RewardAddiction2022 (1).pptx

Neurobiology and Neurochemistry of Reward and Addictive Behaviours The presentation is for personal use only and must not be copied or used outside of BSMS Dr Natasha Sigala [email protected] Module 202 Neuroscience & Behaviour 1 Outline and Learning Outcomes Drug use and harm. Dependence, tole...

Neurobiology and Neurochemistry of Reward and Addictive Behaviours The presentation is for personal use only and must not be copied or used outside of BSMS Dr Natasha Sigala [email protected] Module 202 Neuroscience & Behaviour 1 Outline and Learning Outcomes Drug use and harm. Dependence, tolerance and neuroplastic changes. Metabotropic receptors and intracellular signalling. The role of neurotransmitter pathways in addictions. Commonly abused drugs By the end of this lecture, the successful student should be able to: Describe the pathway of reward in the brain Describe the mechanism of action of common drugs of abuse Select an appropriate medication for the treatment of alcohol or opiate dependence 2 Addiction / substance dependence : A persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual. Both physical and psychological. 3 Withdrawal symptoms: Negative physiological and emotional features that occur when the drug is not taken. Different for each drug of abuse, but generally opposite to positive experience induced by the drug. 4 Tolerance: Diminished response to the effects of a given amount of drug following repeated exposures to the drug. This implies that increasingly larger doses of the drug are required to induce the same behavioural effect. 5 Where do drugs act in the brain? Drugs hijack the natural reward system Mesolimbic system Mesocorticolimbic pathway Mesocortical system (reward & reinforcement, provides stimulus salience) Addiction also involves: PFC (impulsiveness, decision making, self monitoring) Amygdala Hippocampus Nigrostriatal system, control of movement Hyman, Malenka,& Nestler, 2006, Ann Rev Neurosci Anticipation of reward recruits NAcc Knutson et al. 2001 Reward: $0.20, $1, $5 Punishment: -$0.20, $1, -$5 Experimental conditions: Anticipation of a. large vs. small reward b. reward vs. no outcome c. large vs. small punishment d. punishment vs. no outcome DA as an “error” or “learning” signal Instrumental conditioning DA as an “error” or “learning” signal Schultz, Dayan,& Montague, 2007, Science DA as an “error” or “learning” signal Schultz, Dayan,& Montague, 2007, Science DA as an “error” or “learning” signal The reinforcement system is activated by unexpected reinforcing stimuli, and by presence of reward relative to its prediction. Instrumental behaviours. Schultz, Dayan,& Montague, 2007, Science This response relates to learning Unpredictable stimulus • Nucleus Accumbens Predictable stimulus • Temporal lobe Berns G S et al. J. Neurosci. 2001;21:2793-2798 Functions of the Reinforcement System • • (from Carlson, 9th Ed) Detect reinforcing stimulus • Recognise something good has just happened • Time to learn Strengthen neural connections • Between neurons that detect the stimulus and the neurons that produce the instrumental response • Long term potentiation The mesocorticolimbic dopamine system Dopamine neurons project from the VTA to the Nacc and PFC Hyman & Malenka, 2001, Nat Rev Neurosci Mesocorticolimbic dopamine system Pathway for reward and reinforcement Food Natural reinforcers e.g. Extracellula r DA released in NAcc Sex Addictive drugs activate this system 15 Mesocorticolimbic dopamine system Behaviours activating system are reinforced More likely to be repeated Addictive drugs cause more powerful and reliable activation than natural rewards they hijack the system Blockade of DA in this region attenuates most measurable reinforcing and rewarding effects of addictive drugs 16 This dopaminergic response is a normal reaction The mesolimbic system will be activated in response to many stimuli – central to motivation 17 Common drug effects on DA system All drugs have effect on DAergic system Though through different mechanisms – e.g. Drug Action Psychostimula nts