Obesity Research and Leptin Functions
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Questions and Answers

What is the purpose of parabiosis experiments in the context of obesity research?

  • To study the effects of shared blood supply on weight loss
  • To explore genetic differences in fat storage
  • To determine the nutritional requirements of mice
  • To identify key hormones affecting fat reserves (correct)

    • Leptin is produced by muscle cells.

    False

    What hormone is identified as the key player in reducing obesity in Ob/Ob mice?

    Leptin

    Leptin regulates body mass by acting on neurons in the __________.

    <p>hypothalamus</p> Signup and view all the answers

    What is the primary effect of leptin on Ob/Ob mice?

    <p>Normalizes body weight and reduces eating</p> Signup and view all the answers

    Leptin was discovered through its function in treating eating disorders in normal mice.

    <p>False</p> Signup and view all the answers

    Match the following concepts related to leptin:

    <p>Leptin = Hormone released by adipocytes Ob/Ob mice = Models for studying obesity Hypothalamus = Brain region that regulates appetite Energy expenditure = Caloric burning process</p> Signup and view all the answers

    Explain the role of leptin as an energy reserve signal.

    <p>Leptin inhibits feeding and helps regulate body weight by signaling the brain about fat reserves.</p> Signup and view all the answers

    What neural area showed a positive correlation with craving during exposure to cocaine-related cues?

    <p>Dorsolateral prefrontal cortex</p> Signup and view all the answers

    Chronic psychostimulant users exhibit increased DA release compared to non-users.

    <p>False</p> Signup and view all the answers

    What is the significance of cocaine-related cues in the context of drug craving?

    <p>Cocaine-related cues significantly increase subjective cravings.</p> Signup and view all the answers

    Chronic psychostimulant users experience ________ for non-drug related rewards.

    <p>anhedonia</p> Signup and view all the answers

    Match the following effects with their descriptions in chronic psychostimulant users:

    <p>Decreased DA synthesis = Lower manufacturing of dopamine Lower DA per synaptic vesicle = Each vesicle contains less dopamine Fewer vesicles = Reduced number of dopamine containers Absence of drugs is aversive = Not using drugs causes discomfort</p> Signup and view all the answers

    What does chronic use of cocaine lead to in terms of drug response?

    <p>Tolerance where the same amount no longer elicits a large response</p> Signup and view all the answers

    Chronic psychostimulant use is associated with an increase in the number of dopamine vesicles.

    <p>False</p> Signup and view all the answers

    What is meant by the term 'shunted dopaminergic tone' in chronic users?

    <p>It refers to a state where dopamine activity is reduced during normal conditions.</p> Signup and view all the answers

    What cognitive impairments are associated with cocaine use?

    <p>Poor decision making</p> Signup and view all the answers

    Cocaine use can lead to increased gray matter in the prefrontal cortex.

    <p>False</p> Signup and view all the answers

    What neurotransmitter's release is stimulated by amphetamines?

    <p>Dopamine</p> Signup and view all the answers

    Amphetamines cause the dopamine transporter (DAT) to act in a ______ direction, releasing dopamine into the extracellular fluid.

    <p>reverse</p> Signup and view all the answers

    Match the following effects of cocaine with their descriptions:

    <p>Attentional Deficits = Impairs focus and concentration Poor Decision Making = Leads to irrational and impulsive choices Working Memory Deficits = Difficulty retaining and manipulating information Reduced Gray Matter = Loss of brain tissue in the prefrontal cortex</p> Signup and view all the answers

    Which of the following mechanisms does amphetamine NOT directly promote?

    <p>Decreased intracellular DA levels</p> Signup and view all the answers

    Amphetamines only increase extracellular dopamine levels without affecting dopamine production.

    <p>False</p> Signup and view all the answers

    What area of the brain is primarily affected in terms of reduced gray matter due to cocaine use?

