 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

 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

 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

 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

 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

 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

 An innocuous substance that has no specific physiological effect
 Often used for control groups in clinical drug studies

 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

 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)

 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)

 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)

 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

 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

 Catecholamines:
 Dopamine
 Norepinephrine
 Epinephrine
 Indolamines
 Serotonin




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

 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

 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

 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

 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

 At least 8 amino acids have been suggested to serve additionally as NT
 Glutamate
 GABA
 Glycine
 Peptides

 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

 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

 Inhibitory NT in SC and lower portions of brain
 Receptor is ionotropic, controls chloride channel, and thus produces inhibitory postsynaptic potentials
 Strychnine – glycine antagonist

 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

 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

 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

 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.