Direct action on DAergic neurons in NAcc Opiates Indirectly – inhibit GABAergic interneurons in VTA = disinhibition of VTA DA neurons Alcohol Disinhibition of VTA DA neurons Nicotine Increases Nacc DA directly and indirectly, stimulates nicotinic cholinergic receptors on 19 Emotional Dependence (e.g. psychomotor stimulants) Compensatory changes in VTA / NAcc to lower DA transmission Inhibits VTA neuron firing and NAcc DA release Less DA release in NAcc In absence of drugs boosting DA function, not enough DA for natural rewarding stimuli - anhedonia, dysphoria, anxiety on withdrawal 20 Drugs increase DA release in the NAcc Drug taking is reinforced But how do we get addicted? Tolerance - diminishing effect of drug after repeated administration - need more drug to get the same effect HOMEOSTATIC CHANGES – NEURONAL ADAPTATIONS Dependence - physical or emotional - adaptive state - homeostatic response to repeated drug administration - unmasked by withdrawal Sensitization - repeated administration elicits escalating effects - effect of psychostimulants (used in animal models) ASSOCIATIVE LEARNING PROCESSES – SYNAPTIC PLASTICITY Addiction - compulsive taking - craving and relapse - persistent for many years 21 Cocaine and amphetamine – DA agonists Potentiate monoaminergic transmission by inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) reuptake transporters • Cocaine blocks and inhibits transporter to prolong pool of extracellular DA • Amphetamine reverses transporter to increase extracellular DA levels Action at dopamine transporter (DAT) most directly related to reinforcing effects Feelings of euphoria etc. through activation of this pathway or actions at transporters located elsewhere Cocaine and amphetamine extracellular DA in NAcc 22 23 Cocaine and amphetamine have different actions Though similar net effect -> Increased synaptic DA Hyman, Malenka,& Nestler, 2006, Ann Rev Neurosci Binding sites of cocaine following acute administration Striatum: contains the nucleus accumbens Fowler et al (1989) Synapse 4: 371377 Cocaine and amphetamine Effects: Psychotic behaviour (Evidence DA involvement in the positive symptoms of schizophrenia) Adverse long-term effects on the brain, e.g. DA transporters / terminals Cellular and molecular changes that promote dysregulation, e.g. increased activity of VTA tyrosine hydroxylase, CREB, GluR1 (AMPA) Hypofrontality Increased excitatory strength 24 hours after injection Hyman, Malenka,& Nestler, 2006, Ann Rev Neurosci • All drugs of abuse - significant increase in the AMPA/NMDA ratio • An increase in basal excitatory synaptic strength. • Neuronal basis of many forms of learning • One injection – changes persist for 5 days • Animal receives injections for 2 weeks – changes persist in VTA 27 Fewer D2 receptors in addiction Decreased dopamine (D2) receptors in cocaine addict The dopamine system central to conditioning and motivation Changes above likely responsible for reduced sensitivity to natural rewards that develops with addiction. Associative Learning - what makes drugs addictive? “cells that fire together wire together” Coincident firing between sensory pathways and the mesocorticolimbic pathway will induce LTP and strengthen synaptic connections Reminder – LTP = Long Term Potentiation • A persistent strengthening of synapses based on recent patterns of activity • Used to explain memory Sites of LTP Associative learning cont. Potential sites for LTP Glutamatergic synapses on reciprocal connections between NAcc, VTA, cortex, hippocampus and amygdala Thus sensory information, people, places, emotions etc. present at the time when drug induced DA release occurs will become associated with taking the drug 30 So: take cocaine In this environment And nightclubs become associated with cocaine use Clinical relevance? Highest risk of relapse will be if returns to nightclub Increase in cravings etc. 31 Dopamine enhances Long Term Potentiation Dopamine at D1 receptor (Gs coupled) adenylyl cyclase - cAMP - PKA - modifies glutamatergic transmission allowing LTP - CREB mediated gene transcription