    <p>Prefrontal cortex</p> Signup and view all the answers

    Which region of the hypothalamus triggers feeding behavior when hormone levels are reduced?

    <p>Lateral hypothalamus</p> Signup and view all the answers

    The periventricular zone of the hypothalamus detects deviations from optimal temperature ranges.

    <p>True</p> Signup and view all the answers

    What is the role of the hypothalamus in regulating body composition?

    <p>The hypothalamus surveys hormone levels and initiates compensatory mechanisms to maintain body weight around a setpoint.</p> Signup and view all the answers

    The hypothalamus integrates information from the cerebral cortex, amygdala, and _____ to compare with biological setpoints.

    <p>hippocampal formation</p> Signup and view all the answers

    Match the components of response to homeostatic drive with their functions:

    <p>Humoral = Stimulates pituitary hormone release Visceromotor = Adjusts outputs of the autonomic nervous system Somatic motor = Induces appropriate motor behavior Setpoint hub = Compares input to biological setpoints</p> Signup and view all the answers

    What happens in the brain of mice with an Ob/Ob knockout?

    <p>Their brains think fat reserves are low</p> Signup and view all the answers

    The lateral hypothalamus is responsible for suppressing feeding behavior.

    <p>False</p> Signup and view all the answers

    What are the three components of the response to homeostatic drive?

    <p>Humoral, Visceromotor, Somatic motor</p> Signup and view all the answers

    The hypothalamus receives sensory inputs from visceral and _____ sensory pathways.

    <p>somatic</p> Signup and view all the answers

    What is the primary function of the hypothalamus as the 'setpoint hub'?

    <p>To compare sensory input with biological setpoints</p> Signup and view all the answers

    What role does the VTA play in dopamine release?

    <p>Releases dopamine in response to reward-related stimuli</p> Signup and view all the answers

    Cocaine was first purified in the 1850s and became widely adopted in Europe in 1885.

    <p>True</p> Signup and view all the answers

    What are the two types of calcium-dependent protein kinases activated by NMDARs?

    <p>CaMKII and CaMKIV</p> Signup and view all the answers

    Cocaine increases synaptic DA levels by binding to the DA transporter and blocking _______.

    <p>reuptake</p> Signup and view all the answers

    Match the following effects of cocaine with their corresponding descriptions:

    <p>Euphoria = Feelings of intense happiness Increased sociability = Enhancement of social interaction Tachycardia = Increased heart rate Vasoconstriction = Narrowing of blood vessels</p> Signup and view all the answers

    What is the primary effect of dopamine release in response to reward-related stimuli?

    <p>Mood elevation and reinforcement of behaviors</p> Signup and view all the answers

    Cocaine's subjective high peaks at approximately one hour after use.

    <p>False</p> Signup and view all the answers

    What physiological effects can high doses of cocaine induce?

    <p>Aggression</p> Signup and view all the answers

    Cocaine is considered ________ because it readily passes the blood-brain barrier.

    <p>lipophilic</p> Signup and view all the answers

    What effect does cocaine NOT have on rodents?

    <p>Decreased sociability</p> Signup and view all the answers

    What is the primary effect of leptin binding to its receptors in the arcuate nucleus?

    <p>Increases metabolic rate</p> Signup and view all the answers

    Leptin supplementation is effective for all individuals suffering from obesity.

    <p>False</p> Signup and view all the answers

    Which neurons in the arcuate nucleus are responsible for inhibiting feeding behavior?

    <p>αMSH and CART neurons</p> Signup and view all the answers

    A fall in leptin levels stimulates feeding behavior by activating neurons containing __________ and __________.

    <p>NPY, AgRP</p> Signup and view all the answers

    Match the following peptides with their functions:

    <p>αMSH = Inhibits feeding AgRP = Stimulates feeding CART = Inhibits appetite NPY = Stimulates appetite</p> Signup and view all the answers

    What is the result of lesions restricted to the lateral hypothalamus?

