Lecture 15: SUD Treatment and Animal Models

What Key Questions Must Be Answered When Using Animal Models to Understand Addiction and Finding Treatments

• Are the animal models appropriate for studying addiction?

• Do they accurately reflect the human condition and the underlying neurobiology of addiction?

• How translatable are these models to clinical contexts?

• How do existing treatments perform in these models?

• Are there alternative compounds that mimic the drug of abuse and act similarly within the model?

What are the Strengths and Weakensses of Using Animal Studies?

• They are essential in understanding the mechanism behind addiction and predicting treatment efficacy

• Invaluable for investigating new theraputic stratergies

• Limited by spiecies differences, e.g. in receptor distribution, metabolism and behavioural responses, which must be carefully accounted for

What is Cannabis Use Disorder

• Cannabis use causes adverse effects on both physical and mental health

• THC (Δ9-tetrahydrocannabinol) is the main psychoactive component and a partial agonist at CB1 receptors → activates dopamine reward system → produces “high”

  • CB2 receptor actions partially modulate effects

• Risk factors:

  • Increasingly potent cannabis strains, e.g. Godfather OG (34–35% THC) → higher risk of dependence and abuse.

  • Synthetic cannabinoids (e.g., Spice): full CB1 agonists → much stronger effects and higher addiction potential

• Disease is recognised in DSM-5 and ICD-11

• No approved pharmacological treatments

What Are The Goals of CUD Treatment?

• To provide treatments that can help

  • decrease or stop cannabis use

  • Reduce withdrawal symptoms,

  • Prevent craving and relapse

What considerations are important when selecting animal models to study THC and cannabis use disorder?

• Species sensitivity: Not all animals are equality sensitive to THC

  • Rodents: relatively insensitive; THC can be toxic

  • Squirrel monkeys: preferred; sensitive to THC show reliable self-administration

• Modelling addiction phases → Approrpiate paradigms required for:

  • Binge/intoxication

  • Withdrawal/negative affect

  • Reinstatement/relapse

• Translatability: Paradigms are typically reproducible and reflect human addiction mechanisms

Which compounds are used as controls or treatments in THC animal models, and what are their limitations?

• Rimonabant: CB1 receptor antagonist

  • Often used as a control, but not effective for treating CUD

• Dopamine antagonists:

  • Can reduce THC effects

  • Unreliable, cause side effects, unsuitable for long-term use as therapies

• Highlights the challenge of developing effective pharmacological treatments for CUD

Why is studying THC self-administration in rats challenging, and what alternative models are more suitable?

• Poor reproducibility of THC self-administration in rats

• Better options include primates e.g., squirrel monkeys, which show reliable self-administration

• Other translatable paradigms:

  • Conditioned Place Preference (CPP)

  • Drug discrimination

  • Reinstatement models

• Rimonabant (CB1 antagonist) was tested for blocking THC effects

What is Ro 61-8048

• A kynurenine-3-hydroxylase inhibitor

  • Prevents conversion of L-kynurenine → 3-hydroxykynurenine

  • Increases kynurenic acid levels, which acts as a:

    • Glutamate receptor antagonist

    • Nicotinic α7 negative allosteric modulator

• Mechanism in reward circuits: Reduces glutamatergic signalling → decreases dopamine release in VTA and NAc, resulting in diminished THC rewarding effects

• Behavioural paradigm example: Green light cue signals THC (4 mcg/kg IV) available after 10 lever presses; Ro 61-8048 reduces lever-pressing by decreasing THC reward

How does Ro 61-8048 affect THC self-administration in experimental models, and what mechanisms are involved?

• Experimental paradigm: THC (4 µg/kg, IV) available after 10 lever presses signalled by a green light

• Ro 61-8048 reduces lever pressing and total THC self-administered

• Mechanism:

  • Increases kynurenic acid → diminished glutamate receptor activation

  • Leads to reduced dopamine release in NAc and reward pathways

  • THC’s rewarding potential decreases

• Nicotinic α7 mechanism is likely irrelevant in IV THC (no nicotine), but may matter in humans where THC is inhaled alongside nicotine

How does Ro 61-8048 affect THC-seeking behaviour during reinstatement in animal models, and what does this suggest for relapse?

• Reinstatement paradigm: After withdrawal, THC and drug-associated cues are reintroduced → lever pressing increases (drug-seeking behaviour)

• Ro 61-8048 significantly reduces lever pressing and THC intake, suggesting decreased perceived reward, craving, and relapse potential

• Ro 61-8048 may be a potential treatment for preventing relapse in cannabis use disorder (CUD)

• Further studies are needed to confirm whether reduction is clnically meaningful and not due to confounding factors e.g. sedation or reduced motor activity

  • Clinical relevance remains to be established

What are the effects of THC withdrawal in animal models, and how do rimonabant and naltrexone influence this?

• THC withdrawal: Stopping THC administration → lever pressing decreases

  • Motivation to seek THC returns upon reinstatement

• THC + Rimonabant (CB1 antagonist) precipitates withdrawal → THC can no longer elicit reward (CB1 receptor is blocked)

  • Lever pressing drops significantly → animal in withdrawal

• THC + Naltrexone (μ-opioid antagonist) initially dulls THC responses but does not fully block reward

  • Suggests a limited role of opioid systems in THC reward → Naltrexone unlikley to be an effective treatment for CUD

How can dronabinol be used to manage THC withdrawal?

• Synthetic form of THC that replaces THC effects → reduces withdrawal symptoms

  • Used clinically to stimulate appetite in AIDs

• Dose-dependent reduction of withdrawal

  • Higher doses → better withdrawal control

  • Allows controlled management and exit from addiction

• Considerations:

  • A longer half-life reduces relapse risk

  • Abuse potential must be low to be clinically viable

• It can help reduce withdrawal, but its use as a treatment depends on its own pharmacokinetics and abuse risk

Can CB1 antagonists block responses to morphine, and what does this indicate for treatment?

• Rimonabant (CB1 antagonist): does not block responses to morphine

• Naltrexone (μ-opioid antagonist): effectively blocks morphine effects

• Implication:

  • CB1 antagonists are specific to cannabinoids

  • Not suitable as treatments for opioid use disorder