"We had two bags of grass, seventyfive pellets of mescaline, five sheets of highpowered blotter acid

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• "We had two bags of grass, seventy-five pellets
  of mescaline, five sheets of high-powered blotter
  acid, a salt shaker half-full of cocaine and a
  whole galaxy of multicolored uppers, downers,
  screamers, laughers... also a quart of tequila, a
  quart of rum, a case of beer, a pint of raw
  ether, and two dozen amyls. But the only thing
  that worried me was the ether... -HST

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Ch. 44Drug Reward and Addiction

• Drug dependence
• Drug abuse
• Reinforcing actions
• Drug reward
• Extended Amygdala
• Negative effects
• Neurochemical adaptation

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Drug Use in America

• 14.8 million Americans currently use illicit
  drugs
• 3.5 million dependent on illicit drugs (1)
• 8.3 million dependent on alcohol (1)
• 47 million current smokers (16)
• Population of the U.S. 291,500,000 (Source 2003
  World Population Data Sheet.)

• Source 1999 National Household Survey on Drug
  Abuse of the United States.

4
Drug dependence and addiction

• Compulsion to take a drug
• Inability to limit intake
• Changes in behaviour
• Development of tolerance

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Substance Abuse (harmful use of a drug)
Substance Dependence (Addiction)

• Tolerance
• Withdrawal
• Unsuccessful effort to cut back
• Spending a lot of time to get substance
• Trading social activities for substance
• Continued use despite medical reasons to stop

• Reoccurant use
• Inability to fulfill major obligations
• use under hazardous conditions
• legal problems
• Continued use despite social or interpersonal
  problems

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Reinforcement and Motivation

• Reinforcement process by which stimuli increase
  the probability of a subjects responding (ex. an
  emotional award for continued use)
• Motivation tendency to produce organized
  activity. (ex. withdrawal as motivation)

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4 Sources of Reinforcement

• 1. Positive (Pleasure)
• 2. Negative (Self-medicating)
• 3. Conditioned Positive (Habit)
• 4. Conditioned Negative (Habit)

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Neuroadaptive Processes

• Tolerance loss of an effect of a drug with
  repeated administration.
• Withdrawal Appearance of symptoms associated
  with the termination of chronic drug use.
• Sensitization the increased response to a drug
  that follows its repeated and intermittent
  presentation

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Behavioral Tests and Drug Reinforcement

• Predicts abuse in humans
• Behavorial tests
• Drug self-administration
• intercranial self-stimulation (ICSS)
• Place conditioning

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Drug Reinforcement
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Rats on drugs

• Rats adjust self
• Administered cocaine to
• keep dose stable
• and regular.
• With dopamine antagonists
• There is a decrease in the
• reinforcing potency of
• Cocaine. Rats then increase
• use of cocaine b/c more
• drug is needed to overcome
• antagonism

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Cocaine Dose-Effect
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Intercranial Self-Stimulation

• Electrical self-stimulation rewarding for humans
  animals
• Stimulation encourages self-administration of
  drug
• Hypothesis ICSS directly activates neuronal
  award circuits.
• Drugs of abuse
• ICSS more rewarding
• Decrease ICSS threshold

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• Drugs of abuse act on dopamine nerve terminals at
  the nucleus accumbens or at the cell bodies of
  the neurons in the VTA to activate the award
  system
• Dopamine reward ICSS behavior learned
• No Dopamine reward ICSS behavior not learned

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Place Conditioning

• Rats are treated by pairing distinct
  environmental cues with administration of a drug.
  
• Rats are later tested by being presented with an
  opportunity to spend time in the presence of cues
  paired with the drug or in the presence of cues
  not paired with the drug.
• Rats prefer time in environments paired with
  drugs classified as positive reinforcers.
• Avasive experience -- negative reinforcer.

Source (D. van der Kooy, 1987 Squire et al.,
2003)
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Drug Reward

• Midbrain and forebrain invol. in motivated
  behavior through connections of medial forebrain
  bundle (asc. desc. pathways monamine system).
• Medial forebrain bundle invol. Brain
  stimulation reward and natural reward.

