Neurobiology Lecture 7: Neuropharmacology of Addiction PDF

11/1/2024 SC/BIOL 4370 – 3.0 [Fall 2024] Neurobiology Lecture 7: Then Neuropharmacology of Addiction 1 1 1 ...

11/1/2024 SC/BIOL 4370 – 3.0 [Fall 2024] Neurobiology Lecture 7: Then Neuropharmacology of Addiction 1 1 1  11/1/2024 Housekeeping Final Exam TBD Short- and long-answer format 3 Hours ~100-110 marks Based on lectures and slides from this lecture forward (non-cumulative with first half of course) Pay attention to weighting of questions (how many marks per question) Quiz 1 marked: 4 quizzes left! 2 2  11/1/2024 SCHEDULE 3 3 3  11/1/2024 OBJECTIVES Introduce motivations circuitry Articulate how the dopaminergic system influences motivation Understand the neurobiological basis of addiction Explain how some drugs of abuse impact neurobiological processes 4 4 4  11/1/2024 Motivation in response to homeostatic drive Homeostasis = processes that maintain internal environment within a narrow physiological range Requires transduction of signals both internally and externally Hypothalamus = key role in regulation of Body temperature Fluid balance (thirst) Energy balance (Hunger) 5 5 5  11/1/2024 Motivation in response to homeostatic drive Homeostasis How? Regulated parameter (ex. temperature) detected by specialized sensory neurons Deviations from optimal range detected by: periventricular zone of hypothalamus These neurons trigger an orchestrated (multi-brain region) response to restore optimal levels 6 6 6  11/1/2024 Motivation in response to homeostatic drive How? Response has 3 components: 1) Humoral : Hypothalamic neurons stimulate/inhibit pituitary hormone release 2) Visceromotor : Neurons in hypothalamus adjust sympathetic and parasympathetic outputs of the ANS 3) Somatic motor: Lateral hypothalamus induces appropriate motor behavior (motivated response) 7 7 7  11/1/2024 Hypothalamus as “setpoint hub” Contextual information (Cerebral cortex, amygdala, Integrates information from the hippocampal formation) forebrain, brainstem and spinal cord Receives sensory and contextual information Compares this information with Hypothalamus biological setpoints (Compares input to Activates relevant motor, Biological set points) neurohormone and somatic Visceral motor, systems Somatic motor, Allows for coordinated response Neuroendocrine, across brain regions for restoring Sensory inputs Behavioral response homeostasis (Visceral and somatic sensory pathways, chemosensory and humoral signals) 8 8 8  11/1/2024 Hypothalamic regulation of body composition Feeding = Hypothalamus “surveys” hormone levels Detects changes = initiates compensatory mechanisms Attempts to maintain body weight around a “setpoint” 9 9 9  11/1/2024 Stimulation of Feeding Behavior Feeding = stimulated Lateral when neurons detect Hypothalamus reduced levels of a hormone signal Detected by pariventricular zone neurons Neurons of lateral hypothalamus then initiate feeding Adapted from Biological Psychology, 6e, Fig. 13.22 10 10  11/1/2024 Connection between body fat and feeding 1960s Investigated Ob gene Postulated that Ob gene codes for hormone signalling fat reserve status Mice with Ob/Ob knockout: Brain is “fooled” into thinking fat reserves are low Demonstrate abnormally high levels of motivation to eat 11 Figure reproduced from Ingalls et al (1950). 11 11  11/1/2024 Parabiosis experiments to determine key hormone Parabiosis = long-term physiological and anatomical fusion of two animals Share common blood supply Parabios normal and Ob/Ob mice Resulted in reduction in eating and obesity in Ob/Ob mice! Used to identify leptin as key hormone for transmitting status of fat Leptin reserves Created in BioRender.com 12 12 12  11/1/2024 Leptin normalizes body weight in obese mice 13 Adapted from Harris, 2013; Fig. 1.. 13 13  11/1/2024 Leptin as energy reserve signal: inhibits feeding Friedman, 1994 Isolated leptin protein (Greek for “slender”) Treating Ob/Ob mice with leptin reversed obesity and eating disorder Leptin is released by adipocytes (fat cells) Regulates body mass by acting on neurons in hypothalamus that decrease appetite and Ob/Ob mouse + increase energy Ob/Ob mouse expenditure Leptin 14 Figure reproduced from Ingalls et al (1950). 