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STORM Therapeutics: From Lead to Pre-Candidate Nomination in 18 Months
STORM Therapeutics: From Lead to Pre-Candidate Nomination in 18 Months
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Substance Use Intoxication (Binge): Insights from Preclinical Models
Focusing on the intoxication phase of addiction, this article examines how behavioral pharmacology models capture reward, reinforcement and binge‑like drug use in preclinical studies.
What Is Substance Use Intoxication?
Substance use intoxication, often referred to as binge use, describes the phase in which a person consumes a drug for its rewarding and pleasurable effects often increasing the amount and frequency as time progresses. This is the phase that most people associate with addiction and the harm it can cause.
What begins as infrequent use can rapidly escalate as the body adapts to the drug’s effects. As tolerance develops, higher doses or more direct routes of administration (smoking and injection) are required to achieve the same reward. Preventing or reducing the rewarding effects of drugs, or making the experience unpleasant, is therefore a potential strategy for the treatment of drug addictions.
Modelling Intoxication In Preclinical Studies
In animal models, intoxication can be modelled by making the drug freely available in drinking water or food or delivered only after a specific behavior has been performed. Due to the temporal nature of addition (rewards are most strongly recognized when they are instant), faster delivery of the drug to the brain produces a stronger association between the action and the reward. For this reason, models that deliver a drug intravenously are often more robust than models which deliver drugs orally.
Continuous vs Limited Access Models of Binge-Like Drug Use
Animals can be provided with continuous or limited access to a drug. Limited access models are frequently used to induce binge-like behavior, as unpredictable availability encourages animals to consume larger quantities over a short period of time. These models work particularly well for alcohol and palatable foods, such as chocolate in binge eating models.
For example, when chocolate is made available to rats sporadically in 2-hour sessions, the amount of chocolate ingested in each session increases rapidly. The presence of the palatable reward also drives overeating of the standard chow drive that is always available.
Overeating is for pleasure rather than energy, and each session is followed by a period of consuming less standard diet. Such models allow researchers to assess whether novel pharmacotherapies reduce the amount of drug or palatable food consumed during each binge session.
Consumption of standard chow diet (available ad libitum) and chocolate (available in 2-hour sessions) under a limited access binge model. Chocolate consumption becomes hedonic (not associated with metabolic need) and induces overeating of standard chow (red circles).
Operant Self-Administration Models of Intoxication
Another widely used approach involves requiring animals to perform a behavior to obtain the drug. Often the behavior required is pressing a lever or inserting their node into a hole. These operant self-administration models allow research to quantify the amount of work that an animal is willing to perform to obtain the drug.
The behavioral demand can easily be adjusted by increasing the number of responses required before drug delivery. This enables assessment of two critical questions:
- Does the treatment reduce the total drug consumption?
- Does the treatment reduce the effort an animal is willing to perform to receive the drug?
Together, these measures provide insight into both reinforcement and motivation, key components of substance use disorders.
Self-administration, particularly intravenous self-administration, models have been used in preclinical safety testing since the 1960s to determine whether new drugs are likely to have abuse potential in humans. Therefore, there is a wealth of literature that demonstrates rodents and non-human primates will readily self-administer most drugs which humans find pleasurable, with the notable exception of psychedelics.
However, for these models to be useful in assessing novel pharmacotherapies for drug addictions, they must also demonstrate that current clinical interventions translate back into animals.
Case Study: Validating an Intravenous Self-Administration Model Using Naltrexone
At Sygnature Discovery, we evaluated whether naltrexone, an FDA-approved treatment for opioid use disorder, would decrease heroin self-administration in rats. In the clinic, long-acting naltrexone implants reduce opioid use by blocking the rewarding and pleasurable effects. We validated our intravenous self-administration model with a clinically relevant control so that it can be utilized in assessing efficacy of novel treatments.
Rats were implanted with a jugular vein catheter for efficient drug delivery. Rats were then given daily access to a lever, which when pressed administers a small dose of heroin. Over several weeks, rats were self-administering approximately 17 doses of heroin within each 2-hour session.
To confirm that level pressing was drive by reward, heroin was replaced by saline. Within one week, the number of self-administered doses had reduced to less than 6 per session. When heroin was reintroduced, responding gradually returned to 17 self-administrations per session.
Finally, to assess pharmacological intervention, rats were administered with either vehicle or naltrexone (0.25, 1 or 2 mg/kg) 30 minutes before each session. Vehicle-treated rats continued to self-administer heroin as before. In contrast, rats treated with naltrexone showed a marked reduction in heroin intake. At 1 and 2 mg/kg, heroin self-administrations fell to 6 doses per session, similar to when they were receiving only saline.
These results demonstrate that naltrexone reduces heroin self-administration in rats, mirroring its clinical efficacy and validating this intravenous self-administration model for assessing novel treatments for opioid use disorder.
Mean number of infusions received per session when lever pressing provides; 1) heroin 2) saline 3) heroin following vehicle pre-treatment 4) heroin following naltrexone (0.25, 1 & 2 mg/kg) pre-treatment. ***p<0.001 versus vehicle pre-treatment.
Explore our addiction research models
This article forms part of a four-part series exploring substance use disorders through the three-phase model of addiction and the preclinical behavioral pharmacology models used to support drug discovery.
Together, these articles examine how addiction develops, why it is so persistent, and how validated in vivo models are used to assess new therapeutic approaches.
An introduction to substance use disorders, the three-phase addiction model, and the role of behavioral pharmacology.
- Preclinical Models of Substance Use Intoxication (Binge)
How reward-driven drug use and escalation are modelled in vivo.
Assessing dependence, withdrawal symptoms and maintenance therapies.
Understanding cue-induced relapse using reinstatement paradigms.
Continue the series
Next: Preclinical Models of Substance Use Withdrawal
Focusing on the withdrawal phase of addiction, this article examines how behavioral pharmacology models assess drug dependence and therapeutic intervention in preclinical studies.
CNS & Pain Models
Addiction research depends on validated in vivo behavioral pharmacology models to assess reward, reinforcement, dependence and relapse-relevant behaviors.
These approaches form part of Sygnature Discovery’s CNS & pain in vivo pharmacology capabilities, supporting translational neuroscience and substance use disorder drug discovery from early research through to clinical decision-making.
