Transcript Chapter 4 lec 2
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Mind and Brain
Psychopharmacology
Chapter 4
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Chapter Preview
Principles of Psychopharmacology
Sites of Drug Action
Neurotransmitters and Neuromodulators
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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.
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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
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Figure 4.5 Drug Affects on Synaptic Transmission
Amino Acids Peptides Monoamines Acetylcholine
Neurotransmitters
Nucleosides Soluble Gases Lipids
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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)
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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
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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 REM sleep learning (basal forebrain) memory
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Figure 4.5 Drug Affects on Synaptic Transmission
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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
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Figure 4.5 Drug Affects on Synaptic Transmission
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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
Dopamine Norepinephrine Epinephrine
Indolamines
Serotonin
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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)
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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
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DA
Dopamine receptors Several different types All metabotropic 2 most common: D 1 receptors Exclusively postsynaptic D 2 receptors Found both presynaptically and postsynaptically
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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
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Figure 4.5 Drug Affects on Synaptic Transmission
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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
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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
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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.
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NE
Adrenergic receptors (all sensitive to NE and E) β 1 - and β 2 -adrenergic receptors α 1 - and α 2 -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
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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
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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-HT 1A-1B , 5-HT 1D-1F , 5-HT 2A-2C and 5-HT 3 all are metabotropic except the 5-HT ionotropic 3 receptor, which is 5-HT 3 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
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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
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Glutamate Amino Acids Glysine GABA
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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
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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.
2.
3.
4.
Metabotropic Glutamate Receptor – a category of metabotropic receptors that are sensitive to glutamate.
AMPA Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by AMPA; most common.
Kainate Receptor – an ionotropic glutamate receptor that controls a sodium channel; stimulated by kainic acid.
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.
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Figure 4.19 NMDA Receptor
Increased decreased Indirect antagonist 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 2 nd 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
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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
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GABA
GABA (gamma-aminobutyric acid) An amino acid; the most important inhibitory neurotransmitter in the brain. Two types of GABA receptors GABA A – ionotropic; controls a chloride channel Complex; contains at least 5 different binding sites GABA B – metabotropic; controls a potassium channel Can be both a postsynaptic receptor and a presynaptic autoreceptor
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Figure 4.20 GABA
A
Receptor
•Barbiturates, steroids and benzodiazepines all promote activity of GABA receptor (indirect agonists) •Picrotoxin inhibits activity of GABA receptor (indirect antagonist)
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Glycine
Glycine An amino acid; an important inhibitory neurotransmitter in the lower brain stem and spinal cord.
Glycine receptor Ionotropic; controls a chloride channel
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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
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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
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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.
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Lipids
Lipids
Endocannabinoids Endogenous ligand for cannabinoid receptors CB 1 and CB 2 Both are metabotropic CB 1 receptors found in brain (frontal cortex, anterior cingulate cortex, basal ganglia, cerebellum, hypothalamus and hippocampus; very low levels in the brainstem) CB 2 receptors found outside the brain, in cells of the immune system CB 1 receptors serve as presynaptic heteroreceptors
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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)
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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
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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!!!