of Principles Psychopharmacology psychopharmacology: the study of the effects of drugs on the nervous system and on behavior drug effect: the changes a drug produces in an animal's physiological processes and behavior -effects of cocaine Feeling of euphoria Excitement Reduced hunger Feeling of strength Dizziness Headache Movement problems Anxiety Insomnia Depression Hallucinations sites of action: the locations at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of the these cells drug: 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 must enter body, blood stream, carried to organ(s) they act on.. For us, CNS Pharmacokinetics pharmacokinetics: the process by which drugs are absorbed, distributed within the body, metabolized, and excreted Routes of Administration drug is dissolved in liquid intravenous (IV) injection: injection of a substance directly into a vein - hospital -heroin, amphetamines - fast acting - need increased care & skill intraperitoneal (IP) injection: injection of a substance into the peritoneal cavity - the space that surrounds the stomach, intestines, liver, and other abdominal cavities -cancer treatment longer half-lives of drugs - rapid, but not as fast as IV - most common for small laboratory animals intramuscular (IM) injection: injection of a substance into a muscle -arm, thigh, butt -absorbed into blood stream through capillaries that supply the muscle - for slow absorption, can be mixed with another drug that constricts blood vessels and retards the flow of blood subcutaneous (SC) injection: injection of a substance into the space beneath the skin -hormones -dissolved in oil preferred route - if the drug can be painful - only small amounts (too painful)
oral administration: administration of a substance into the mouth, so that it is swallowed -most common for humans -some can't be administered orally because of destruction by stomach acid or digestive enzymes or not absorbed from the digestive system into bloodstream sublingual administration: administration of a substance by placing it beneath the tongue -nitroglycerin angina (chest pain due to inadequate blood supply); causes blood vessels to dialate -absorbed into bloodstream by capillaries in mucous membrane that lines mouth intrarectral administration: administration of a substance into the rectum -drugs that may upset human's stomach inhalation: administration of a vaporous substance into the lungs -very rapid effects topical administration: administration of a substance directly onto the skin or mucous membrane -through nose = very rapid intracerebral administration: administration of a substance directly into the brain intracerebroventricular (ICV) administration: administration of a substance into one of the cerebral ventricles -widespread distribution -very rarely used in humans Distribution of Drugs Within the Body depot binding: binding of a drug with various tissues of the body or with proteins in the blood albumin: a protein found in the blood; serves to transport free fatty acids and can bind with some lipid-soluble drugs -drugs can also bind fat tissue, bones and muscle - some anesthetics; fat bind very well reducing their effect lipid solubility - more lipid soluble = more rapid effects Drug Effectiveness dose-response curve: a graph of the magnitude of an effect of a drug as a function of the amount of drug -reach a point of maximum effect -margin of safety between two different drugs therapeutic index: the ration between the dose that produces the desired effect in 50 percent of the animals and the dose that produces toxic effects in 50 percent of animals -obtained by administering varying doses of the drug to a group of lab animals -lower therapeutic index = more care taken in prescribing drug affinity: the readiness with which two molecules join together variation in effectiveness -different sites of action: brain versus damaged tissue -affinity of the drug with its site of action High affinity = produce effects at relatively low concentrations Effects of Repeated Administration tolerance: a decrease in the effectiveness of a drug that is administered repeatedly -heroin - drug users need to take more to have desired effect
