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Psychopharmacology

Chapter 4

Mind and Brain

+Chapter Preview

Principles of Psychopharmacology

Sites of Drug Action

Neurotransmitters and Neuromodulators

+Routes of Administration

Intravenous (IV) Injection – injection of a substance directly into a vein.

Intraperitoneal (IP) Injection – injection of a substance into the peritoneal cavity, the space that surrounds the stomach, intestines, liver, and other abdominal organs.

Intramuscular (IM) Injection – injection of a substance into a muscle.

Subcutaneous (SC) Injection – injection of a substance into the space beneath the skin

Oral Administration – administration of a substance into the mouth so that it is swallowed.

Sublingual Administration – administration of a substance by placing it beneath the tongue.

+Routes of Administration Intrarectal Administration – administration of a substance

into the rectum.

Inhalation – administration of a vaporous substance into the lungs.

Topical Administration – administration of a substance directly onto the skin or mucous membrane.

Insufflation – sniffing drugs; contacts mucous membranes of the nasal passages; sniffing not same as inhalation!

Intracerebral Administration – administration of a substance directly into the brain.

Intracerebroventricular (ICV) Administration – administration of a substance into one of the cerebral ventricles.

Thinking about routes of drug administration..

What advantage is there to using a cannula to put the drug directly into the brain?

Copyright © 2006 by Allyn and Bacon

+Figure 4.5 Drug Affects on Synaptic Transmission

Neurotransmitters

Acetylcholine

Monoamines

Amino Acids

Peptides

LipidsNucleosides

Soluble Gases

+Neurotransmitters and Neuromodulators

Neurotransmitters have 2 general effects on postsynaptic membranes EPSP (depolarization)

Glutamate IPSP (hyperpolarization)

GABA, glycine (spinal cord and lower brainstem)

Most of the activity of local circuits of neurons involves balances between the excitatory and inhibitory effects of Glutamate and GABA (info transmitted within the brain) All sensory organs transmit information to the brain through

axons whose terminals release glutamate (except pain)

+Neurotransmitters and Neuromodulators

All other neurotransmitters have modulating effects rather than information-transmitting effects Secretion of Ach activates the cerebral cortex and facilitates

learning But the information that is learned and remembered is

transmitted by neurons that secrete glutamate and GABA Secretion of NA increases vigilance and enhances readiness

to act Secretion of 5-HT (serotonin) suppresses certain categories of

species-typical behaviors and reduces the likelihood that the animal acts impulsively

Secretion of DA (dopamine) activates voluntary movements (does not specify which movements) or reinforces ongoing behaviors

+ACh

Acetylcholine (ACh) Primary neurotransmitter secreted by efferent axons of the

PNS. All muscular movement accomplished by release of ACh ACh found in the ganglia of the autonomic nervous

system ACh found at the target organs of the parasympathetic

branch of ANS Major concentrations of ACh in the CNS include:

Dorsolateral Pons (role in REM sleep) Basal Forebrain (role in learning) Medial Septum (role in memory)

Figure 4.9 Acetylcholinergic Pathways in a Rat Brain

(basal forebrain)

REM sleep

learning

memory

+Figure 4.5 Drug Affects on Synaptic Transmission

+ACh

Nicotinic Receptor – an ionotropic ACh receptor that is stimulated by nicotine and blocked by curare. Muscle fibers, which must be able to contract rapidly,

contain the ionotropic nicotinic receptors Some nicotinic receptors found at axoaxonic synapses in

the brain, where they produce presynaptic facilitation (nicotine addiction)

Muscarinic Receptor – a metabotropic ACh receptor that is stimulated by muscarine and blocked by atropine. While the CNS contains both types of receptors, the

muscarinic receptors predominate

+Figure 4.5 Drug Affects on Synaptic Transmission

+Monoamines

The Monoamines A class of amines that includes indolamine, such as

serotonin; and catecholamines, such as dopamine, norepinephrine, and epinephrine.

