The Chemical Bases of Behavior: Neurotransmitters and Neuropharmacology

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The Chemical Bases of Behavior Neurotransmitters
and Neuropharmacology
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4 The Chemical Bases of Behavior
Neurotransmitters and Neuropharmacology

• Many Chemical Neurotransmitters Have Been
  Identified
• Neurotransmitter Systems Form a Complex Array in
  the Brain
• Research on Drugs Ranges from Molecular Processes
  to Effects on Behavior (a focus by
  psychopharmacology)

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4 The Chemical Bases of Behavior
Neurotransmitters and Neuropharmacology

• Drugs Affect Each Stage of Neural Conduction and
  Synaptic Transmission (synapse pharmacology or
  neuropharmacology)
• Drugs That Affect the Brain Can Be Divided into
  Functional Classes
• Drug Abuse is Pervasive

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4 Many Chemical Neurotransmitters Have Been
Identified

• Neurochemistry focuses on the basic chemical
  composition and processes of the nervous system.
• Neuropharmacology is the study of compounds that
  selectively affect the nervous system.

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4 Many Chemical Neurotransmitters Have Been
Identified

• Criteria for neurotransmitters chemicals
  released onto target cells
• Substance exists in presynaptic axon terminals
  (precursor)
• synthesized in presynaptic cells
• released when action potentials reach axon
  terminals
• Receptors for the substance exist on postsynaptic
  membrane
• When applied, substance produces changes in
  postsynaptic potentials
• Blocking substance release prevents changes in
  postsynaptic cell
• Deactivation by enzyme or re-uptake transporter

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4 Many Chemical Neurotransmitters Have Been
Identified

• Types of neurotransmitters
• Amine neurotransmitters acetylcholine,
  dopamine, serotonin
• Amino acid neurotransmitters GABA, glutamate
• Peptide neurotransmitters
• Gas neurotransmitters

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4 Many Chemical Neurotransmitters Have Been
Identified

• Neurotransmitters affect targets by acting on
  receptors protein molecules in the postsynaptic
  membrane
• Ionotropic receptors are fast open an ion
  channel when the transmitter molecule binds
• Metabotropic receptors are slow when activated
  alter chemical reactions in the cell, such as a G
  protein system, to open an ion channel

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4 Many Chemical Neurotransmitters Have Been
Identified

• Receptor subtypes the same neurotransmitter may
  bind to a variety of subtypes, which trigger
  different responses
• DA1, DA2, DA3, DA4, DA5

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Figure 4.1 The Versatility of Neurotransmitters
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4 Many Chemical Neurotransmitters Have Been
Identified

• A ligand is a substance that binds to a receptor
  and has one of three effects
• An agonist initiates the normal effects of the
  receptor
• An antagonist blocks the receptor from being
  activated by other ligands
• An inverse agonist initiates an effect that is
  the opposite of the normal function

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4 Many Chemical Neurotransmitters Have Been
Identified

• Endogenous occurs naturally within the body
• Endogenous ligands substances that the brain
  produces (neurotransmitter)
• Exogenous introduced from outside the body
• in opiates, endorphin/enkephalin vs. morphine

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Co-localization or co-release occurs when
  nerve cells contain more than one type of
  neurotransmitter.
• Acetylcholine (ACh) was mapped by the enzymes
  involved in its synthesis.
• Cholinergic nerve cell bodies and projections
  contain ACh.

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Figure 4.2 Cholinergic Pathways in the Brain
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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Two types of ACh receptors
• Nicotinic most are ionotropic and excitatory
• Example muscles use nicotinic ACh receptors
  paralysis can be induced with an antagonist, such
  as curare
• Muscarinic are metabotropic and can be
  excitatory or inhibitory
• Muscarinic ACh receptors can be blocked by
  atropine or scopolamine to produces changes in
  cognition.

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Two main classes of monoamine neurotransmitters
• Catecholamines dopamine (DA), epinephrine,
  norepinephrine (NE)
• Indoleamines serotonin (5-HT), melatonin

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Dopamine (DA) is found in neurons in
• (1) The mesostriatal pathway originates in the
  midbrain, specifically the substantia nigra, and
  innervates the striatum
• - This pathway is important in motor control and
  neuronal loss is a cause of Parkinsons disease.
• (2) The mesolimbocortical DA pathway originates
  in the midbrain in the ventral tegmental area
  (VTA) and projects to the limbic system and
  cortex.
• - This pathway is involved in reward,
  reinforcement and learning abnormalities are
  associated with schizophrenia.