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Principal Components of MFB

• Ventral tegmental area (VTA) A10 cell grp
• Basal forebrain (incl. nucleus accumbens,
  olfactory tubercle, frontal cortex amygdala)
• DA connection btwn. VTA basal forebrain
  (Mesolimbic DA System)
• Additional Components
• -- Opioid peptide systems
• GABA systems
• Serotonin systems

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Rat brain Neurochemical systems implicated in
the reinforcing effects of drugs of abuse
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Psychomotor stimulants Mesolimbic DA System

• Decreases thresholds for reinforcing brain
  stimulation increases drug use
• Increase availability of monamine nts
• By blocking reuptake, cocaine amphetamines
  increase synaptic availability of DA, NE 5HT
• Reinforcing effects depend on DA

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• Low doses of DA receptor agonist injected into
  the nucleus accumbens, amygdala or bed nucleus of
  the stria terminalis block cocaine and
  amphetamine self-administration in rats
• Neurotoxin induced lesions in the mesolimbic DA
  system cause a longterm decrease in
  cocaine/amphetamine use

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Reinforcing effects of Opiates

• Effects of opiate self-administration much like
• those for cocaine.
• Reinforcing effects of opiates involve opiate
• peptide mediated circuits.
• µ- opioid antagonists cause dose-dependent
• decreases in heroin use
• µ-knock-out mice on morphine show loss of reward
• and its analgesic effects.

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Intercerebral Opioids

• Opioid antagonists block heroin
  self-administration in nondependent rats when
  given into the VTA or nucleus accumbens.
• Microinjections lower thresholds for ICSS
• Effects dependent on mesolimbic DA function
• Opiates indirectly stimulate dopamine by
  activating other chemical pathways, which in turn
  increase dopamine activity.

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Brain on Nicotine

• Direct agonist at nAch receptors
• Nicotine stimulates dopamine neurons effect is
  less than with cocaine or amphetamine.
• Activates mesolimbic DA system opioid peptide
  system
• Antagonism of dopaminergic systems can block
  self-administration

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The brain on alcohol

• Reduces anxiety (anxiolytic properties)
• Does not interact with a specific receptor in the
  brain
• appears to stimulate the release of many
  neurotransmitters
• Effects dependent on DA, opioid and multiple nts
  (GABA, serotonin and glutamate)

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Tetrahydrocannibinol (Cannabis)

• Decreases ICSS reward thresholds produces a
  place preference in rats.
• Increases extracellular levels of dopamine in the
  nucleus accumbens and striatum

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Extended Amygdala

• the shell of the nucleus accumbens, the bed
  nucleus of the stria terminalis, the centromedial
  amygdala, and continuous cell columns in the
  sublenticular substanitia innominata.
• These structures may have similar functions
• Imp. for understanding how memories influence
  drug cravings relapse

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Effects of drugs on the extended amygdala
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Negative Affects

• Withdrawal
• Causes behavioral and physiological symptoms.
• Increases ICSS reward threshold in rats
• Effect is time-dependent

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Neurochemical Adaptation

• Extracellular DA and 5-HT levels in the nucleus
  accumbens decrease in motivational systems
  mediating acute drug reinforcement from cocaine,
  opiate, and alcohol.
• Increases are seen in stress systems involved in
  dependence ( CRF locus coeruleus)

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Drug Reinforcement Relapse

• Changes in drug reinforcement mechanisms suggests
  molecular mechanisms are long-lasting.
• Research being done looking at gene
  transcription cAMP response element binding
  protein (CREB) and Fos-related antigens (FRAs)
• Fos-B molecular switch may increase vulnerability
  to relapse.

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CRF in the nervous system

• Modulates behavioral responses to stress
• CRF antagonists reverse responses to stress.
• NE in limbic brain may also play a role in opiate
  withdrawal.
• Bed nucleus of stria terminalis may be invol. in
  feed forward CRF-NE-CRF system

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Theories drug use, abuse and dependence

• Sensitization theory incentive salience neural
  state produces craving. Caused by drug induced
  sensitization of mesolimbic DA system.
• Neuroadaptation theories (opponent process)
  tolerance due to the positive negative
  affective states.
• Allostasis above both contribute to hedonic
  state points. Maintain award function through
  change in brain reward mechanisms.