14 14  11/1/2024 Human obesity and Leptin supplementation Humans lacking leptin: Excessive food craving Slowed metabolism Morbidly obese Leptin gene mutations (rare): Brain and body respond as if starving Leptin supplementation largely ineffective Problem may be decreased leptin sensitivity 1) Decreased BBB penetration by leptin 2) Reduced leptin receptor expression 3) Altered CNS response to Adapted from Gibson et al., 2004 pg. 4823 hypothalamic activity 15 15 15  11/1/2024 The Hypothalamus and feeding 1940s Hetherington and Ranson Small bilateral lesions of rat’s hypothalamus Lesions restricted to lateral hypothalamus = anorexia Anorexia = severely diminished appetite Adapted from Biological Psychology, 6e, Fig. 13.22 16 16 16  11/1/2024 The Hypothalamus and Feeding Small bilateral lesions of rat’s hypothalamus Lesions restricted to ventromedial hypothalamus Results in overeating and obesity Adapted from Biological Psychology, 6e, Fig. 13.22 17 17 17  11/1/2024 Effects of Leptin in Hypothalamus Leptin binds leptin receptors in arcuate nucleus (AN) Arcuate nucleus releases: Alpha Melanocyte Stimulating Hormone; αMSH and Cocaine and Amphetamine Regulated Transcript; CART 18 Adapted from Bear et al., 2016; Fig. 16.7 18 18  11/1/2024 Effects of Leptin in Hypothalamus Following a big meal, leptin binds leptin receptors in arcuate nucleus Arcuate nucleus then releases αMSH and CART Elevated αMSH and CART trigger changes in: 1) Humoral response = increased secretion of Thyroid stimulating hormone (TSH) and Adrenocorticotropic hormone (ACTH) THS and ACTH act on thyroid and adrenal glands to raise metabolic rate of cells 19 Adapted from Bear et al., 2016; Fig. 16.7 19 19  11/1/2024 αMSH and CART αMSH and CART neurons Activate neurons in paraventricular nucleus (PVN) to initiate humoral response PVN controls secretion of TSH and ACTH from anterior pituitary Arcuate nucleus inhibits feeding behavior through projections to lateral hypothalamus Adapted from Bear et al., 2016; Fig. 16.7 20 20  11/1/2024 Effects of Leptin in Hypothalamus Elevated αMSH and CART trigger changes in: 2) Visceromotor response = increases sympathetic tone which increases metabolism by raising body temperature 3) Somatic motor response = decreases feeding behavior Adapted from Bear et al., 2016; Fig. 16.7 21 21 21  11/1/2024 αMSH and CART αMSH and CART injection into brain mimics elevated leptin levels “anorectic peptides” = diminish appetite Blocking receptors for these peptides stimulates feeding Act as brain’s appetite suppressants Adapted from Bear et al., 2016; Fig. 16.8 22 22  11/1/2024 Effects of increased leptin in hypothalamus Leptin decreases feeding Rise in leptin is detected by: PVN Neurons in the arcuate nucleus that contain αMSH/CART Arcuate nucleus neurons LH project to paraventricular nucleus (PVN) PVN projects to spinal cord, αMSH lower brain stem CART Inhibits feeding behavior Modified from: CC BY-NC-ND 3.0 23 23 23  11/1/2024 Effects of decreased leptin on hypothalamus Fall in leptin levels = stimulates feeding behavior Through activation of alternative PVN arcuate nucleus neurons These neurons contain: NPY (neuropeptide Y) and AgRP LH (agouti-related peptide) Activate melanin-concentrating peptide (MSH) containing neurons of the lateral hypothalamus that stimulate feeding αMSH “orexigenic” peptides = stimulate CART feeding behavior These neurons project to both PVN and lateral hypothalamus Modified from: CC BY-NC-ND 3.0 24 24 24  11/1/2024 Lateral hypothalamus regulates feeding behavior αMSH and AgRP act as “antagonistic neurotransmitters” Alter feeding onset through stimulation (αMSH) or inhibition (AgRP) of the MC4 receptor MC4 is a postsynaptic receptor αMSH found in the lateral hypothalamus CART Activation of this receptor inhibits feeding behavior Modified from Vicent MA et al., (2018) e2006188. https://doi.org/10.1371/journal.pbio.2006188 25 25 25  11/1/2024 Lateral hypothalamus regulates feeding behavior Lesions of the lateral hypothalamus stop eating behaviors Electrical stimulation of lateral hypothalamus induces eating, even in satiated animals Arcuate nucleus projects to neurons that contain melanin concentrating hormone (MCH) These lateral hypothalamus