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Figure 4.3 Dopaminergic Pathways in the Brain
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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Norepinephrine (NE) is released in three
  brainstem regions
• Locus coeruleus (pons)
• Lateral tegmental system (midbrain)
• Dorsal medullary group
• NE is also known as noradrenaline cells
  producing it are noradrenergic

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Noradrenergic fibers from the locus coeruleus
  project broadly.
• The CNS has four subtypes of NE receptors all
  metabotropic.
• The NE systems modulate processes including mood,
  arousal, and sexual behavior.

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Figure 4.4 Noradrenergic Pathways in the Brain
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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Serotonin (5HT) cell bodies are mainly found in
  the raphe nuclei. Serotonergic fibers projecting
  from the dorsal raphe exert widespread influence.
• Serotonin is implicated in sleep, mood, sexual
  behavior, and anxiety.
• Antidepressants such as Prozac increase 5HT
  activity, with effects depending on which
  receptor subtype is affected.

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Figure 4.5 Serotonergic Pathways in the Brain
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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Amino acid transmitters
• Glutamate and aspartate
• excitatory (to generate EPSP)
• Glutamatergic transmission uses AMPA, kainate,
  and NMDA receptors.

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Glutamate also acts on mGluRs slower
  metabotropic receptors
• Excitotoxicity neural injury such as stroke may
  cause excess release of glutamate, which is toxic
  to neurons
• Astrocytes are involved in the uptake of
  glutamate from the synapses.

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Other amino acid transmitters
• Gamma-aminobutyric acid (GABA) and glycine
  inhibitory

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• GABA receptors are in 3 classes
• GABAA - ionotropic, producing fast, inhibitory
  effects
• GABAB - metabotropic, slow inhibitory effects
  through neurogliaform interneurons
• GABAC - ionotropic with a chloride channel
• GABA agonists, like Valium (a benzodiazepine),
  are potent tranquilizers to facilitate sleep
  anti-anxiety

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• Peptides act as neurotransmitters at some
  synapses, or as hormones
• Opioid peptides mimic opiate drugs such as
  morphine
• Peptides in gut (e.g. cholecystokinin, CCK)
• Peptides in spinal cord or brain (e.g. neural
  growth factor NGF)
• Pituitary hormones (e.g. oxytocin, ACTH)

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4 Neurotransmitter Systems Form a Complex Array
in the Brain

• The gas, nitric oxide (NO), differs from other
  neurotransmitters
• produced in locations other than axon terminals
  mainly in dendrites, and diffuses as soon as it
  is produced, rather than released
• diffused into the target cell and to activate
  cyclic GMP
• to serve as a retrograde transmitter by diffusing
  back into the presynaptic neuron

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Many drugs are ligands that act upon specific
  receptor molecules.
• Drugs may target one or a few receptor subtypes.
  (selectivity or specificity)
• Because receptor subtypes have different
  localizations and functions, drug actions can
  have widely varying effects. (?????,?????)

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• The binding affinity (or affinity) is the degree
  of chemical attraction between a ligand and a
  receptor.
• The efficacy (or intrinsic activity) is the
  ability of a bound ligand to activate the
  receptor.

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Figure 4.6 Using Binding Affinity to Compare
Drug Effectiveness
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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Agonists to activate the receptor and its
  function.
• Partial agonists produce a medium response
  regardless of dose.
• Competitive ligands are drugs that bind to the
  same receptor site as the neurotransmitter.
• A noncompetitive ligand binds instead to a
  modulatory site on the receptor.
• competitive vs. non-competitive antagonist (next
  slide)

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Figure 4.7 The Agonistic and Antagonistic
Actions of Drugs
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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• A dose-response curve (DRC) is a graph of the
  relationship between drug doses and the effects.
• The DRC is a tool to understand pharmacodynamics
  the functional relationship between drugs and
  their targets.

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• A DRC has a characteristic slanted S shape
• No response at low doses
• Maximal response adding more drug cannot
  produce any further response
• At very high doses receptors are saturated
• ED50 (effective dose 50) gives a half-maximal
  response

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Box 4.1 (A) Mind the Curves
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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Relative potency of two drugs can be compared by
  their ED50 values.
• A drug that has comparable effects at lower doses
  is more potent.
• Chemically related drugs congeners are
  compared this way.

