Obesity Research and Leptin Functions

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.

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.