    <p>Anorexia</p> Signup and view all the answers

    Leptin primarily affects feeding behavior by acting on the lateral hypothalamus.

    <p>False</p> Signup and view all the answers

    What consequence does increased sympathetic tone have on metabolism?

    <p>Raises body temperature</p> Signup and view all the answers

    αMSH and CART are also known as __________ peptides because they diminish appetite.

    <p>anorectic</p> Signup and view all the answers

    Match the components with their corresponding roles in feeding regulation:

    <p>Leptin = Decreases feeding behavior NPY = Stimulates feeding αMSH = Inhibits feeding CART = Inhibits appetite</p> Signup and view all the answers

    What effect do leptin levels have on the activation of the paraventricular nucleus (PVN)?

    <p>Inhibits feeding behavior</p> Signup and view all the answers

    The MC4 receptor, when activated, stimulates feeding behavior.

    <p>False</p> Signup and view all the answers

    What are the two components that can be increased in response to elevated αMSH and CART?

    <p>TSH and ACTH</p> Signup and view all the answers

    Blocking the receptors for __________ and __________ peptides stimulates feeding.

    <p>αMSH, CART</p> Signup and view all the answers

    Match the type of response to its description:

    <p>Humoral response = Increased secretion of TSH and ACTH Visceromotor response = Increases sympathetic tone Somatic motor response = Decreases feeding behavior</p> Signup and view all the answers

    Study Notes

    Neurobiology Lecture 7: Neuropharmacology of Addiction

    • Upcoming final exam is TBD, short- and long-answer format, 3 hours, approximately 100-110 marks.
    • Exam will cover lecture and slide material from this lecture onwards, not cumulative with the first half of the course.
    • Students should pay close attention to question weighting.
    • Quiz 1 was marked, 4 quizzes remain.

    Objectives

    • Introduce motivation circuitry
    • Articulate how the dopaminergic system influences motivation
    • Understand the neurobiological basis of addiction
    • Explain how psychoactive drugs impact neurobiological processes

    Motivation in Response to Homeostatic Drive

    • Homeostasis maintains a narrow physiological range.
    • Transduction of internal and external signals is required.
    • The hypothalamus plays a key role in body temperature, fluid balance, and energy balance.

    Hypothalamus as a "Setpoint Hub"

    • The hypothalamus integrates information from the forebrain, brainstem, and spinal cord; receives sensory and contextual information; compares input against biological setpoints; activates relevant motor, neurohormone and somatic systems; allows for coordinated response across brain regions to restore homeostasis.
    • Sensors detect deviations from optimal ranges and trigger a response to restore balance.

    Hypothalamic Regulation of Body Composition

    • Feeding behavior is controlled by hypothalamic hormone levels.
    • Detecting changes in hormone levels triggers compensatory mechanisms to maintain body weight around a setpoint.

    Stimulation of Feeding Behavior

    • Feeding is triggered when neurons detect reduced hormone levels.
    • Neurons in the lateral hypothalamus initiate feeding.

    Connection between Body Fat and Feeding

    • The 1960s investigation of the Ob gene highlighted its role in hormone signaling related to fat reserve status.
    • Mice with an Ob/Ob knockout have brains "fooled" into thinking fat reserves are low, leading to abnormally high levels of motivation to eat.

    Parabiosis Experiments (Key Hormone)

    • Parabiosis involves surgically fusing two animals, allowing them to share a common blood supply.
    • This experiment demonstrates leptin's role in regulating eating habits and maintaining fat reserve equilibrium.
    • Results show a reduction in eating and weight gain in mice with the Ob/Ob mutation.

    Leptin Normalizes Body Weight in Obese Mice

    • Leptin's role in regulating body weight is evident.

    Leptin as an Energy Reserve Signal

    • Leptin, a hormone produced by adipocytes, regulates body mass by acting on hypothalamic neurons.
    • It suppresses appetite and increases energy expenditure, leading to the maintenance of stable body weight.

