Neuroscience of Drug Addiction - Exam 3

Nicotine

A highly addictive stimulant found in tobacco products, which affects neurotransmitter systems and can lead to dependency

• an active alkaloid

How many mg’s of nicotine typically reach a smokers bloodstream?

~ 1 - 3 mgs

What percentage of tobacco users are ultimately killed by it?

~ 50% of users

When do most smokers initiate usage?

During adolescence or young adulthood

Which group has the highest reported rate of past tobacco use?

Adolescent males (18-25)

• ~ 45%

• likely an underestimate

Which format of nicotine administration is currently the most prominent?

E-cigarettes

• between 6% - 10% of middle & highschool students report using this form of tobacco delivery

Electronic Nicotine Delivery System (ENDS)

A device that allows users to inhale vaporized nicotine, typically including e-cigarettes and vape pens.

• have gained popularity among youth & are often used as an alternative to traditional tobacco products

Which form of nicotine consumption has the fastest rate of delivery to the plasma?

Cigarettes

• very fast acting w/ nicotine wave hitting the brain in ~ 7 seconds

C-fos

A transcription factor that is commonly used as a marker of neuronal activation, often studied in the context of drug addiction and neuroplasticity

• its expression is commonly used in nicotine studies

Is striatal C-fos expression greater with shorter or longer durations of nicotine administration?

Shorter

• much greater after 5-seconds of duration than 100 seconds

Half-Life of Nicotine

~ 2 hours

Major Metabolite for Nicotine

Cotinine

Cotinine

The primary metabolite of nicotine, formed in the liver and often used as a biomarker for nicotine exposure.

• inhibited by menthol

• may actually be the source of many of the ‘beneficial’ effects seen after smoking

Primary means of nicotine elimination/excretion:

Through the urine

• also excreted through breast milk

What are the 2 cholinergic receptor types?

• Muscarinic

• Nicotinic

Muscarinic Receptors

A type of acetylcholine receptor that is paired with G-proteins and mediates various physiological effects in the body, including neural signaling and muscle contraction

• M1 - M5 subtypes

Which muscarinic receptors are inhibitory?

M2 & M4 subtypes

Which muscarinic receptors are stimulatory?

M1, M3, & M5 subtypes

Nicotinic Receptors (nAChRs)

A ligand-gated ionotropic class of ACh receptors that mediate fast synaptic transmission in the nervous system, influencing muscle contraction and neurotransmitter release.

• requires 2 ACh molecules to be bound

Primary mechanism by which ACh is eliminated:

Acetylcholinesterase (AChE) enzyme degradation

Acetylcholinesterase (AChE)

An enzyme that breaks down the neurotransmitter acetylcholine in the synaptic cleft, terminating its action & ensuring efficient signaling in the nervous system

Vesicular Acetylcholine Transporter (VAChT)

Vesicular transporter responsible for packaging acetylcholine into vesicles in the presynaptic neuron

• distinctly different from the monoamine transporter VMAT-2

Choline Acetyltransferase

An enzyme that synthesizes acetylcholine from acetyl-CoA and choline, playing a crucial role in neurotransmitter production in the neuron.

What pattern does the reinforcing effect of nicotine follow?

An inverted U-shape

• indicates that moderate doses of nicotine enhance reinforcement, while low or high doses diminish it

Why might higher doses of nicotine not be particularly reinforcing as lower doses?

Increased rate of unpleasant side effects/development of aversive reactions, thus reducing nicotines reinforcing properties.

Negative Allosteric Modulator

A substance that binds to a receptor and decreases its activity, altering the receptor's response to the primary ligand

• menthol functions in this way, reducing nicotines efficacy at opening ion channels

• may ultimately lead to compensatory upregulation

TRPM8 Channels

Thermal and menthol receptors involved in cold sensation and nociception, playing a role in sensory processing and modulation of pain

• activation of this receptor masks the harshness of smoke

• facilitates easier inhalation of smoke, enabling higher intake

How does nicotine activate the dopaminergic system?