See Table 4.1

Catecholamines Indolamines

Dopamine Serotonin

Norepinephrine

Epinephrine

+DA

Dopamine (DA) A catecholamine synthesized from L-DOPA. DA can produce both EPSP and IPSP depending on the

postsynaptic receptor. Functions:

Movement, attention, learning, reinforcing effects of drugs of abuse

Major CNS dopaminergic systems include (originate in midbrain): Nigrostriatal System (role in movement) Mesolimbic System (role in reinforcement/reward) Mesocortical System (role in short-term memory,

planning, and problem solving)

Figure 4.13 Dopaminergic Pathways in a Rat Brain

Nigrostrial = cell bodies in substantia nigra send axons to striatum = movement (parkinson’s)

Mesolimbic = VTA to limbic system including NA, AMYG, & HIP (NA important for rewarding effects of stimuli including drugs of abuse)

Mesocortical = VTA to prefrontal cortex (short-term memories, planning and problem solving)

+Parkinson’s Disease

Degeneration of DA neurons that connect the substantia nigra with the caudate nucleus

Characterized by: Tremors, rigidity of the limbs, poor balance, difficulty

initiating movements

Treatment: L-DOPA, DA precursor L-DOPA passes the BBB, unlike DA Increased DA to be released by surviving DA neurons

+DA

Dopamine receptors Several different types All metabotropic 2 most common:

D1 receptors

Exclusively postsynaptic D2 receptors

Found both presynaptically and postsynaptically

+DA

Agonists: Cocaine – blocks DA reuptake Amphetamine – causes transporter to run in reverse Methylphenidate (ritalin) – blocks DA reuptake

May be involved in Schizophrenia Hallucinations, delusions, disruption of normal, logical

thought Drugs – chlorpromazine blocks D2 receptors

+Figure 4.5 Drug Affects on Synaptic Transmission

+Catecholamines

Norepinephrine (NE) – one of the catecholamines a neurotransmitter found in the brain and in the

sympathetic division of the ANS. noradrenalin

Epinephrine – one of the catecholamines a hormone secreted by the adrenal medulla; serves also

as a neurotransmitter in the brain. adrenalin

+NE

Almost every region of the brain receives input from noradrenergic neurons

The cell bodies of the most important noradrenergic system are located in the locus coerulus

Locus Coeruleus (LC) – a dark-colored group of noradrenergic cell bodies located in the pons near the rostral end of the floor of the fourth ventricle.

Figure 4.16 Noradrenergic Pathways in a Rat Brain

Increased vigilance, attentiveness to events in the environment

+NE

Most neuron that release NE do not do so at terminal buttons but through axonal varicosities

Axonal Varicosities – beadlike swellings of the axonal branches, contains synaptic vesicles and releases a neurotransmitter or neuromodulator.

+NE

Adrenergic receptors (all sensitive to NE and E) β1- and β2-adrenergic receptors

α1- and α2-adrenergic receptors

All are metabotropic, coupled to G proteins that control production of second messengers

All are found in various organs in addition to the brain Adrenergic receptors produce both excitatory and inhibitory

effects but, in general, the behavioral effects of NE release are excitatory

+5-HT

Serotonin (5-HT) An indolamine neurotransmitter; also called 5-

hydroxytryptamine. Behavioral effects are complex

Regulation of mood Control of eating, sleep and arousal Regulation of pain Dreaming

Most important clusters of serotonergic cell bodies are found in the dorsal and medial raphe nuclei

Figure 4.18 Serotonergic Pathways in a Rat Brain

+5-HT

Like NE, 5-HT is released from varicosities rather than terminal buttons

There are least 9 different types of 5-HT receptors 5-HT1A-1B, 5-HT1D-1F, 5-HT2A-2C and 5-HT3

all are metabotropic except the 5-HT3 receptor, which is ionotropic

5-HT3 receptor controls a chloride channel, which means it produces IPSPs

Drugs that inhibit the reuptake of 5-HT (SSRIs) treat mental illness Fluoxetine – treats depression

Fenfluramine – treats obesity

+5-HT

Several hallucinogenic drugs produce their effects by interacting with 5-HT transmission

LSD – distortions of visual perceptions direct agonist for 5-HT2A

MDMA (ecstasy) – NE and 5-HT agonist Excitatory and hallucinogenic effects Causes NE and 5-HT transporters to backwards Can damage 5-HT neurons and cause cognitive deficits

+

Amino Acids

Glutamate

GABA

Glysine

+Glutamate

Glutamate An amino acid; the most important excitatory

neurotransmitter in the brain. In addition to producing PSPs by activating postsynaptic

receptors, glutamate (and GABA) have direct excitatory and inhibitory effects on axons; they raise or lower the threshold of excitation, thus affecting the rate at which action potentials occur

+Glutamate

Glutamate receptors 4 major types of glutamate receptors: 3 are ionotropic and

named after the artificial ligands that stimulate them. The other is metabotropic (about 8 different subtypes)

1. Metabotropic Glutamate Receptor – a category of metabotropic receptors that are sensitive to glutamate.

2. AMPA Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by AMPA; most common.

3. Kainate Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by kainic acid.

4. NMDA Receptor – a specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; contains at least 6 different binding sites.

