blocker

– a drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor (Step 7)

 Some receptors have multiple binding sites; NT can bind to main sites, while other ligands can bind to alternative sites

 these alternative sites can be blocked by a drug, termed noncompetitive binding

 drug attached to alt site could prevent ion channels from opening; indirect antagonist

 drug attaches to alt site and facilitates opening of ion channel; indirect agonist

 some presynaptic membranes have autoreceptors that regulate amount of NT released; stimulation of autoreceptors causes less NT to be released

 drugs that activate autoreceptors act as antagonists  less NT released (Step 8)

 drugs that block autoreceptors act as agonists  more NT released (Step 9)

Sites of drug action

 Effects on reuptake or destruction of NT

 drugs can attach to transporter molecules responsible for reuptake and block it; thus NT in synapse for longer duration; agonist (Step 10)

 drugs can bind with enzyme that destroys NT, preventing enzyme from working; agonist (Step 11)

Neurotransmitters and Neuromodulators

 In the brain, most synaptic communication is accomplished by 2

NT:

 One with excitatory effects: glutamate

 One with inhibitory effects: GABA

 Most of the activity of local circuits of neurons involves balances b/t the excitatory and inhibitory effects of these chemicals

 Most other NT have modulating effects, i.e. they tend to activate or inhibit entire circuits of neurons that are involved in particular brain functions

Acetylcholine

 Primary NT secreted by efferent axons of the CNS

All muscular movement is accomplished by the release of ACh, also found in ganglia of ANS and at target organs of the parasymp branch of the ANS

Involved mostly in 3 systems in brain:

 Dorsolateral pons, basal forebrain, & medial septum

Composed of choline and acetate

 Synthesis:

 Acetyl-CoA and choline are combined by choline acetyltransferase (ChAT)

 2 drugs affect the release of ACh:

 Botulinum toxin – ACh antagonist; prevents release by terminal buttons; found in improperly canned food

 Black widow spider venom – stimulates release of ACh

Deactivated by acetylcholinesterase (AChE), which is present in the presynaptic membrane, and produces choline and acetate

Two types of ACh receptors:

 Nicotinic – ionotropic ACh receptor that is stimulated by nicotine and blocked by curare

 Muscarinic – metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine; slower action, longer lasting

Monoamines

 Catecholamines:

 Dopamine

 Norepinephrine

 Epinephrine

 Indolamines

 Serotonin

Dopamine (DA)

Produces both excitatory and inhibitory postsynaptic potentials, depending on postsynaptic receptor

Implicated in movement, attention, learning, and reinforcing effects of drugs

Synthesis of catecholamines:

1.

Tyrosine (obtained via diet) converted to L-

DOPA by tyrosine hydroxylase

2.

L-DOPA converted to DA by DOPA decarboxylase

3.

DA converted to

Norepinephrine (NE) by

DA

β-hydroxylase

Dopaminergic systems

 Nigrostriatal system – originates in the substantia nigra and terminates in the neostriatum (caudate and putamen); control of movement

 Mesolimbic system – originates in ventral tegmental area (VTA) and terminates in the nucleus accumbens, amygdala, & hippocampus; reward pathway

 Mesocortical system – originates in VTA and terminates in prefrontal cortex; formation of STM, planning, strategies

Dopamine

 Parkinson’s disease – a neurological disease caused by degeneration of DA neurons in nigrostriatal system; movement disorder with symptoms of tremors, rigid limbs, poor balance, difficulty initiating movements; individuals with Parkinson’s are given L-DOPA as Tx

 Several types of DA subreceptors: D

1

 Other drugs effecting DA and D

2 most common

 AMPT

 Reserpine

 Apomorphine

 Monoamine oxidase (MAO) – enzyme that destroys catecholamines

Norepinephrine (NE) & Epinephrine

 Aka Noradrenaline & adrenaline

 NE found in neurons in ANS

 Epinephrine produced by adrenal glands

 NE synthesis is finished in the vesicles of the terminal button

DA fills the vesicles, and is then converted to NE via DA

β-hydroxylase

Fusaric acid blocks activity of this enzyme and prevents production of NE without affecting DA

 Excess NE is destroyed by MAO, type A

 Cell bodies of most important NE system are in locus coeruleus

 Most noradrenergic cells release NE via axonal varicosities (beadlike swellings of the axonal branches) instead of terminal button

