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Behavioral Pharmacological:
Update
University of North Carolina School of Medicine
[email protected]
History: Psychiatry,
Neuropharmacologist or Alchemist
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We are but Dwarfs on the backs of giants
Galileo, Bacon/Descartes/William James
Instrumentality – what we know is useful
because it predict what will happen.
Reason is bane of science; experiment is the key;
Cogito ergo est
Pragmatist
Anthropomorphizing/just the behavior, Ma’am
“Modern” Science
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Evidenced based medicine- the shoulders;
Bacon is alive and well; Descartes is rolling over
Empiricism, categorical diagnosis, description
psychiatry; leave etiology to the Shamans
Inductive-deductive reasoning: do the most
recent findings explain the phenomenon
Pharmacogenomics; molecular genetics and
neurobiology- newer is better, or is it?
This presentation is not for sissies
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Behavioral models- can be autopsied and teach
us new things
We are a generation of reductionistsProgramming- the concept of timing, critical
periods and interactive specialization
Shiva and brain development- neurogenesisapoptosis; LTP/LTD- synaptic pruning;
Glymphatics, inflammatory autophhagy
Challenging Behaviors
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Disruptive social , aggressive, self-injurious, and
repetitive behaviors, fear-related behaviors
Functional behavioral analysis- ABCs,
operationalized, quantitative and qualitative data
Boundary between behavioral excesses and
deficiency states
Biopsychosocial, ethological factors
Challenging Behavior- Treatment
Issues
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Limited success finding drugs for specific
behaviors
Most challenging behaviors are extremely
heterogeneous conditions
Functional Behavioral Analysis is a critical step
but more information is needed
Relationship between brain function,
neurochemistry, and target behavior
Analysis of Functional Behavioral
Analysis
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Function: approach-avoidance, intensity of
drive, valence of reinforcement, arousal, positive
negative affective state
Antecedents: assessment of stimulus/setting,
pos/neg affective valence
Behaviors: careful subtyping
Consequences: ease of reinforcement; resistance
to extinction
Analysis of Function
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Function of behavior- arousal, reactivity,
motivational state, approach-avoidance,
autonomic regulation
Drive or craving, reward potential, hedonic drive
Neuroticism- negative, emotional reactivity
Behavioral inhibition, conflict
Escape behaviors-sensitivity, threshold, anxiety
tolerance, perception
Another Look at Antecedents and
Behavior
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Antecedents or trigger events, positive/negative
experience, setting, memory, conditioning
experiences, social factors
Classical conditioning (initiating)- CS/CR
impact motivation (escape); intensity of reward
potential (approach); Temperamental and
presence of psychiatric disorders
Fear conditioning- LTP (panic disorder)
Other Factors Affecting
Consequences
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Ease of conditioning, extinction, reversal
learning
Operant learning- valence of re-inforcer
Extinction- LTD (long term depression)
Extinction spurt or increased appetitive
behaviors
Multiple layers of conditioning- panic disorder
with agoraphobia
Behavioral Psychopharmacology
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Merges behavioral and pharmacological models
Neurobiology and neurochemistry of behavior
and learning
Look at the plasticity and changes in gene
expression due to “environmental” factors
Molecular genetics of some behavioral
phenotypes
SIB: A Diverse Collection of
Behaviors
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Topography, typology, intensity, frequency,
setting and trigger events
Functional Behavioral Analysis is a critical tool
but has limits
Relationship to genetic disorders- specific
topographies
Developmental models- do not always address
special vulnerabilities
SIB: Behavioral Pharmacological
Dissection
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Why do some people develop progressive SIB
when others in the same environment don’t?
Why does it persist in spite of pain, tissue
destruction?
What initiates and maintains this particular
typography?
What gets in the way of extinction- selfrestraint?
Behavioral Pharmacology of SelfInjurious Behaviors
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Complex relationship between SIB, behavioral
phenotypes, and environment
Gene expression is continually influenced by
environmental events and learning
Temperamental style influences helps shape life
experiences and learning environment
Think in terms of an ecosystem
Summary
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Behavioral pharmacology- neurobiological
mechanisms associated with behavioral modelsmotivation, reinforcement, extinction etc
Adds another layer of analysis to functional
behavioral analytic data; makes things more
complicated
D-cycloserine, fenobam, NAC, antiinflammatory drugs - new age of ideas
How to Approach Treatment
Nonresponders
Ideas on Drug Classification
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Challenging behavior- anti-aggressive drug
Syndrome specific- antidepressant or
antipsychotic
Mechanism specific- serotonin re-uptake inh. or
dopamine antagonist
Behavioral pharmacology- drug effects on
learning and types of conditioning
Basics of psychopharmacology
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Drug mechanisms- more complex than
originally described
Pharmacokinetics- how do the drugs get there;
genetic differences in rates
Pharmacodynamics- what the drugs do when
they get there; genetics of receptor variability
Pharmaco-genomics
Pharmacology of Learning
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Motivational states- reward potential (BFS),
inhibition (BIS)
Linkage to VTA-n accumbens: reward pathways
Septo-hippocampal system, memory circuitry,
LTP/LTD
MPF/orbital cortex- top down regulation
Attachment/social pathways
What exactly is a nonresponder?
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Wrong person, wrong diagnosis or learning
model, wrong drug or intervention
Incomplete functional behavioral analysis
Incomplete understanding of the bio-behavioral
issues
Drug issues- wrong dose; theory of drug effect
and connection between it and behaviors is
incomplete
Theories
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Intrinsic reinforcement- shift from positive to
negative maintenance strategies; what happens
to endorphins
Factors that trigger SIB- stress, urge to act,
balance between aggression and SIB when
restricted; craving and HPA axis
Problem with extinction- requires learning at a
molecular biological level, LTD;
Glutamate/NMDA activity; ACTH/AVP
Pharmacology of Learning
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Motivational states- reward potential (BFS),
inhibition (BIS)
Reward pathways
Memory circuitry, LTP/LTD
Top down regulation- extinction
Attachment/social pathways
What Does All This Mean?
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We need to think beyond medications as
syndrome or target behavior specific
We need to expand our concept of functional
behavioral analysis to include neurobiological
and molecular genetic input
We need to rethink our gene-environment;
behavioral-psychiatric shibboleths
Summary and Conclusions
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Don’t abandon any models, combine them
where you can, apply new syntheses to problem
cases first. Research Domain Criteria
Functional Behavioral Analysis- there is no black
box, no black slate
Genetic disorders- genes are blueprints not the
final product, think in transactional terms
Summary and Conclusions- cont’d
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Most psychopharmacological agents are not
really syndrome specific- the brain is too
complex
Theories of action change and are often either
wrong or incomplete
Drugs can affect gene function, some are being
applied to specific behavioral phenotypes
Summary and Conclusions- cont’d
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Target symptoms, challenging behaviors and
psychiatric disorders are final common pathways
We aren’t very good at treating core features, yet
Drugs effects on gene expression is a step
beyond simple neurotransmitter models
How Do We Do This?
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Look at our existing tools of analysis- how can
we adapt what we have
Keep up as best you can with the neurosciences
of developmental and genetic disorders
Take a careful look at programs that don’t work,
scatter plots, ethograms, and consider the
neurobiology of function