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Key Points

• Mesolimbic DA system imp. reinforcing actions
  (opiate, nicotine, alcohol)
• Opioid peptide systems imp. opiate, nicotine
  alcohol reinforcement.
• GABA, 5-HT, glutamate in extended amygdala imp.
  Alcohol reinforcement
• Abstinence decreases DA, 5-HT opioid peptide
  systems. Increases CRF, Locus coeruleus
• Sensitization hypersensitive DA brain stress
  mechanisms

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Ch. 45 Human Brain Evolution
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Topics

• Evolution Comparative Principles
• Cladistics Phylogenic Trees
• Homology Analogy
• Brain Evolution
• Origins of the Neocortex
• Mammal Brains
• Primate Brains
• Human Brains
• Brain Size

Taung child
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Evolution and Comparative Principles

• Three ways to study brain evolution
• 1. Fossil record
• 2. Comparative method
• 3. Mechanisms modes of brain development
  constraints placed on brain evolution.

KNM-ER 1470, Homo habilis
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Fossil Record

• Primate Hominid Endocasts
• Brain reorganization and elaboration
• Expansion of brain most evident in visual and
  association areas of the neocortex
• Expansion in areas involved w/ the hand
• Decreased reliance on sense of smell

A. africanus
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Neocortex and Brain Fissures

• Early primates had more neocortex than other
  early mammals
• David Van Essen (1997)
• Densely interconnected regions resist separation
  during growth form gyri.
• Poorly interconnected regions fold form sulci

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Comparative Method

• Examining brains of extant species
• Determine what features are shared
• Inherited from a common ancestor or evolved
  separately

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Cladistics

• An approach to classification that makes
  evolutionary interpretations based solely on
  analysis of certain types of homolgous (ie.
  derived characteristics modified from the
  ancestral condition)
• Has a time-component implies
  ancestor-dependent relationships.
• Makes hypothesis regarding ancestor-descendent
  relationships

Phylogenic Trees
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Mammalian Evolution
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Comparing brains
Human
Macque

• Brains of living mammals may not fully represent
  the ancestral condition
• Should be evaluated trait by trait b/c any
  feature could be ancestral or derived.

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Homology and Analogy

• Homologies similarities btwn. organism based on
  descent from a common ancestor
• Analogies Similarities btwn. organisms based on
  common function w/ no assumed common evolutionary
  descent.
• Homoplasy The separate evolutionary development
  of similar characteristics in different groups of
  organisms.

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Early Brain Evolution

• Theory Ancestors of vertebrates inverted their
  bodies so that the nervous system was dorsal
  rather than ventral as in anthropods

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Origins of the Neocortex

• Cerebral cortex (pallidum) covers deep parts of
  forebrain (telencephalon)
• Three parts
• Paleocortex (olafactory piriform)
• Archicortex (hippocampus subiculum)
• Neocortex (Isocortex)

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Changes from Past to Present

• Laminar organization of neocortex similar in most
  mammals.
• Most mammals have 6 layers (various roles). Early
  mammals had distinct areas.
• Diversified its neuron types, differentiated its
  laminar structure, alternated connections,
  changed in size, and changed the sizes of
  cortical areas.
• Split into specialized modular processing units
  cortical columns.

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Summary Origin of Neocortex

• Reptilian to Mammal appearance of the neocortex
• Early mammals not too brainy little neocortex
  (sensory
• motor areas).
• Brain organization varies, mostly through changes
  in
• neocortex
• Number of cortical areas have increased by
• addding new areas.
• Patterns of connections have changed.

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Evolution of Primate Brains

• 60-70 mya
• 3 main lines
• Prosimians (lemurs, lorises, bushbabies)
• Tarsiers (tarsier)
• Anthropoids (monkeys apes)

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Suborders of Primates

• Strepsirhini (moist nose and ancestral
  features) Includes all Prosimii, except tarsiers.
• Haplorhini -- (dry nose and reduced olafactory
  system) Includes all Tarsiers and Anthropoids
• Infraorders of suborder Anthropoidea
• Platarhini (New World Monkeys) Broad noses,
  dental for most 2-1-3-3, some have prehensile
  tails
• Catarrhini (Old World monkeys, apes, hominids)
  Narrow nose, dental 2-1-2-3, no prehensile tails.