-result of the body's attempt to compensate for the effects of the drug -compensatory mechanisms Receptors become less sensitive to the drug (decreased affinity) or receptors decrease in number Process that couples the receptors to ion channels in the membrane or to the production of second messengers -> repeated use, one or more steps in coupling process becomes less effective sensitization: an increase in the effectiveness of a drug that is administered repeatedly -cocaine - repeated use; more and more likely to produce movement disorders withdrawal symptom: the appearance of symptoms opposite to those produced by a drug when the drug is administered repeatedly and then suddenly no longer taken -tolerance -withdrawal symptoms are usually the opposite of drug -heroin - euphoria -withdrawal - disphoria Placebo Effects placebo: an inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug if a person thinks that a placebo has a physiological effectk, then administration of the placebo may actually produce that effect control groups - same "traumas" as noncontrol groups Sites of Drug Action most drugs affect behavior by affecting synaptic transmission antagonist: a drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell -e.g. decrease enzymes that synthesize NT agonist: a drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell -increase enzymes that synthesize NT Effects on Production of Neurotransmitters when a precursor is administered, rate of synthesis and release of neurotransmitter is increased -acts as an agonist when a drug inactivates a precursor, prevents neurotransmitter from being produced -acts as an antagonist Effects on Storage & Release of Neurotransmitter molecules of drug can bind with a particular site on transporter and inactivate it causing the synaptic vesicles to remain empty and therefore no neurotransmitter is released -antagonist can deactivate proteins that cause docked vesicles to fuse with the presynaptic membrane -antagonist can bind with these proteins and directly trigger release of neurotransmitter -agonist
Effects on Receptors direct agonist: a drug that binds with and activates a receptor -mimic the effects of NT -morphine binds certain kinds of opioid receptors- acts as agonist receptor blocker: a drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor direct antagonist: a synonym for receptor blocker noncompetitive binding: binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand indirect antagonist: a drug that attaches to a binding site on a receptor and interferes with the action of the receptor; does not interfere with the binding site for the principal ligand indirect agonist: a drug that attaches to a binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding site for the principal ligand -cocaine- blocs dopamine transporter - blocks reuptake presynaptic heteroreceptor: a receptor located in the membrane of a terminal button that receives input from another terminal button by means of an axoaxonic synapse; binds with the neurotransmitter released by the presynaptic terminal button drugs can block or facilitate presynaptic inhibition or facilitation, depending on whether they block or activate presynaptic heteroreceptors drugs that bind with and active dendritic autoreceptors will serve as antaonists drugs that bind with and block dendritic autoreceptors will serve as agonists, because they will prevent the inhibitory hyperpolarizations Effects on Reuptake or Destruction of Neurotransmitters molecules of the drug attach to the transporter molecules responsible for reuptake and inactivate them, thus blocking reuptake molecules of the drug bind with the enzyme that normally destroys the neurotransmitter and prevents the enzymes from working Neurotransmitters and Neuromodulators Acetylcholine acetylcholine -first NT to be discovered -all muscular movement is accomplished by the release of acetylcholine -adequately functioning memory Alzheimer's patients have depleted levels of Ach Some Alzheimer's treatments include drugs that inhibit the action of AChE -acetylcholinergic neurons located in the dorsolateral pons are responsible for eliciting most of the characteristics of REM sleep Where Ach is found in rat brain -locus coeruleus -caudate nucleus, putamen & nucleus accumbens -medial septum -nucleus basalis acetyl-CoA: a cofactor that supplies acetate for the synthesis of acetylcholine (CoA with an