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Box 4.1 (B) Mind the Curves
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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Drug efficacy is based on maximal responses, not
  doses.
• A partial agonist or antagonist has only moderate
  efficacy.

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Secondary Binding
• A nonmonotonic DRC is the result of very high
  doses after a point the effects begin to
  reverse or fluctuate
• The drug has saturated all of its high affinity
  sites and is beginning to act elsewhere on lower
  affinity sites

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• The therapeutic index of a drug measures its
  safety the separation between useful and toxic
  doses
• Compares ED50 with LD50 (lethal doses) or TD50
  (toxic doses)

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Box 4.1 (E) Mind the Curves
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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Drug tolerance can develop successive (in
  chronic) treatments have decreasing effects
• Metabolic tolerance organ systems become more
  effective at eliminating the drug
• Functional tolerance target tissue may show
  altered sensitivity to the drug

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Changes in numbers of receptors can alter
  sensitivity in the direction opposite to the
  drugs effects
• Neurons down-regulate in response to an agonist
  drug fewer receptors available
• They up-regulate in response to an antagonist.

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Cross-tolerance is tolerance to a whole class of
  chemically similar drugs.
• Withdrawal symptoms may be caused by drug
  tolerance and generally appeared in an abrupt
  stop for drug taking.
• Sensitization occurs when drug effects become
  stronger with repeated treatment.

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• The amount of drug that is bioavailable free to
  act on the target varies with route of
  ingestion.
• Duration of a drugs effect is determined by how
  it is metabolized.
• Biotransformation produces active metabolites
  that may produce side effects.

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4 Research on Drugs Ranges from Molecular
Processes to Effects on Behavior

• Pharmacokinetics refer to factors that affect the
  movement of a drug through the body.
• The blood-brain barrier tight junctions within
  the CNS that prevent the movement of large
  molecules can limit drug availability.

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4 Drugs Affect Each Stage of Neural Conduction
and Synaptic Transmission

• Presynaptic events are affected by drugs
• Inhibit axonal transport
• Prevent release of neurotransmitter
• Example botulism toxin prevents the release of
  ACh onto muscles

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4 Drugs Affect Each Stage of Neural Conduction
and Synaptic Transmission

• Neuromodulators affect either transmitter release
  or receptor response.
• Caffeine is an exogenous neuromodulator that
  blocks the effect of adenosine, an endogenous
  neuromodulator that normally inhibits
  catecholamine release.

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4 Drugs Affect Each Stage of Neural Conduction
and Synaptic Transmission

• Caffeine thus stimulates catecholamine release,
  causing arousal.
• Adenosine is normally released along with the
  catecholamines and acts on autoreceptors
  receptors on the same terminal that released it.

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Figure 4.8 Steps in Synaptic Transmission That
Are Affected by Drugs (Part 1)
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4 Drugs Affect Each Stage of Neural Conduction
and Synaptic Transmission

• Postsynaptic receptors can be blocked or
  activated by drugs.
• Prolonged transmitter receptor activity can
  alter behavior
• Cholinesterase inhibitors inhibit the breakdown
  of ACh at the synapse by the enzyme AChE, causing
  prolonged muscle contraction

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Figure 4.8 Steps in Synaptic Transmission That
Are Affected by Drugs (Part 2)
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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Antipsychotic (neuroleptic) drugsa class of
  drugs to treat schizophrenia
• Typical neuroleptics are selective dopamine D2
  anagonists.
• Atypical neuroleptics block serotonin receptors
  and may reduce negative symptoms of schizophrenia.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• 2 types of Antidepressants treat depression.
  (1/2)
• Monoamine oxidase inhibitors (MAOIs) prevent the
  breakdown of monoamines at the synapses.
• Accumulation of monoamines and prolonging their
  activity is a major feature of antidepressants.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• (2/2) Tricyclics antidepressant drugs increase
  norepinephrine and serotonin at the synapses by
  blocking their reuptake into presynaptic axon
  terminals.
• Selective serotonin reuptake inhibitors (SSRIs)
  like Prozac or Zoloft allow serotonin to
  accumulate in the synapses, with fewer side
  effects than tricyclics.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Anxiolytics, or tranquilizers, are depressants
  drugs that reduce nervous system activity.
• Benzodiazepine agonists act on GABAA receptors
  and enhance the inhibitory effects of GABA.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• GABA receptors have several binding sites, some
  that enhance and some that inhibit GABAs
  effects.
• Benzodiazepines bind at an orphan receptor no
  endogenous ligand has been found.
• Allopregnanolone, a steroid related to
  progesterone, as released under stress, is a
  candidate.
• Other neurosteroids (steroids produced in the
  brain) may act on GABAA sites.