    Human Obesity and Leptin Supplementation

    • While leptin supplements can be ineffective in humans, the decrease in leptin sensitivity and issues with BBB penetration may contribute.

    The Hypothalamus and Feeding

    • Lesions to the lateral hypothalamus lead to anorexia (severely diminished appetite).
    • Lesions to the ventromedial hypothalamus lead to overeating and obesity.

    Effects of Leptin in the Hypothalamus

    • Leptin binds to receptors in the arcuate nucleus, triggering the release of aMSH and CART.
    • This leads to changes in humoral response (increasing TSH and ACTH secretion), raising metabolic rate.
    • The outcome also includes visceromotor response, (increased sympathetic tone, increased body temperature) and somatic motor response, (decreased feeding behavior).

    MSH and CART Neurons

    • aMSH and CART neurons activate neurons in the paraventricular nucleus (PVN) to initiate humoral responses.
    • PVN controls the secretion of TSH and ACTH from the anterior pituitary.
    • aMSH and CART neurons inhibit feeding behavior through projections to the lateral hypothalamus.

    Effects of Increased Leptin in Hypothalamus

    • A rise in leptin detected by arcuate nucleus neurons triggers a cascade of actions, leading to a decrease in feeding behavior.
    • Also involves projects to the paraventricular nucleus (PVN) which then projects to the lower brain stem, inhibiting feeding.

    Effects of Decreased Leptin in Hypothalamus

    • A fall in leptin stimulates feeding behaviors by activating NPY and AgRP neurons in the arcuate nucleus and projecting to the lateral hypothalamus.

    Lateral Hypothalamus Regulates Feeding Behavior

    • aMSH and AgRP act as antagonistic neurotransmitters, altering feeding onset through either stimulation or inhibition of the MC4 receptor.
    • MC4 acts as a postsynaptic receptor in the lateral hypothalamus; activation inhibits feeding behavior.

    Marijuana and "The Munchies"

    • THC, the active ingredient in marijuana, stimulates the CB1 receptors in the hypothalamus, which is an orexigenic effect.
    • THC disinhibits olfactory bulb neurons, increasing olfaction and feeding.

    Motivation Centers: Driving Goal-Directed Behavior

    • Brain regions like the ventral tegmental area (VTA) are crucial; stimulation of these centers can create reinforcing behavioral responses, such as self-stimulation of a lever.
    • Animals will ignore primary needs like food and water to pursue the rewarding stimulation of the lever.

    Dopamine Signaling and Behavior

    • VTA neurons record activity related to receiving a reward (e.g., a sip of juice) prior to the onset of the reward stimulus (e.g., light).
    • Repeated pairing of stimuli leads to neurons' firing in response to the anticipatory signal (i.e., light).
    • Firing decreases when the stimulus is not coupled to the reward.
    • DA neurons signal errors in reward prediction; less rewarding outcome results in less firing.
    • Classic testing apparatus involves implanting electrodes to stimulate or monitor DA pathways, providing insight into drug impact on reward pathways.

    Cocaine and Nicotine Affect Electrical Self-Stimulation

    • Cocaine and nicotine modulate the rate of self-stimulation; the rate increases with the increase in electric stimulation frequency.
    • These drugs reduce the frequency of self-stimulation, indicating that these drugs increase reward saliency.

    Brain Reward Circuits

    • Dopamine from the VTA to the NAc is crucial for the reward circuit.
    • VTA projections release dopamine in response to reward-related stimuli.

    Drugs of Addiction Recruit Synaptic Plasticity

    • Dopamine and glutamate pathways, NMDARs and calcium signaling, are involved in addiction-related synaptic plasticity (changes in synapses).
    • This involves the activation of kinases in response to increased calcium levels, as evident in the diagram.
    • These changes are part of how addiction reinforces behavior.

