PYB260 2024W2_Lec2Neurobiol Reinf.pdf

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 2: Review of neurobiology & neurobiology of reinforcement PYB260 Melanie White, QUT  ACKNOWLEDGEMENT OF TRADITIONAL OWNERS QUT acknowledges the Turrbal and Yugara, as the First Nations...

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 2: Review of neurobiology & neurobiology of reinforcement PYB260 Melanie White, QUT  ACKNOWLEDGEMENT OF TRADITIONAL OWNERS QUT acknowledges the Turrbal and Yugara, as the First Nations owners of the lands where QUT now stands. We pay respect to their Elders, lores, customs and creation spirits. We recognise that these lands have always been places of teaching, research and learning. ​ QUT acknowledges the important role Aboriginal and Torres Strait Islander people play within the QUT community.​ CRICOS No.00213J Faculty of Health  Lecture Outline Models of drug taking behaviour Neurophysiology & neurotransmitters Conditioning, withdrawal and tolerance Diagnostic classification of substance-related disorders  Reflection Questions Think of a substance you or someone you know have developed a ‘habit’ for consuming, and answer these Qs: Which model of drug taking covered today do you think best explains your habit? Why? Which structures in your CNS are likely to be involved in reinforcement of that consumption? How do they interact with each other? What are some of the ways in which the substance might be affecting neurotransmitter systems (e.g., agonistic vs antagonistic actions) If I told you that substance is known to bind to ionotropic receptors, what does that tell you? How does that differ from binding to metabotropic receptors? Have you developed tolerance for the substance? What does that look like? Which type of tolerance covered today do you think best fits this example?  Why do people take drugs: Models of addictive behaviour  Drug use models Disease model Physical dependence model Hedonic dysregulation Positive reinforcement model Incentive sensitization theory  Disease model Definitions of addictive behaviour Compulsive (impaired control over use of the drug) & self-destructive (harmful consequences to user) What could account for such irrational behaviour? Moral bankruptcy? Sin? Abnormality…illness….disease  the disease model of drug taking behaviour Alcoholics Anonymous; alcoholism a disease by WHO (1951) + AMA (1953); “addiction” added to DSM in 1987 Predisposition theories & exposure theories  Disease model Strengths: may make accessing treatment easier rules that usually govern behaviour may not apply to drug taking, since this behaviour is abnormal can account for individual differences in response to drugs Limitations: “what is the disease?” (but, to what extent do we need to be able to identify the disease?) May reduce individual responsibility for behaviour An alternate model… 8  Physical dependence model “The state in which the discontinuation or reduction of a drug would cause withdrawal symptoms” (McKim & Hancock, 2013, p. 43) Withdrawal effects: Repeated drug administration → body learns to adjust to drug-induced changes Drug removed → body readjusts again (withdrawal) Withdrawal symptoms: usually opposite symptoms incurred by drug Can be stopped by re-administering the drug, or a similar drug (cross- dependence). drug may be re-administered to counteract withdrawal effects  Physical dependence model (cont.) Strengths: compatible with disease model; plausible explanation for addiction to drugs with withdrawal effects Limitations: cannot account for… individual differences as well as the disease model can; substances of addiction that show little to no withdrawal sickness; voluntary withdrawal (despite symptoms) Attempts to refine model: psychological dependence Circular reasoning Difficult to assess outward manifestations  Positive Reinforcement Model Drugs are self-administered because they act as positive reinforcers (operant conditioning) Positive reinforcer: “any stimulus that increases the frequency of a behaviour it is contingent on” (McKim & Hancock, 2013, p.108). Drugs that are self-administered by animals even in the absence of physical dependence/withdrawal (intragastric, intracranial, intraventricular, inhalation & oral routes)  Positive reinforcement model Limitations: Can the positive consequences of behaviour outweigh the costs (positive reinforcement paradox)? Circularity: drug is positive reinforcer because ↑ drug taking behaviour; then positive reinforcement cannot explain drug taking Strengths: accounts for drug-taking behaviour in absence of dependence/withdrawal; compatible with disease/physical dependence model; compatible with general models of reinforcement…(see next slide).  Classical & operant conditioning Principles that govern behaviour controlled by conditioning (classical & operant) apply to drug taking. E.g.,: 1. Reinforcing effects of drugs can be paired with other stimuli through conditioning. 