and new protein synthesis (steps in late phase LTP) - synaptic remodelling - increased spines and dendritic branches - long term molecular and cellular changes remain months after abstinence - memories in these pathways may trigger relapse years later 32 Opiates (e.g. morphine and heroin) • Action: • endogenous opioid receptors (Gi coupled) • Inhibitory - decrease adenylyl cyclase activity - lead to open K+ channels, close Ca2+ channels • Different receptor subtypes (m, k, d) • Most of morphine’s analgesic and rewarding properties are through actions at m (mu) receptors • Reward and reinforcement by: • a) Disinhibition of DA neurons in VTA • b) Action at opiate receptors in the NAcc - independent of DA release (m or d) 33 Alcohol (EtOH) 1) GABAA agonist (inhibitory) 2) NMDA antagonist (blocks excitation) - Large doses inhibit functioning of most voltage gated channels EtOH leads to increased DA release in NAcc NMDA antagonism of cortical inputs to VTA disinhibits VTA DA neurons resulting in increased DA release in NAcc. Ethanol rewarding effects blocked by DA receptor antagonists in NAcc Opiate system involvement Naltrexone (an opiate antagonist) - reduces EtOH self administration in animals - used as a treatment to reduce EtOH consumption, relapse and craving in alcoholics Nicotine Acts at nicotinic acetylcholine receptors (nAChRs) -Ligand gated ion channels located pre or post-synaptically (present throughout brain, excitatory or modulatory) -Presynaptic receptors - influx of Ca2+ - transmitter release Nicotine treatment increases DA release in the NAcc Opiate system involvement Both opiate and DA antagonists can block nicotine induced behaviours and self administration (Naltrexone as a drug to aid smoking cessation and associated weight gain, encouraging preliminary results) Physical dependence to opiates Opiate receptors present in mesocorticolimbic circuits but also other systems e.g. Spinal cord and pain pathways Locus coeruleus (LC) - Noradrenergic nuclei controlling attention, arousal and vigilance (responsible for eliciting “fight or flight” autonomic responses) Chronic activation of opiate receptors leads to homeostatic mechanism that compensates for the functional changes leading to tolerance and physical dependence Acute morphine - acutely inhibits firing of LC neurons Chronic treatment - LC neurons return to their normal firing rates Withdrawal - dramatic increase in LC firing - correlates with the physical withdrawal symptoms - trigger overactivation of the autonomic nervous system - can be blocked by clonidine (a2 adrenergic receptor agonist) Intracellular mechanism in LC neurons leads to the compensation (same events will result in tolerance to analgesic effects) Physical dependence to opiates Chronic activation of opiate receptors leads to homeostatic mechanism that compensates for the functional changes leading to tolerance and physical dependence Locus coeruleus Gs Gi Acute morphine - acutely inhibits firing of LC neurons through Gi pathway Gs Gi Chronic treatment - LC neurons return to their normal firing rates (Gs pathway component upregulate to match Gi) Withdrawal - dramatic increase in LC firing (In absence of Gi inhibiton Gs hypersensitive) Gs Gi Gi Gs Physical dependence to alcohol Acute effects of alcohol -agonist at GABAA receptor ( ) -antagonist at NMDA receptor ( ) out     in Cells inhibited from firing Cl- ClChronic alcohol Down regulation of GABAA receptors out  in Upregulation of NMDA receptors In presence of alcohol firing rates Cl- Na+ return to normal Withdrawal out in absence of alcohol in balance shifts to excitation physical symptoms Na+ - agitation, tremors, hypertension, seizures Cl- Na+   Na+ Na+ Na+ Na+ Na+ Summary Drug addiction - neuroplastic changes in the brain Drug use and harm. Dependence, tolerance and neuroplastic changes. Metabotropic receptors and intracellular signalling. The role of neurotransmitter pathways in addictions. Commonly abused drugs Reading materials Carlson, Physiology of Behavior, Chapter 18 Pinel, Psychobiology, Chapter 15 http://www.nida.nih.gov/