By stimulating nicotinic acetylcholine receptors, which leads to increased dopamine release in areas like the nucleus accumbens (NAc)

What effect does destroying dopaminergic terminals in the NAc (via 6-OHDA) have on nicotine administration?

Destroys the reinforcing effects of nicotine, reducing its ability to enhance dopamine release and diminish cravings

• greatly reduces lever pressing for nicotine

How does systemic nicotine administration affect dopaminergic activity?

Greatly increases of midbrain DA cells, altering their patterns of firing to a ‘burst’ mode

• increases DA release at terminals in the striatum & NAc

• doubled avg firing rate of VTA dopaminergic neurons

Effect of chronic smoking on nAChRs:

Upregulation and desensitization of high-affinity nAChRs, particularly in the PFC

• altering their function and contributing to dependency and withdrawal symptoms

How does nicotine affect reward threshold?

Lowers it by enhancing the release of DA, making rewarding stimuli feel more pleasurable & easier to attain

What experimental strategies have been used to study nicotines effects on dopamine?

• ICSS

• Destruction of DA terminals in the NAc w/ 6-OHDA

• Microdialysis

• Intraperitoneal (IP) injection into the VTA

Cholinergic Pathways

Neural pathways that utilize acetylcholine (ACh) as a neurotransmitter, influencing various cognitive and physiological functions such as memory and reward.

Nicotine-induced stimulation produced what effect in VTA dopaminergic neurons?

Doubling of the avg firing rate of neurons relative to baseline & subsequently increased DA release

• changed their pattern of firing to a ‘burst’

• subsequently increased DA release from terminals in the striatum

Phasic Burst

A pattern of neuronal firing characterized by rapid bursts of action potentials, typically in response to stimuli

• in the context of DA neurons, this pattern is associated with reward and reinforcement signaling

Striatum

A subcortical part of the brain involved in the coordination of movement and reward

• plays a crucial role in the processing of reinforcement and is affected by various drugs and addictive behaviors.

Ventral Striatum

A subregion of the striatum that plays an integral role in the brain's reward system, mediating the effects of rewarding stimuli & reinforcing behaviors associated with drug addiction

• closely linked to the processing of motivation and pleasure.

Desensitization of nAChRs by nicotine:

The process by which nicotine reduces the responsiveness of nicotinic acetylcholine receptors (nAChRs) after prolonged exposure

How does the rate of recovery from desensitization of nicotine compare to that of ACh?

Nicotine recovers more slowly than acetylcholine (ACh), leading to prolonged effects on receptor responsiveness

Why might nicotine prolong receptor desensitization?

Due to its persistent binding & high affinity for nAChRs, which disrupts normal receptor cycling and signaling.

Desensitization of central nAChRs leads to what?

Acute tolerance

Classical Desensitization

Occurs when receptors become less responsive after prolonged stimulation by an agonist, resulting in reduced cellular response to the ligand.

• induced by relatively high agonist concentrations

High-Affinity Desensitization

A form of desensitization that occurs at lower agonist concentrations, leading to a sustained decrease in receptor responsiveness even with continued exposure to the agonist.

Properties of Desensitization

Refers to the characteristics that define how receptors adapt to prolonged stimulation, impacting their responsiveness to agonists

What pathway do most drugs of abuse take advantage of?

The mesolimbic dopamine pathway

Components of the mesolimbic pathway?

• Ventral tegmental area (VTA)

• Nucleus Accumbens (NAc)

• Prefrontal cortex (PFC)

• Amygdala

• Hippocampus

• many more

Medium Spiny Neurons (MSNs)

The principal projection neurons in the striatum, playing a critical role in the processing of dopamine signals and mediating reward-related behaviors.

What neurotransmitters regulate dopamine release from the VTA?