2. An extinction phase can be demonstrated 3. Responses to operant reinforcement schedules can be elicited as predicted 4. Responses can be elicited following priming 5. Response patterns to substances that act as aversive stimuli are consistent with avoidance behaviours 6. A conditioned compensatory response can be demonstrated  Positive reinforcement & neurobiology Positive reinforcers activate motivational circuits may ↑likelihood of behaviour repeating “Reinforcement centre”/ motivational circuit (neuroanatomy) (McKim & Hancock, 2013, Fig 5-3, p.116 [Fig 5-2, p.102 in Hancock & McKim, 2018) Motivational circuit relies on activity of neurotransmitters (NTs) Incentive salience (natural & acquired) Neuroanatomy of motivation & reinforcement Motivation Control System of the Brain (McKim & Hancock, 2013, Fig 5-3) (Hancock & McKim, 2018, Fig 5-2)  Neuroanatomy of Motivation & Reinforcement “Wanting” vs. “Liking” in reinforcement “Pleasure centres” Drugs as reinforcers Stress (both present & past) & reinforcement Addiction Drugs alter (“hijack”) the functioning of the motivation system & behaviour  dopamine (DA) in mesolimbic dopamine system  Incentive Sensitization Theory (Robinson & Berridge) Repeated drug administration sensitization of mesolimbic DA response & motivation circuitry incentive salience of drug & associated stimuli  craving Drug craving – desire/urge to experience the effect(s) of a previously experienced psychoactive substance (‘wanting’) Strengths: accounts for the development of addiction over time/use explains craving triggers (associated stimuli that have acquired incentive salience) & priming effects  Hedonic Dysregulation & Adaptation Modern version of physical dependence model (e.g., Koob & le Moal) Allostatic process Repeated use &/or cessation of use  opponent process or compensatory response (depression) – disrupted NT functioning & neuroadaptation Contrast to homeostasis (changing/lowered set point)  tolerance to pleasurable (‘liking’) effect of drug &  insensitivity to pleasure Dysphoria; withdrawal mechanism of psychological dependence Can explain relapse long after physical withdrawal symptoms gone  Disruption of Brain Control Circuits A dysfunction in information processing & integration amongst multiple brain regions (Volkow et al.) Circuits that regulate: 1. “reward/saliency” (e.g., nucleus accumbens & ventral tegmental area) 2. “motivation/drive” (e.g., orbitofrontal cortex & motor cortex) 3. “memory/conditioning” (e.g., amygdala & hippocampus) 4. “inhibitory control/executive function” (e.g., dorsolateral prefrontal cortex & anterior cingulate gyrus) all interconnected circuits; receive input from DA neurons How do drugs have their effects? Neurophysiology  Neurophysiology Neurons: a refresher Neurons are responsible for receiving sensory information, integrating & storing information & controlling muscles & glands.  Neurophysiology Parts of the Neuron: a refresher Cell body (soma): contains the nucleus Nucleus: contains genetic information & controls metabolism of the cell Membrane: surrounds the cell; semipermeable; filled with cytoplasm Dendrites: fibres extending from axon; connect to other cells Axon: length of the neuron Axon hillock: place where axon is attached to cell body Myelin sheath: fatty substance surrounding the axon Terminal buttons: swelling at the end of the axon  The Neuron A typical nerve cell. Fig 4-1, McKim & Hancock (2013) Figure 4.1 A prototypical nerve cell. Fig 4-1, Hancock & McKim (2018) (Pinel, 2011) Figure 3.7  Lipid bilayer (McKim & Hancock, 2013) (Hancock & McKim, 2018)  Neurophysiology (cont.) Neurons are connected to each other via synapses Neurotransmitters (NTs): chemical messengers that operate between synapses NTs released at synaptic vesicles into synaptic cleft & occupy receptor sites on post-synaptic neuron Receptor site may depolarize or hyperpolarize post-synaptic cell Figure 4.2 Resting potential (Fig 4-2 Hancock & McKim, 2018)  Neurophysiology: APs & PSPs Stimulation of the axon Action Potential (AP) The breakdown & restoration of the resting potential Firing; all-or-none law Depolarization (EPSP) Moves toward zero & positive numbers Hyperpolarization (IPSP) Moves further away (more negative) from zero Threshold of excitation Voltage gated ion channels Stimulation of dendrites & cell body Postsynaptic potentials (PSPs): graded; excitatory (EPSP) vs. inhibitory (IPSP); summation across time & space Figure 4.3. The flow of ions during an action potential. (Fig 4-3 Hancock & McKim, 2018)  Neurophysiology: the synapse Action at a synapse NTs (“1st messengers”) – effects depend on receptor site binds to Receptors - ionotropic vs. metabotropic Second Messengers Special molecule is released into the postsynaptic cell Multiple mechanisms & durations of effect Figure 4.5 Ionotropic and metabotropic receptors (Fig 4-5 Hancock & McKim, 2018) (Pinel, 2011) Figure 3.7 Figure 4.6 The relation between a signal cascade Figure 4.6 Hancock & McKim (2018)  Neurophysiology: Neurotransmitters Acetylcholine (ACh) Monoamines: Catecholamines (CA) Epinephrine (E) Norepinephrine (NE) Dopamine (DA) Serotonin or 5-Hydroxytryptamine (5-HT) Adenosine Endocannabinoids (e.g., anandamine) Amino Acids: GABA(-), Glycine(-), Glutamate(+) Opioid Peptides Enkephalines or Endorphins  Figure 4.12 Actions of neurotransmitters (Fig 4-12 Hancock & McKim, 2018)  Neurotransmitter action Most drugs work by interfering with the chemical process that occurs at a synapse Drugs alter the synaptic process by: 1. Mimicking NTs & occupying their receptor sites 2.  