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Behavioral Pharmacological: Update University of North Carolina School of Medicine [email protected] History: Psychiatry, Neuropharmacologist or Alchemist 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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? 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 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 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? 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 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 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 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? 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