+Figure 4.19 NMDA Receptor

4 binding sites on exterior and 2 binding sites deep in ion channel•When channel is open both Na and Ca ions move inside the cell, causes depolarization•Ca also serves as 2nd messenger and activate enzymes important for learning and memory•Must also have glycine binding for channel to open•Also Mg ion must not be attached to Mg binding site

•Mg repelled if membrane is partially depolarized

•Need glutamate & depolarization•Voltage and NTS-dependent ion channel

decreased

Increased

Indirect antagonist

+Glutamate

PCP – angel dust PCP, when attached to its binding site, prevents Ca from

passing into the ion channel Not a natural ligand (not produced in the brain)

Alcohol serves as an antagonist of NMDA receptors

+GABA

GABA (gamma-aminobutyric acid) An amino acid; the most important inhibitory

neurotransmitter in the brain. Two types of GABA receptors

GABAA – ionotropic; controls a chloride channel

Complex; contains at least 5 different binding sites GABAB – metabotropic; controls a potassium channel

Can be both a postsynaptic receptor and a presynaptic autoreceptor

+Figure 4.20 GABAA Receptor

•Barbiturates, steroids and benzodiazepines all promote activity of GABA receptor (indirect agonists)•Picrotoxin inhibits activity of GABA receptor (indirect antagonist)

+Glycine

Glycine An amino acid; an important inhibitory neurotransmitter

in the lower brain stem and spinal cord. Glycine receptor

Ionotropic; controls a chloride channel

+Peptides

Peptides 2 or more amino acids linked together by peptide bonds Released from all parts of the terminal button, not just

from active zone (only portion released into synaptic cleft Others act on receptors belonging to neighboring cells Most serve as neuromodulators; but some act as

neurotransmitters Once released, they are destroyed by enzymes (no re-

uptake or recycling) Sometimes co-released with a ‘classical’ neurotransmitter

+Peptides

Peptides Endogenous Opioids

A class of peptides secreted by the brain that act like opiates (opium, morphine, heroin). Enkephalin – one of the endogenous opioids.

Opiate receptors At least 3 different types: μ(mu), δ(delta) and

κ(kappa)

* Opioid refers to endogenous chemicals and opiates refers to drugs

+Peptides

Activation of opiate receptors Analgesia Inhibits species-typical defensive response such as

fleeing and hiding Simulates a system of neurons involved in

reinforcement (reward)

Naloxone – a drug that blocks opiate receptors; reverse opiate intoxication.

+Lipids Lipids

Endocannabinoids Endogenous ligand for cannabinoid receptors CB1 and CB2

Both are metabotropic CB1 receptors found in brain (frontal cortex,

anterior cingulate cortex, basal ganglia, cerebellum, hypothalamus and hippocampus; very low levels in the brainstem)

CB2 receptors found outside the brain, in cells of the immune system

CB1 receptors serve as presynaptic heteroreceptors

+Endocannabinoids

Binds with THC, the active ingredient of marijuana. THC

Analgesia, sedation, simulates appetite, reduces nausea (cancer drugs), relieves asthma attacks, decreases pressure in eye (glaucoma), reduces symptoms of certain motor disorders

Interferes with concentration and memory, alters visual and auditory perception, and distorts perceptions of the passage of time

Anandamide – the first cannabinoid to be discovered.

2-arachidonyl glycerol (2-AG)

+Nucleosides

Compounds that consist of a sugar molecule bound with a purine or pyrimidine base. Adenosine – a nucleoside; a combination of ribose and

adenine; serves as a neuromodulator in the brain. Adenosine receptors are coupled to G proteins and open

potassium channels (IPSP) Caffeine – a drug that blocks adenosine receptors.

Prolonged use of caffeine leads to a moderate amount of tolerance

Withdrawal symptoms – headaches, drowsiness, difficulty concentrating

Caffeine does not produce compulsive drug-taking behaviors

Lab animals will not self administer caffeine

+Soluble Gases

Soluble Gases NO and CO

Nitric Oxide (NO) – a gas produced by cells in the nervous system; used as a means of communication between cells. Released by diffusion as soon as it is produced Triggers production of second messengers (cyclic GMP) in

adjacent cells

Functions: Control of muscles in the wall of the intestines Dilates blood vessels in brain Stimulates the changes in blood vessels that produce penile

erections May play a role in learning

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Table 4.4!!!