activity of enzymes that create or destroy NTs 3. Altering NT reuptake 4. Altering the activity of a second messenger 5. Interfering with ion channels 6. Changing the amount of NT released  Figure 4.13 Mechanisms of drug effects. () () (Fig 4-13 Hancock & McKim, 2018)  Drug effects on NT: an illustration Acetylcholine (ACh) Acetylcholinesterase (AChE) - enzyme in synapse which normally breaks down Ach Drugs may interfere with AChE or with receptor sites Insecticides, Nerve Gases Cholinergic synapses Nicotinic Stimulated by nicotine Blocked by curare & Botox Muscarinic Stimulated by muscarine Blocked by atrophine & scopolamine  Plasticity of physiology & neurophysiology CNS is not static; changes make take place in the CNS in response to drug taking (e.g., ↑receptor sites, ↑sensitivity of receptors etc.) Such plasticity may account for another aspect of drug taking - tolerance  Tolerance Tolerance:  effectiveness (or potency) of drug usually resulting from repeated administrations; necessity of ↑ dose to maintain its effect Related concepts: cross-tolerance: tolerance to one drug diminishes the effect of another drug A special case: Acute tolerance & tachyphlaxsis: tolerance after one drug administration  How does tolerance work? Various mechanisms proposed to explain tolerance; must account for these important properties of tolerance: 1. tolerance develops & dissipates to different effects of drugs, at different rates* *a related concept (specific & general tolerance) 2. tolerance will only develop in a circumstance where a drug places a demand on the homeostatic mechanisms ** ** this is known as functional disturbances may be due to a combination of the following mechanisms…  Tolerance: Mechanisms Metabolic tolerance (aka ‘pharmacokinetic tolerance’): rate of metabolism ↑, usually due to ↑in enzyme used to break down the drug (enzyme induction) Physiological tolerance (aka ‘pharmacodynamic tolerance’): homeostasis is mechanism by which the body maintains a constant internal environment; can result in tolerance E.g., downregulation or upregulation of receptor action Behavioural tolerance: through experience with a drug organisms can learn to  behavioural effect of the drug (both through classical & operant conditioning)  Tolerance (cont.) Conditioned drug tolerance: environment drug is administered in can be a stimulus (CS) for the body’s effort to resist a drug  eliciting physiol. compensatory conditioned responses (CR) that  effect of drug/ ↑ tolerance Sensitisation (reverse tolerance): less common than tolerance, refers to ↑effects of a drug usually following repeat administrations Cross-sensitisation to other drugs  Identifying people with addictions: Diagnostic Criteria Diagnostic & Statistical Manual of Mental Disorders (DSM-IV- TR) Substance-related and addictive disorders DSM-5 Substance use disorder & substance-induced disorder (intoxication, withdrawal, & other substance/medication-induced mental disorders) Access online via library databases, “Psychiatry Online” International Statistical Classification of Diseases and Related Health Problems (ICD-11) https://icd.who.int/en  Substance use Substance Substance disorders intoxication withdrawal Alcohol X X X Caffeine X X Cannabis X X X Hallucinogens Phencyclidine X X Other X X hallucinogens Inhalants X X Opioids X X X Sedatives, hypnotics, or X X X anxiolytics Stimulants** X X X Tobacco X X Other (or unknown) X X X Adapted from DSM-V-TR Table 1 “Diagnoses associated with substance class” https://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425787 46  Conclusion At the end of this topic you should: Be able to define addictive behaviours Be familiar with models of drug-taking behaviour (including strengths & limitations) Understand basic neurophysiology & the role of neurotransmitters in mediating drug responses Be familiar with concepts such as dependence, withdrawal, & tolerance Have an understanding of DSM-V classification criteria for substance use disorder  Reflection Questions Think of a substance you or someone you know have developed a ‘habit’ for consuming, and answer these Qs: Which model of drug taking covered today do you think best explains your habit? Why? Which structures in your central nervous system are likely to be involved in reinforcement of that consumption? How do they interact with each other? What are some of the ways in which the substance might be affecting neurotransmitter systems (e.g., agonistic vs antagonistic actions) If I told you that substance is known to bind to ionotropic receptors, what does that tell you? How does that differ from binding to metabotropic receptors? Have you developed tolerance for the substance? What does that look like? Which type of tolerance covered today do you think best fits this example?  Reminder & further information Tutorials: This week (Tute 1, Week 2): Read first starter article (QUT Readings) by Giles et al. Next week (Tute 2, Week 3): read Tute 2 handout & the 6 tutorial caffeine readings on QUT Readings (if you have not already finished these): read & bring them to your second tute. Additional references/ Further info Textbook (7th or 8th editions) (particularly, Chapters 3, 4, & 5) DSM-V-TR ‘Substance-Related and Addictive Disorders’ accessed via Psychiatry Online library database (https://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425787 )