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• The evolution and classification of primates

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Early Primate Features

• Early primates small-bodied, nocturnal,
  insectivore frugivores
• Adapted to rainforests by emphasizing vision and
  grasping (see and grab ripe fruit).
• Forward-facing eyes
• Opposable big toes/thumbs
• Digits w/ nails

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Early Primate Features

• Haplorhines 60 mya
• Shift nocturnal to diurnal
• Increased fruit eating
• Reduced dependence on smell, enhanced visual
  system, enlarged body size
• No tapetum lucidum
• Ratio of cones to rods increased
• Fovea (cones-enhance central visual acuity)
• Trichromatic or dichromotic vision
• Emphasis on social relations

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Early Primate Features -Anthropoids

• Diverged in Africa 2-30 mya
• Old World Monkeys and Apes
• Apes diverged 5-6 mya
• Chimps Bonobos
• Hominids

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Early Hominids

• Bipedal
• Small body
• Brain slightly larger than apes
• Adapted to dry grassland/savanna
• Emerged 2 mya
• First of Homo genus Homo habilis (2.0 mya to
  1.7 mya)
• Cranial est. 590 -710 cc

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Archaic Homo

• Homo erectus (Asia Africa, 1.7mya-
  27,000-53,000 ya)
• Cranial capacity 1000cc
• Archaic Homo sapiens emerged from an African pop.
  250,000 to 300,000 yrs ago.

Homo erectus, Java
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Neandertal and Homo

• Archaic homo split
• H. Neanderthalensis 130 kya - 35 kya
• H. sapiens 35kya
• Neandertal brains 1520cc
• H. sapiens 1400cc

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Evolution of apes and humans
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Brains of Early Primates

• Early evidence of brain organization
• Early primates exp. temporal occipital lobes
  (vision)
• Calcerine and Sylvian fissures others

Human brain and sm. Prosimian brain
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Primate Vision

• Galago visual system contains features common to
  all primates.
• Visual areas MT, modules in V1 (blobs) and V2
  (bands), sep. magnocellular parvocellular
  layers in LGN representation of sup.
  Colliculus in contralateral visual hemifield.
• Premotor areas present.Primitive somatosensory

Galago brain
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Early Anthropoid Brains

• Larger brains (more neocortex)
• High acuity diurnal vision
• S2 and PV no activating inputs from VP
• Expanded somatosensory system (incl 4 areas on
  ant. Parietal lobe
• 3a, 3b (w/in S1), 1 and 2

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Processing more serial than parallel in monkeys

• Somatosensory processing in prosimian primates
  and anthropoid primates

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Evolution of Hominid Brains

• Human brain increased 3-4 times in size
• Further increase in cortical areas
• Functional/anatomical asymmetries in 2 cerebral
  hemispheres
• Special areas for language and cognition
  (Wernickes and Brocas area in frontal lobe)
• Greater prefrontal contex
• Larger exp. of occipitoparietal infratemporal
  cortex.
• More neuronsmore connections

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Evolution of Hominid Brains
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Differences between Species. Aprimary
visual cortex in one cerebral hemisphere B
surface area of the neocortex
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Brain Size

• Brain increases mean increased dendrites axons
• Dendrites increase 4x in diameter
• axon length width is doubled
• Brain increases neurons increase
• As areas increase neurons become to local
  center-surround comparisons
• 2 things to increase connection
• Become more modular
• Reduce connections that require long thick axons

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Sources

• The Lycaeum. Picture (slide 2) Url http//
  lycaeum.org/
• The Vaults of Erowid (drug pictures)
• http//www.erowid.org/chemicals/cocaine/cocaine_im
  ages.shtml
• National Household Survey on Drug Abuse 1999.
  Url http//www.samhsa.gov/oas/nhsda.htm
• Squire, Larry R., Floyd E. Bloom, Susan K.
  McConnell, James L. Roberts, Nicholas C.
• Spitzer, and Michael J. Zigmond. Fundamental
  Neuroscience. Second Edition, New York
• Academic Press 2003, pp. 1127-1166.
• Thompson, Hunter S. 1998. Fear and Loathing in
  Las Vegas A Savage Journey to the Heart of the
• American Dream. New York Vintage Books.
  Illustrations by Ralph Steadman.
• van der Kooy, D. (1987), Place conditioning A
  simple and effective method for assessing
• the motivational properties of drugs. In M.A.
  Bozarth (Ed.), Methods of assessing the
• reinforcing properties of abused drugs (pp.
  229-240). New York Springer-Verlag.