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Figure 4.9 The GABAA Receptor Has Many Different
Binding Sites
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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Alcohols effects are biphasic an initial
  stimulant phase followed by a depressant phase.
• Alcohol activates GABAA receptors and increases
  inhibitory effects.
• This contributes to social disinhibition and loss
  of motor coordination.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Alcohol also stimulates dopamine pathways,
  causing euphoric effects.
• Alcohol abuse damages nerve cells especially in
  the frontal lobe, cerebellum hippocampus, yet
  some damage is reversible.
• Korsakoffs syndrome with thiamine deficiency
• Fetal alcohol syndrome is the result of pregnant
  women abusing alcohol, with permanent damage to
  the fetus.

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Figure 4.10 The Effects of Alcohol on the Brain
63
4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Alcoholism has a genetic component
• 20-50 of sons and 8-10 of daughters of
  alcoholics will eventually develop the disease
• Periodic overconsumption, or bingeing, may cause
  brain damage and reduces neurogenesis. (????,????)

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Opium contains morphine, an effective analgesic,
  or painkiller.
• Morphine and heroin are both highly addictive.
• These opiates bind to opioid receptors in the
  brain, especially in the locus coeruleus and the
  periaqueductal gray.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Endogenous opiates- peptides that bind to opioid
  receptors (µ, ?, d) and relieve pain- also are
  addictive
• Enkephalins
• Endorphins
• Dynorphins

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Marijuana is derived from Cannabis sativa its
  active ingredient is
  ?9-tetrahydrocannabinol (THC)
• Effects vary - include relaxation, mood
  alteration, stimulation, hallucination and
  paranoia
• Sustained use can cause addiction.

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Figure 4.13 An Indoor Marijuana Farm
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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• The brain contains orphan cannabinoid receptors
  to mediate the effects of THC and other
  compounds.
• Endocannabinoids (eg. anandamide)
• - homologs of marijuana produced in the brain
• - act as retrograde messengers and may influence
  the release of neurotransmitter from the
  presynaptic neuron

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Anandamide is an endocannabinoid with many
  effects
• Altered memory formation
• Appetite stimulation
• Reduced pain sensitivity
• Protection from excitotoxic brain damage
• Other endocannabinoids 2-arachidonyl-glycerol
  (2-AG), oleamide

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Stimulants increase nervous system activity.
• Nicotine from tobacco
• to increase heart rate, blood pressure,
  hydrochloric acid secretion, and bowel activity
• to activate nicotinic ACh receptors in the
  ventral tegmental area (VTA) of mesolimbic DA
  pathway
• functionally related to drug addiction
• excitatory action of nicotinic receptors in CNS
  as to that on the neuromuscular junction in PNS

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Leaves from the coca shrub alleviate hunger,
  promote endurance and enhance sense of
  well-being.
• Cocaine, the purified extract
• used as an local anesthetic
• increases of catecholamine stimulation
• to enhance the release to block the re-uptake
• highly addictive

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Crack cocaine is smoked and enters the brain more
  rapidly.
• Cocaine blocks monoamine transporters, especially
  dopamine slows reuptake of neurotransmitters,
  enhancing their effects
• Dual dependence is addiction to the effects of
  the interaction of two drugs, frequently seen in
  cocaine abuser

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Figure 4.15 Cocaine-Binding Sites in the Monkey
Brain
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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Amphetamine and methamphetamine are synthetic
  stimulants that resembles catecholamines in
  structure.
• They cause the release of neurotransmitters even
  in the absence of action potentials.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Short-term effects of amphetamine include
  alertness, euphoria and stamina (the enhanced
  power in physical mental).
• Long-term use leads to sleeplessness, weight
  loss, and schizophrenic symptoms.
• Cocaine- and amphetamine-regulated transcript
  (CART) - a peptide produced in the brain which
  may be involved in the pleasure sensations from
  the drugs

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Hallucinogens alter sensory perception and
  produce peculiar experiences.
• LSD (acid), mescaline (peyote), and psilocybin
  (magic mushrooms) have mainly visual effects.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Hallucinogens have diverse neural actions,
  including on the noradrenergic, serotonergic, and
  ACh systems.
• LSD resembles serotonin in structure and it acts
  as an agonist on 5-HT receptors, including in the
  visual cortex.