neurons innervate cortical centers involved in goal- Adapted from Bear et al., 2016; Fig. 16.8 directed behavior 26 26 26  11/1/2024 Lateral hypothalamus regulates feeding behavior Lateral hypothalamus also contains orexin cells which initiate feeding behavior Work in tandem with melanin concentrating hormone (MCH)+ cells Activation of orexin cells promotes meal initiation MCH prolongs consumption Adapted from Bear et al., 2016; Fig. 16.8 27 27 27  11/1/2024 Marijuana and “the Munchies” Active ingredient: D-tetrahydrocannabinol (THC) Stimulates cannabinoid receptor-1 (CB1) Activation of CB1 receptors in hypothalamus is orexigenic = stimulates feeding and enhances smell Olfactory cortex sends projections to olfactory bulb CB1 reduces excitatory inputs onto inhibitory granule cells Disinhibits olfactory bulb neurons = increases olfaction and feeding 28 28 28  11/1/2024 Motivation centers: Driving goal-directed behavior Food is reinforcing (rewarding) Where is the “reward” center? Rats implanted with electrodes Rats explored a box; when in certain region, provided stimulation Rats preferred the part of the box associated with stimulation Adapted from Carlezon and Chartoff, 2007 29 29 29  11/1/2024 Motivation centers: Driving goal-directed behavior Lever coupled to a stimulator “Electrical self-stimulation” Sometimes, would persist and ignore food, water and sex Only stopped when they collapsed from exhaustion Self-stimulation of the brain appeared to provide a reward that reinforces the behavior Systematically varied electrode location Rewarding effects observed when placed in the ventral tegmental area 30 30 30  11/1/2024 31 31 31  11/1/2024 Motivation centers: Driving goal-directed behavior Identified site of stimulation as axons projecting from ventral tegmental area (VTA) VTA provides dopaminergic projections VTA > lateral hypothalamus > forebrain regions controlling goal-directed behavior Blocking dopamine receptors reduced self-stimulation in rats Mesocorticolimbic dopamine system Modified from Scarr E, Gibbons AS, Neo J, Udawela M, Dean B - Frontiers in cellular neuroscience (2013) 32 32 32  11/1/2024 Self-stimulation in humans Heath, 1960s Implanted electrodes in patients with severe narcolepsy (involuntary deep sleep onset) Patient could self-stimulate through one of several electrodes Preferred stimulating septal area Similar results with a second patient However, preferred stimulating medial thalamus “Feels like about to recall a memory” VTA sends DA projections to the septum Bear Pg. 567 33 33 33  11/1/2024 Dopamine as a motivation signal Dopamine was believed to provide “hedonic” (pleasure) reward More complicated than this: Destruction of DA axons failed to block pleasure response to food Rats still “smack lips” in response to savory foods Behaves as if the animal likes food, but won’t seek it out Loss of motivational component of food seeking 34 Modified from Scarr E, Gibbons AS, Neo J, Udawela M, Dean B - Frontiers in cellular neuroscience (2013) 34 34  11/1/2024 Dopamine signaling and behavior Wolfram Schultz VTA neuron activity recordings Monkeys given sip of juice before a light is turned on Neurons slightly increase firing in response to reward without associative conditioning 35 35 35  11/1/2024 Dopamine signaling and behavior VTA neuron activity recordings With repeated pairings (juice + light), associative conditioning takes place Light now cues reward onset Now, VTA neurons fire in response to light VTA neuron activity serves as an anticipatory signal No response to the juice alone! 36 Bear Pg. 569 36 36  11/1/2024 Dopamine signaling and behavior Dissociated the pairing of juice and light Firing decreases at normal time of reward DA neurons are signalling errors in reward prediction Outcome “worse than expected” = firing of VTA neurons 37 Bear Pg. 569 37 37  11/1/2024 Dopamine signaling and behavior Classic testing apparatus for self-stimulation experiments. Electrode is implanted in brain area that produces self-stimulation behavior Activates dopaminergic pathways emanating from the ventral tegmental area (VTA) Can use to determine which drugs impact reward detecting pathways 38 Kandel pg 1067 38 38  11/1/2024 Dopamine signaling