    Dopaminergic System Modulators: Cocaine

    • Cocaine is an alkaloid derived from coca leaves, commonly used recreationally or medicinally.
    • It shows quick absorption when ingested, smoked, or injected.
    • It's lipophilic and readily passes the blood-brain barrier (BBB) within a half-life of .5- to 1.5 hours.
    • Elevated dopamine levels result from cocaine binding to the dopamine transporter (DAT), which usually transports dopamine back into the presynaptic neuron.

    Cocaine: Mechanism of Action

    • Cocaine acts to increase synaptic DA levels by blocking the dopamine transporter (DAT).
    • Cocaine also inhibits 5-HT and NE transporters, but its addictive effects are most closely linked to DAT inhibition of dopamine.

    Cocaine: Increased Synaptic DA

    • Cocaine rapidly increases synaptic dopamine (within 5 seconds when given IP) by directly blocking dopamine transporters and also increasing the firing rate of VTA neurons and increasing frequency of transient DA release events.

    Dopaminergic System Modulators: Cocaine (Cont)

    • Cocaine's effects can induce feelings of euphoria and elevated self-esteem, increasing sociability, but also aggression in dose-dependent fashions.
    • It has sympathomimetic properties: tachycardia, vasoconstriction, and hypertension.

    Cocaine-Based Recruitment of Reward Circuits

    • Cocaine increases extracellular dopamine levels in the nucleus accumbens (NAc), which plays a role in reward signaling and motivation.
    • This contributes to the reinforcing effects of cocaine use.
    • Lesions to the NAc reduce cocaine-related psychomotor behaviors.

    Drug Craving Induced by Cocaine Cues

    • The striatum (specifically the caudate and putamen) is associated with habit forming aspects of drug addiction and reward, as well as with the relationship between striatal DA release and cocaine craving, notably the video cues.
    • There's a significant correlation between cue-induced cocaine craving and heightened striatal dopamine release.

    Drug Craving Induced by Cocaine Cues (Cont)

    • PET scans reveal a correlation between cocaine craving and activity in the dorsolateral prefrontal cortex and medial temporal lobe when exposed to cocaine-related stimuli.

    Psychostimulants: Effects of Chronic Use: Tolerance

    • Chronic use of psychostimulants can lead to a decrease in dopamine synthesis and changes in synaptic vesicles, leading to reduced dopamine release.
    • This can result in tolerance (where a response is reduced, and potentially no longer observable).
    • This tolerance may mask other neurological or psychological behaviors that are triggered by the drug, but not entirely the effect, though it masks the initially large effect.

    Psychostimulants: Tolerance (Cont)

    • Similar effects of chronic use of psychostimulants are seen in the nucleus accumbens (NAc) where reduced extracellular and intracellular dopamine levels are observed.

    Cocaine-Based Affects on Cognition

    • Cocaine use is linked to deficits in attention, impulse control, decision-making, working memory, and monitoring of behavior.
    • Cocaine impacts the prefrontal cortex (PFC) by affecting things like dendritic spines, synapse loss, and neuronal death.
    • This damage to the PFC further reinforces drug use by limiting normal cognitive control mechanisms that would otherwise curtail use.

    Psychostimulants: Amphetamines

    • Amphetamines (AMPH) enter dopamine nerve terminals and stimulate dopamine release from vesicles.
    • This mechanism may cause a reversal in the action of dopamine transporters, increasing dopamine in the synapse.

    Psychostimulants: Amphetamines (Cont)

    • Methamphetamine-induced loss of tyrosine hydroxylase immunoreactivity is more pronounced in the nigrostriatal pathway than in the mesolimbic pathway.

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    Description

    This quiz delves into the role of leptin in obesity research, focusing on its effects in Ob/Ob mice and the implications for energy regulation. Additionally, the quiz explores the intersection of leptin and psychostimulant use, particularly the effects of cocaine-related cues on craving and reward systems. Test your understanding of these complex interactions.

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