• Glutamate

• GABA

• ACh

How does nicotine increase DA transmission from the VTA?

• Activation of α4/β2-containing nAChRs on DA neuron cell bodies

• Activation of α4/β2/α6* receptors on DA terminals

• Activation of presynaptic α7 nAChRs on glutamatergic terminals in the VTA

• Sustained low levels of nicotine, as occurs in the brains of smokers, can desensitize α4/β2* nAChRs on GABAergic terminals

Activation of α4/β2-containing nAChRs on DA neuron cell bodies leads to what?

Increased cell body excitability & AP firing

Activation of α4/β2/α6* receptors on DA terminals leads to what?

Increased DA release onto medium spiny neurons (MSNs) in the NAc

Activation of presynaptic α7 nAChRs on glutamatergic terminals in the VTA leads to what?

Increased glutamate release onto DA neurons, further stimulating those neurons

• also results in the induction of LTP on those synapses

How might the induction of LTP affect dopaminergic signaling in the context of nicotine activation?

Contributes to heightened excitability & synaptic strength of DA neurons in the VTA facilitating prolonged dopaminergic signaling in response to nicotine

• may contribute to the reinforcement of addictive behaviors.

Desensitized α4/β2* nAChRs on GABAergic terminals in the VTA, as a result of chronic low levels of nicotine, can lead to what?

Decreased GABA release onto DA neurons, thereby reducing inhibitory tone

• this will shift inhibitory balance in the VTA & promote excessive dopaminergic activity

Medial Habenula (MHb)

A brain structure that modulates dopaminergic activity and plays a critical role in the aversive effects of drugs, influencing addiction & withdrawal processes

Interpeduncular Nucleus (IPN)

A brain region involved in the regulation of reward and aversion, influenced by the activity of the medial habenula (MHb) & affecting addiction-related behaviors.

MHb-IPN Pathway

A neural circuit incorporating the medial habenula and the interpeduncular nucleus, involved in processing aversive stimuli & signs of nicotine withdrawal

If the MHb-IPN pathway is disrupted, what is the result?

Increased rate of self-administration of nicotine

Aversive effects of nicotine seem to be mediated by the activation of what subunit?

alpha-5 nAChRs subunits along the MHb -IPN pathway

• knockout mice of this subunit experience a loss of aversion

How might nicotine affect attention?

Seemingly enhances focus & attention through its action on the mesocortical DA pathway, leading to improved cognitive performance in certain tasks

Dual Motivation

Model that explain that desire for nicotine consumption involves both direct reward/reinforcement + cognitive enhancement

• rewarding/reinforcing effects are mediated by the mesolimbic pathway

• a second source of reinforcement comes from the cognitive enhancement mediated by the mesocortical DA pathway

Mesocortical DA Pathway

A neural pathway that connects the VTA to the PFC

• involved in cognitive processes & attention.

Deprivation Reversal Model

Posits that the desire to consume drugs increases following a period of abstinence, leading to heightened craving & motivation to use due to the brain's adaptation to the absence of the drug.

Neurobehavioral effects of nicotine:

• Relaxation

• Stress alleviation

• Increased attention/focus

• Some stimulatory effects

Acute administration of certain doses of nicotine has been shown to enhance what? (similar effect to stimulants)

Locomotor activity

The enhancement of locomotor activity by nicotine indicates what?

Sensitization to the rewarding effects of the drug

Nicotine & cocaine self-administration produce similar patterns of what?