and behavior Cocaine and nicotine affect the rate of electrical self-stimulation. The rate at which the animal presses the stimulation lever increases with increases in the frequency of the self-stimulation current These drugs reduce the frequency (lower the threshold for eliciting a reward signal) of self stimulation This means that these drugs enhance reward saliency 39 Kandel pg 1067 39 39  11/1/2024 Brain Reward Circuits The primary reward circuit includes dopaminergic projections from the VTA to the NAc. VTA projections release dopamine.in response to reward-related stimuli 40 Kandel pg 1070 40 40  11/1/2024 Drugs of addiction recruit synaptic plasticity Dopamine and glutamate-activated intracellular signaling pathways linked to drug addiction NMDARs permit calcium which activates two types of Ca2+/calmodulin-dependent protein kinases: CaMKII in the cytoplasm and CaMKIV in the cell nucleus. DA receptors activate cAMP which in turn activates cAMP- dependent protein kinase A (PKA) Once activated in the nucleus, both PKA and CaMKIV phosphorylate cAMP response element binding protein(CREB). CREB recruits CREB-binding protein (CBP) and activates transcription Protein products induce morphological and functional changes in synapses associated with memory formation. 41 Kandel pg 1076 41 41  11/1/2024 Dopaminergic system modulators: Cocaine Cocaine is an alkaloid found in leaves of Erythroxylon coca Purified in 1850s 1885 adopted broadly in Europe, used for medicinal and invigorating properties 1886 additive in soft drink Coca-cola Used for teething pain in infants as local anesthetic Rapid absorption particularly when injected or smoked 42 42 42  11/1/2024 Dopaminergic system modulators: Cocaine Cocaine users report feelings of euphoria and elevated self-confidence Similar to intense orgasm Increases sociability but can increase aggression in a dose-dependent fashion In rodents, increases locomotion, rearing and sniffing Sympathomimetic properties: tachycardia, vasoconstriction, hypertension 43 43 43  11/1/2024 Dopaminergic system modulators: Cocaine Cocaine is lipophilic: readily passed the blood brain barrier (BBB) Potency is dependent upon route of administration Half-life of.5-1.5hrs Subjective high typically peaks at 30 minutes 44 44 44  11/1/2024 Cocaine: Mechanism of action Cocaine increases synaptic DA levels by binding to DA transporter and blocking reuptake of the neurotransmitter. A similar process occurs at serotonergic and noradrenergic synapses because of cocaine’s inhibition of 5-HT (SERT) and NE (NET) reuptake. Higher affinity for 5-HT and NE transporters, but addictive effects attributed to DA transport inhibition 45 45 45  11/1/2024 Cocaine: Mechanism of action Cocaine increases synaptic DA within 5 seconds (!) when given to rats IP Peak DAT inhibition within 30 seconds Cocaine also increases firing of VTA neurons (major source of dopaminergic inputs throughout the brain) Increases the frequency of transient DA release events Mice lacking functional DAT were immune to cocaine effects 46 46 46  11/1/2024 Dopaminergic system modulators: Cocaine Microdialysis probes aimed at the dorsal striatum Microdialysis measures neurotransmitter overflow (i.e., transmitter molecules that have eluded uptake mechanisms). Collected samples for measurement of cocaine and DA concentrations at 2-minute intervals following a 5-second infusion of 2 mg/kg cocaine. Close relationship between these variables is consistent with cocaine causing rapid increases in extracellular DA. 47 47 47  11/1/2024 Cocaine-based recruitment of reward circuits Cocaine increases extracellular DA levels within the NAc. This region processes reward saliency and motivation. Generates reinforcing effects of cocaine use Lesions of NAc reduce psychomotor symptoms and repetitive use of cocaine in rats 48 Kandel pg 1070 48 48  11/1/2024 Drug craving induced by cocaine cues Striatum (caudate and putamen) associated with habit forming aspects of drug addiction. Relationship between striatal DA release and craving elicited by exposure to cocaine-related visual stimuli in cocaine addicted individuals. Shown a video of cocaine-related cues including while undergoing PET scanning of striatal