acetate ion attached to it) -CoA (coenzyme A) is produced in mitochondria choline acetyltransferase (ChAT): the enzyme that transfers the acetate ion from acetyl coenzyme A to choline, producing the neurotransmitter acetylcholine botulinum toxin: an acetylcholine antagonist; prevents release by terminal buttons -antagonist (prevents release of Ach by terminals) black widow spider venom: a poison produced by the black widow spider that triggers the release of acetylcholine -agonist (triggers release of ACh) hemicholinium: a drug that inhibits the uptake of choline antagonist -acetylcholine drugs that deactivate AchE -used as insecticide - readily kill insects but not humans because our blood contains enzymes that destroy them neostigmine: a drug that inhibits the activity of acetylcholinesterase nicotinic receptor: an ionotropic acetylcholine receptor that is stimulated by nicotine and blocked by curare -ionotropic -muscle -neuronal muscarinic receptor: a metabotropic acetylcholine receptor that is stimulated by muscarine and blocked by atropine -metabotropic -5 muscarinic receptors -autonomic regulation -heart rate -CNS funtion -slower & more prolonged atropine: a drug that blocks muscarinic acetylcholine receptors -from belladonna plant -can be deadly -ophthalmologist use it, or a form of it, to dilate pupils curare: a drug that blocks nicotinic acetylcholine receptors -horrific death, victim stays awake until loss of consciousness -causes paralysis -used on tips of darts -used now in surgery to relax muscles, can still feel pain biosynthesis of acetylcholine -in the presence of the enzyme choline acetyltransferase (ChAT), the acetate ion is transferred from the acetyl-CoA molecule to the choline molecule, yileding a molecule of Ach and one of ordinary CoA. The Monoamines monoamine: a class of amines that includes indolamines such as serotonin and catecholamines
such as dopamine, norepinephrine, and epinephrine catecholamine: a class of amines that includes the neurotransmitters dopamine, norepinephrine, and epinephrine Dopamine dopamine (DA): a neurotransmitter; one of the catecholamines -behavior & cognition -motor activity -motivation & reward -regulates milk production -important in functions such as movement, attention, learning and the reinforcing effects of drugs that people tend to abuse -synthesis more complicated than that of Ach; precursor molecule is modified slightly, step by step, until it achieves its final shape L-DOPA: the levorotatory form of DOPA; the precursor of the catecholamines; often used to treat Parkinson's disease because of its effect as a dopamine agonist 3 important pathways: nigrostriatal system: a system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen) -movement mesolimbic system: a system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus -reward (reinforcement) mesocortical system: a system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex -short term memory, planning, problem solving Parkinson's disease: a neurological disease characterized by tremors, rigidity of limbs, poor balance, and difficulty in initiating movements; caused by degeneration of the nigrostriatal system -substantia nigra -treated with L-DOPA which is converted to dopamine in brain -> more dopamine released -MPTP model - glia convert to MPP+ AMPT: a drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of the catecholamines -DA antagonist reserpine: a drug that interferes with the storage of monoamines in synaptic vesicles -blocks the transporters in the membrane of vesicles of monaminergic neurons; empty vesicles -> no NT released -monoamine antagonist location of important groups of dopamine producing neurons -substantia nigra -ventral tegmental area D1 receptors - postsynaptic D2 receptors - both presynaptic and postsynaptic apomorphine: a drug that blocks dopamine autoreceptors at low doses; at higher doses, blocks
postsynaptic receptors as well methylphenidate: a drug that inhibits the reuptake of dopamine monoamine oxidase (MAO): a class of enzymes that destroy the monoamines: dopamine, norepinephrine, and serotonin deprenyl: a drug that blocks the activity of MAO-B; acts as a dopamine agonist chlorpromazine: a drug that reduces the symptoms of schizophrenia by blocking dopamine D2 receptors Norepinephrine norepinephrine (NE): one of the catecholamines; a neurotransmitter found in the brain and in the sympathetic division of the autonomic nervous system -aka noradrenaline -involved in fight or flight response -heart rate -released when a stressful event is encountered -alertness & arousal -also involved in reward system distribution of norepinephrine neurons in brain -locus coeruleus epinephrine: one of the catecholamines; a hormone secreted by the adrenal medulla; serves also as a neurotransmitter in the brain fusaric acid: a drug that inhibits the activity of the enzyme dopamine-B-hydroxylase and thus blocks the production of norepinephrine -doesn't effect the production of dopamine -noradrenergic antagonist moclobemide: a drug that blocks the activity of MAO-A; acts as a noradrenergic agonist -MAO-A destroys norepinephrine in terminals -noradrenergic agonist locus