Altered gene expression

Physiological effects of nicotine on the autonomic nervous system (ANS):

Activation of the sympathetic nervous system

• increased HR

• increased BP

• secretion of NE & Epi from the adrenals

Physiological effects of nicotine on the parasympathetic nervous system (PNS)

• Increased stomach acid

• Increased intestinal motility

Other physiological effects of nicotine:

• Suppression of appetite

• Reduced body weight secondary to increased metabolic rate

Cancers that have been causally related to tobacco smoke exposure:

Lung, throat, mouth, liver, stomach, & bladder cancers

• in addition to many more

Chronic diseases causally related to tobacco smoke exposure:

• Stroke

• Coronary heart disease + aortic aneurysm

• Pneumonia

• Chronic obstructive pulmonary disease (COPD)

• Diabetes

• Overall diminished health

Acute pulmonary effects of E-cigarettes:

• Increased flow resistance

• Increased airflow reactivity

Chronic pulmonary effects of E-cigarettes:

• Higher airway resistance

• Airway obstruction & inflammation

• COPD

• Chronic bronchitis

• Asthma

Acute cardiovascular effects of E-cigarettes:

• Increased HR & BP

• Increased aortic stiffness

Chronic cardiovascular effects of E-cigarettes:

• Increased risk of heart disease

• Atherosclerosis

• Reduced vascular function

• Potential for arrhythmias

Benefits of E-cigarettes:

• No tobacco or smoke combustion = no tar or heavy carcinogen contents

• Negligible harm from second-hand smoke

• May help smokers transition away from cigarettes

Risks of E-cigarettes:

• Still a nicotine addiction

• May allow smokers to expand habit

• May attract younger users w/ flavored/colorful products

What are the 2 strongest predictors of nicotine addiction?

• Total # of cigarettes smoked in a day

• Amount of time from waking to the 1st cigarette

Acute Nicotine Tolerance

Describes the body's decreased response to nicotine after a single exposure, resulting in the need for higher doses to achieve the same effects.

Chronic Nicotine Tolerance

Refers to the reduced sensitivity to nicotine after prolonged use, leading to an increased amount needed for the same pleasurable effects.

Wanting

A motivational state associated with the craving for drug use, which can increase despite the loss of pleasure from the drug.

Craving

The intense desire or urge to use a drug, often linked with withdrawal symptoms and heightened wanting.

Needing

A state characterized by a compelling drive to obtain a drug, often associated with physical dependence & withdrawal symptoms.

Daily Smoking Cycle

Refers to the pattern of smoking behaviors in which individuals smoke at regular intervals throughout the day, often aligning with cravings & withdrawal symptoms

Plasma Nicotine Level (ng/ml)

The concentration of nicotine in the blood plasma, measured in nanograms per milliliter, which influences cravings & withdrawal symptoms in smokers.

How might the plasma nicotine levels of a smoker be characterized over the course of a day?

Typically fluctuate rapidly throughout the day, peaking shortly after smoking and gradually declining during periods of abstinence

• frequent fluctuation between pleasure/arousal & w/drawl

Why would plasma nicotine levels be low in the morning?

Due to overnight abstinence from smoking

• nicotinic receptors resensitize significantly during this time, allowing the cycle to repeat itself each day

What is the relationship between the positive effects of nicotine & withdrawl?

Nicotine-induced positive effects diminished w/ repeated smoking episodes as a result of the rapid tolerance to the drug’s actions, whereas w/drawl simultaneously become more pronounced

Affective Withdrawal

Refers to the negative emotional & psychological symptoms experienced during nicotine withdrawal

• includes anxiety, irritability, depression, & restlessness

Somatic Withdrawal

Refers to the physical symptoms experienced during nicotine withdrawal

• includes tremors, bradycardia fatigue, GI distress, hunger, weight gain, insomnia, & nausea

Cognitive Withdrawal

Refers to the cognitive impairments & difficulties in concentration experienced during nicotine withdrawal

• may include memory deficits, inability to focus, & reduced reaction time.

What is the most common reason for relapse?

Craving

Other than craving, what is the most commonly reported reason for relapse (in the context of smoking)?

Severe stress

Patterns of smokers:

• Native chippers

• Regular smokers

• Converted chippers

Native Chippers

Smokers who use tobacco occasionally & primarily in social situations, often without developing a dependence on nicotine

• ~ 5 smokes/day