DA release measured by DA displacement of radiolabeled raclopride from D2 receptors. The y-axis of the graph plots changes in subjective cocaine craving from before to the end The x-axis plots changes in DA release measured by alterations in raclopride binding. Significant positive correlations were found for both the caudate and the putamen, indicating that cue-induced cocaine craving is associated with heightened striatal DA release. Relationship between striatal DA release and craving elicited by exposure to cocaine-related visual stimuli Cocaine-addicted individuals were exposed to a video of cocaine-related cues including purchase, preparation, and smoking of the drug while undergoing PET scanning of striatal DA release measured by DA displacement of radiolabeled raclopride from D2 receptors. The y-axis of the graph plots changes in subjective cocaine craving from before to the end of the video. The x-axis plots changes in DA release measured by alterations in raclopride binding. Significant positive correlations were found for both the caudate nucleus and the putamen, indicating that cue-induced cocaine craving is associated with heightened striatal DA release. 49 49 49  11/1/2024 Drug craving induced by cocaine cues Positron emission tomography (PET) imaging reveals neural correlates of cue-induced cocaine craving. Subjects were shown neutral or cocaine-related cues and rated their subjective cravings Mean craving score (horizontal is significancy higher for exposure to cocaine-related cues (A) Craving positively correlated with changes in metabolic rate in the dorsolateral prefrontal cortex and medial temporal lobe during exposure to cocaine-related cues. 50 50 50  11/1/2024 Psychostimulants: Effects of chronic use: Tolerance Summary of altered striatal dopaminergic markers in chronic psychostimulant users Chronic psychostimulant users showed: Decreased DA synthesis Lower DA per synaptic vesicle and fewer vesicles Decreased DA release Suggests that tolerance may develop where the same amount of cocaine no longer elicits a large response 51 51 51  11/1/2024 Psychostimulants: Effects of chronic use: Tolerance These findings also indicate the cellular basis for escalation (increasing usage or quantify of drugs) Also indicates that dopaminergic tone may be shunted under basal conditions in chronic users Responsible for anhedonia for non-drug related rewards Therefore, other activities will be less rewarding Absence of drug is actually aversive! 52 52 52  11/1/2024 Psychostimulants: Tolerance Similar affects observed in the NAc Reduced extracellular DA Reduced intracellular DA levels However, may mask sensitization Reduced autoreceptors sensitivity Reduced effects of cocaine on DAT 53 53 53  11/1/2024 Cocaine-based affects on cognition Used associated with attentional deficits, impulse control impairments, poor decision making in reward-based learning tasks working memory deficits, inability to adequately monitor own behavior Correlates with reduced gray matter in prefrontal cortex (PFC) Reduced dendritic spines, synapse loss, and neuronal death in PFC Further reinforces drug use by limiting cognitive control that would limit drug use 54 Kandel pg 1070 54 54  11/1/2024 Psychostimulants: Amphetamines Mechanisms of amphetamine- stimulated DA release Amphetamine (AMPH) molecules enter DA nerve terminals through uptake by the dopamine transporter (DAT) provokes Promotes DA release from the synaptic vesicles into the cytoplasm Also makes DAT transporter act in a reverse direction to release DA from the cytoplasm into the extracellular fluid. 55 55 55  11/1/2024 Psychostimulants: Amphetamines Methamphetamine-induced loss of tyrosine hydroxylase immunoreactivity in the nigrostriatal compared with the mesolimbic DA pathways Mice were given IP injections of methamphetamine and sacrificed 7 days later Coronal brain sections through the caudate–putamen (CPu) and nucleus accumbens were stained using an antibody against tyrosine hydroxylase (TH), a marker of dopaminergic fibers and nerve terminals. Methamphetamine-induced DA neurotoxicity was more pronounced in the nigrostriatal pathway (CPu) than in the mesolimbic pathway 56 56 56  11/1/2024 SCHEDULE 57 57 57