coeruleus: a dark-colored group of noradrenergic cell bodies located in the pons near the rostral end of the floor of the fourth ventricle axonal varicosity: an enlarged region along the length of an axon that contains synaptic vesicles and releases a neurotransmitter or neuromodulator idazoxan: a drug that blocks presynaptic noradrenergic alpha-2 receptors and hence acts as an agonist, facilitating the synthesis and release of NE Receptors for norepinephrine -adrenergic receptors - G-protein - coupled Alpha1 and alpha2 - excitatory & inhibitory Autonomic modulation Sex behavior Appetite B1,2,3 -increase responsiveness of neuron to excitatory input -increased vigilance -autonomic functions Serotonin
serotonin: an indolamine neurotransmitter; also called 5-hydroxytryptamine -plays a role in regulation of mood; in the control of eating, sleep, and arousal; and in the regulation of pain -serotonergic neurons are involved somehow in the control of dreaming -chemistry of well-being -inhibition of anger -aggression -body temp- thermoregulation -sleep -vomiting -sexuality -appetite serotonin synthesis -precursor - tryptophan -tryptophan hydroxylase adds hydroxyl group -5-HTP decarboxylase removes carboxyl group from 5HTP, resulting in 5-HT distribution of most important groups of Serotonin neurons in brain -raphe nuclei PCPA: a drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT -serotonin antagonist fluoxetine: a drug that inhibits the reuptake of -HT -serotonin agonist -SSRI fenfluramine -appetite suppressant - part of Fen-Phen -serotonin agonist 13 different serotonin receptors LSD: a drug that stimulates 5-HT(2A) receptors MDMA: a drug that serves as a noradrenergic and serotonergic agonist, also known as "ecstasy"; has excitatory and hallucinogenic effects serotonin syndrome: extremely high levels of serotonin can have toxic & potentially fatal effects -ecstasy can lead to the same symptoms
Amino Acids Glutamate glutamate: an amino acid; the most important excitatory neurotransmitter in the brain NMDA receptor: a specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; has several other binding sites AMPA receptor: an ionotropic glutamate receptor that controls a sodium channel; stimulated by AMPA kainate receptor: an ionotropic glutamate receptor that controls a sodium channel; stimulated by kainic acid metabotropic glutamate receptor: a category of metabotropic receptors that are sensitive to glutamate
AP5: a drug that blocks the glutamate binding site on NMDA receptors PCP: phencyclidine; a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist GABA GABA: an amino acid; the most important inhibitory neurotransmitter in the brain allylglycine: a drug that inhibits the activity of GAD and thus blocks the synthesis of GABA muscimol: a direct agonist for the GABA binding site on the GABA(A) receptor bicuculline: a direct antagonist for the GABA binding site on the GABA(A) receptor benzodiazepine: a category of anxiolytic drugs; an indirect agonist for the GABA(A) receptor -used to reduce anxiety, promote sleep, reduce seizure activity, and produce muscle relaxation anxiolytic: an anxiety-reducing effect GABA-A receptor: ionotropic and controls a chloride channel GABA-B receptor: metabotropic and controls a potassium channel Glycine glycine: an amino acid; an important inhibitory neurotransmitter in the lower brain stem and spinal cord strychine: a direct antagonist for the glycine receptor Peptides endogenous opioid: a class of peptides secreted by the brain that act as opiates enkephalin: one of the endogenous opioids naloxone: a drug that blocks opiate receptors Lipids endocannabinoid: a lipid; an endogenous ligand for cannabinoid receptors, which also bind with THC, the active ingredient of marijuana THC: the active ingredient in marijuana; activates CB1 receptors in the brain anandamide: the first cannabinoid to be discovered and probably the most important one FAAH: fatty acid amide hydrolase, the enzyme that destroys anandamide after it is brought back into the cell by anandamide transporters rimonabant: a drug that blocks CB1 receptors MAFP: a drug that inhibits FAAH; prevents the breakdown of anandamide AM1172: a drug that inhibits the reuptake of anandamide Nucleosides nucleoside - a compound that consists 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 caffeine: a drug that blocks adenosine receptors Soluble Gases nitric oxide (NO): a gas produced by cells in the nervous system; used as a means of
communication between cells nitric oxide synthase: the enzyme responsible for the production of nitric oxide