Lecture 3: Block 2: Acetylcholine and Nicotine

What is acetylcholine (ACh)?

A neurotransmitter involved in muscle activation, attention, arousal, learning, and reward modulation. In addiction, it interacts with dopamine systems via nicotinic acetylcholine receptors (nAChRs).

What are nicotinic acetylcholine receptors (nAChRs)?

Ligand-gated ion channels activated by ACh or nicotine, allowing sodium and calcium influx to depolarize neurons and release neurotransmitters.

How does nicotine produce its effects?

Nicotine binds to nAChRs in the VTA, stimulating dopamine neuron firing and increasing dopamine release in the nucleus accumbens.

What are the main receptor subtypes relevant to nicotine addiction?

α4β2 and α7 nAChRs — the α4β2 subtype is most critical for nicotine reinforcement and addiction

What happens to nAChRs with chronic nicotine use?

They become desensitized, leading to tolerance, and then upregulated (increased receptor number), contributing to dependence.

How does nicotine affect the autonomic nervous system?

It stimulates both sympathetic (increasing arousal, heart rate) and parasympathetic activity, producing complex physiological effects.

What are the behavioral effects of nicotine?

Increased alertness, improved attention, mild euphoria, reduced anxiety, and appetite suppression.

Why does nicotine reduce stress despite physiological arousal?

Nicotine indirectly modulates norepinephrine and dopamine, activating stress circuits but producing a calming subjective effect due to desensitization and cortical modulation.

How does nicotine withdrawal manifest?

Irritability, anxiety, difficulty concentrating, increased appetite, depressed mood, and craving due to reduced dopaminergic tone and receptor imbalances.

What is the concept of "breaking point" in self-administration studies?

It refers to the amount of effort (e.g., lever presses) an animal will exert to obtain nicotine; higher breaking points indicate higher reinforcement value.

What neurotransmitter interactions are important in nicotine addiction?

Nicotine activates dopamine release (reward), norepinephrine (arousal), serotonin (mood), and glutamate (learning), while reducing inhibitory GABAergic tone in the VTA.

What is the significance of the mesolimbic dopamine system in nicotine addiction?

Nicotine increases firing of VTA dopamine neurons via α4β2 nAChRs, reinforcing smoking behavior.

Why does nicotine have high abuse liability despite being legal?

Its pharmacokinetics (rapid brain delivery through inhalation), conditioning with sensory cues, and withdrawal-driven negative reinforcement sustain strong dependence.

What are common treatments targeting nicotinic receptors?

Varenicline (a partial α4β2 agonist) reduces craving and withdrawal, while nicotine replacement therapy and bupropion aid in cessation.

Which brain regions are key in nicotine's reinforcing effects?

The VTA, nucleus accumbens, amygdala, and prefrontal cortex — the same reward and cue networks involved in other addictions.

What are the two classes of nicotine receptors? Which subunit(s) are associated with addiction?

Nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChRs).
The α4β2 nAChR subtype is most strongly associated with nicotine reinforcement and dependence.

Nicotine: Parenteral or Enteral? Can you provide examples?

Nicotine is primarily parenteral, absorbed through the lungs (inhalation). It can also be absorbed through mucous membranes (nasal sprays, gum) or transdermally (patch). Enteral routes (e.g., ingestion) are ineffective because nicotine is degraded in the liver.

What are chippers?

"Chippers" are occasional smokers who use nicotine intermittently without developing dependence. They exhibit lower reinforcement sensitivity, less upregulation of nAChRs, and stronger prefrontal inhibitory control.

What are the physiological effects of nicotine? How does this relate to Nicotine Abstinence Syndrome?

Nicotine increases heart rate, blood pressure, and alertness (sympathetic activation) but can also produce relaxation. Nicotine Abstinence Syndrome includes irritability, anxiety, poor concentration, and craving, reflecting receptor desensitization and decreased dopamine release after cessation.

What behavioral paradigm is used to assess the binge/intoxication stage? How about the withdrawal stage? What does this tell us about the circuitry involved? The receptors?

Binge/intoxication - assessed using intravenous drug self-administration. Activation of the VTA-NAc dopamine system and α4β2 nAChRs indicates reinforcement. Block b2? Stop craving
Withdrawal - assessed by elevated intracranial self-stimulation thresholds or anxiety tests, → lower Da in amygdala and NAc and lower VTA firing.

For smokers, what else is highly involved in relapse? (think of the three things that result in relapse)

Drug cues, stress, and nicotine priming are the primary relapse triggers. Sensory cues (taste, smell) associated with smoking are especially potent due to conditioning.

What is Nesbitt's Paradox?

Nesbitt's Paradox describes nicotine's ability to act as both a stimulant (increasing arousal) and a relaxant (reducing stress). This dual effect is explained by receptor desensitization and differential activation of sympathetic and dopaminergic systems.

What 3 ways does nicotine effect dopamine release in the mesolimbic pathway.

Directly- By activating DA in the VTA

Indirectly- Increased glutamatergic activation (stimulate glutamate = activate DA in the VTA)

Desensitization- desensitization of GABA receptors.