Albert Hofmann the father of LSD
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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Phencyclidine (PCP) or angel dust, is a
  dissociative drug it produces feelings of
  depersonalization and detachment from reality
• PCP as a NMDA receptor antagonist, indirectly
  stimulating dopamine release
• Its many side effects include combativeness and
  catatonia.
• PCP has been proposed as a chemical model for
  schizophrenia.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• Ketamine (Special K) is a less potent NMDA
  antagonist that works in the prefrontal cortex (?
  metabotropic act.)
• Like PCP it can produce transient psychotic
  symptoms, at high doses.

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4 Drugs That Affect the Brain Can Be Divided
into Functional Classes

• MDMA (Ecstasy) is a hallucinogenic amphetamine
  derivative its major actions are increases in
  serotonin levels (on 5-HT2 R) and changes in
  dopamine and prolactin levels
• Chronic ecstasy use produces persistent effects
  and damage to serotonin-producing neurons.

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Figure 4.17 Long-Term Effects of a Single Dose
of Ecstasy on the Monkey Brain
82
4 Drug Abuse Is Pervasive

• Substance-Related Disorders
• Dependence (addiction) is the desire to
  self-administer a drug of abuse criteria
  include patterns of consumption, craving, time
  and energy, and impact on ones life
• It is a more severe disorder than substance
  abuse, which is a pattern of use that does not
  fully meet the criteria for dependence.

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4 Drug Abuse Is Pervasive

• Models of drug abuse
• The Moral Model blames the abuser for a lack of
  moral character or a lack of self-control
• The Disease Model says the abuser requires
  medical treatment however, researchers have not
  been able to identify an abnormal condition in
  abusers

84
4 Drug Abuse Is Pervasive

• Models of drug abuse
• The Physical Dependence Model called the
  withdrawal avoidance model, says abusers use
  drugs to avoid withdrawal symptoms
• The Positive Reward Model says drug use is a
  behavior controlled by positive rewards or
  incentive, with no disease

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Figure 4.18 Experimental Setup for
Self-Administration of a Drug by an Animal
86
4 Drug Abuse Is Pervasive

• Many addictive drugs cause dopamine release in
  the nucleus accumbens.
• Some axons that terminate here originate in the
  ventral tegmental area (VTA) and are involved in
  the reward pathway.
• The addictive power of drugs may come from
  stimulating this pathway.

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Figure 4.19 A Neural Pathway Implicated in Drug
Abuse (Part 1)
88

Figure 4.19 A Neural Pathway Implicated in Drug
Abuse (Part 2)
89
4 Drug Abuse Is Pervasive

• Factors in susceptibility to addiction
• Biological sex, genetic predisposition
• Personal characteristics aggressiveness,
  emotional control
• Family situation family breakup, poor
  relationships, sibling drug users
• Environmental factors peer pressure, social
  factors

90
4 Drug Abuse Is Pervasive

• Environmental stimuli can become associated with
  the effects of drugs.
• Cue-induced drug use is the increased likelihood
  of using a drug because factors are present that
  were also present when the drug was last used.

91
4 Drug Abuse Is Pervasive

• Cravings that occur with environmental cues are
  mediated by the extracellular signal-regulated
  kinase (ERK) pathway.
• Orexin, a peptide associated with hunger, may
  also contribute to craving.

92
4 Drug Abuse Is Pervasive

• 6 Medications to treat drug abuse
• Drugs for detoxification benzodiazepines and
  drugs to help ease withdrawal symptoms
• Replacement treatment by agonists or analogs of
  the addictive drug these partially activate the
  same pathways, such as methadone or nicotine
  patches

93
4 Drug Abuse Is Pervasive

• Antagonists to the addictive drug block effects
  of the abused drug but may produce withdrawal
  symptoms
• Medications that alter drug metabolism like
  disulfiram (Antabuse), which makes drinking
  produce unpleasant side effects

94
4 Drug Abuse Is Pervasive

• Reward-blocking medications (DA receptor
  antagonist) block positive reward effects of
  the abused drug but may produce anhedonia a
  lack of all pleasurable feelings
• Anticraving medications reduce the appetite for
  the abused substance

95
4 Drug Abuse Is Pervasive

• Vaccines may one day prompt the immune system to
  produce antibodies to remove substances from
  circulation before they reach the brain.
• Viruses can help deliver antibodies across the
  blood-brain barrier and block a drugs effects.