 Several types of subreceptors:

 β

1

& β

2 receptors, and α

1

& α all metabotropic with GPCRs

2 receptors: sensitive to both NE and epinephrine,

 In general, behavioral effects are excitatory

Serotonin (5-HT)

 Complex behavioral effects: regulation of mood, control of eating, sleep, and arousal, regulation of pain

Precursor is tryptophan, which is obtained through diet; converted to 5-HTP by the enzyme tryptophan hydroxylase; which is converted to 5-HT by the enzyme 5-HTP decarboxylase

Most 5-HT neurons found in raphe nuclei of the pons, medulla and midbrain and project to cerebral cortex; also innervate basal ganglia, dentate gyrus and hippocampal formation

5-HT release from varicosities rather than terminal buttons; 2 types

 D system – originates in dorsal raphe nucleus; thin axonal fibers that do not form synapses with other neurons (i.e. 5-HT serves as modulator here)

 M system – originates in median raphe nucleus; thick axonal fibers, form conventional synapses

 2 systems have different behavioral effects

 At least 9 different subreceptors

 Drugs that inhibit reuptake of 5-HT (SSRIs) most widely used clinically for mental disorders (e.g. fluoxetine, or Prozac)

 LSD and MDMA affects 5-HT systems

Amino Acids

 At least 8 amino acids have been suggested to serve additionally as NT

 Glutamate

 GABA

 Glycine

 Peptides

Glutamate

 Principle excitatory NT in the CNS

 Produced in abundance, no way to disrupt synthesis without disrupting other cellular activities

 4 types of receptors:

 NMDA – ionotropic, controls calcium channel that is normally blocked, and allows influx of calcium so it can serve as a 2 nd messenger; involved in forming new memories

 AMPA – ionotropic, controls sodium channel, stimulated by AMPA

 Kainate – ionotropic, controls sodium channel, stimulated by kainic acid

 Metabotropic glutamate receptor – sensitive to glutamate

 PCP – a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist; hallucinogenic drug

GABA

 Primary inhibitory NT in CNS

 Produced from glutamic acid by the enzyme glutamic acid decarboxylase (GAD)

 2 subreceptors:

 GABA

A

– have at least 5 different binding sites:

 primary for GABA, of which muscimol acts a agonist and bicuculline acts as antagonist

 2 nd binding site binds with drugs in benzodiazepines (e.g. Valium; anxiolytic

– anxiety-reducing)

3 rd binding site binds with barbituates

 GABA

B

Glycine

 Inhibitory NT in SC and lower portions of brain

 Receptor is ionotropic, controls chloride channel, and thus produces inhibitory postsynaptic potentials

 Strychnine – glycine antagonist

Peptides

 Neurons in the CNS release a large variety of peptides from all parts of the terminal button, not just active zone, allowing molecules to travel to other cells

 Best known family of peptides is the endogenous opioid family

(opioid refers to natural ligands, opiate to drugs)

 e.g. enkephalin

 3 types of opiate receptors:

 μ (mu)

 δ (delta)

 κ (kappa)

 Several neural systems activated: analgesic, fleeing and hiding behaviors, reinforcement

 Naloxone – opiate receptor antagonist

Lipids

 various substances derived from lipids can serve as NT

 Cannabinoids – endogenous ligand for receptors that bind with

THC, the active ingredient in marijuana

 2 types of cannabinoid receptors: CB

1 and CB

2

, both metabotropic

 THC produces analgesia, sedation, stimulates appetite, reduces nausea (used with cancer treatments), aids in glaucoma; reduces concentration and memory, alters visual and auditory perceptions, etc.

 Anandamide – natural ligand that binds to cannabinoid receptor

Nucleosides

 compound that consists of a sugar molecule bound with a purine or pyrimidine base

 Adenosine – serves as neuromodulator in brain, released when cells are short of fuel or oxygen

 Agonists have general inhibitory effects on behavior

 Caffeine is antagonist, thus producing excitatory effects

Soluble gases

 Neurons use at least 2 simple, soluble gases, nitric oxide (NO) and carbon monoxide (CO), to communicate with each other

 NO used as a messenger in many parts of the body, e.g. control muscle walls of intestines, dilates blood vessels in brain, etc.

Download