Drug abuse & dependence

CENTRAL NERVOUS SYSTEM

Porsolt offers models in all areas of psychopharmacology, epilepsy, sleep-wake, and neurodegenerative disorders. We are uniquely placed to offer a full range of CNS efficacy and safety pharmacology assessments, from basic models and regulatory tests, through the evaluation of abuse and dependence liability and proconvulsant risk using EEG.

Drug abuse & dependence

EARLY INDICATORS OF ABUSE LIABILITY

Evaluating the potential of a novel test substance to possess properties indicative of abuse liability can start at an early stage in a project’s development. Interactions with certain receptors (i.e. dopamine receptor subtypes, glutamatergic receptors and ion channels, benzodiazepine receptors, etc.) or evidence from an Irwin test for certain behavioral signs common to many abused drugs (increased locomotor activity, stereotypies, etc.) would suggest that the class of substance under study might have the potential to be abused. Under these conditions, a more formal demonstration of this potential will usually be required by regulatory bodies.

ASSESSMENT OF ABUSE LIABILITY

Definition of drug abuse (ICD-10 and DSM-IV2)

• Strong desire to take the drug for non-medical use
• Difficulties in controlling its use
• Persisting in its use despite harmful consequences
• A higher priority given to drug use than other activities and obligations
• Increased tolerance
• Sometimes a physical withdrawal state

Models available for evaluating drug abuse liability (reinforcing properties) include the following:

Place preference / Drug discrimination / Self-administration

Place preference

Beyond drug discrimination and self-administration, which are likely to become regulatory requirements, other tests have a specific utility at earlier stages in drug development.

If the binding and behavioral profile suggests a clear and major risk, substances may be first evaluated in the place preference test to determine if marked abuse potential is of a similar level to that of opiates and stimulants. 

Drug discrimination

In drug discrimination, study animals learn to distinguish between two internal states: usually those induced by a drug and its vehicle. Drug discrimination is pharmacologically highly specific and the choice of drug for training should be related to the biochemical target of the test substance.
It should be noted that discrimination itself is not necessarily related to abuse potential but simply an indication that a drug has interoceptive properties, which could be aversive or rewarding.

Training substances (rats)
Amphetamine, Cocaine, DOM, Morphine, Fentanyl, Pentazocine, Alcohol, Midazolam, Chlordiazepoxide, Diazepam,  THC, Tianeptine, DOI

Self-administration

Self-administration is currently considered as the ‘gold standard’ for assessing abuse potential as it gives few false positives and negatives and is considered equally valid in both rats and primates (i.e. both species have concordance rates close to 100% with human data).

Assessment of withdrawal symptoms

In addition to assessing abuse liability, both the EU and US regulatory agencies have indicated how the problem of withdrawal symptoms should be addressed which we cover with two suggested protocols.  Besides the historically well-known drugs, such as opiates, inducing withdrawal phenomena more recent examples such as benzodiazepines and SSRIs have been shown to be associated with withdrawal in some patients that may make it difficult to discontinue treatment. When discontinuation phenomena cannot be circumvented by tapering down the dose this syndrome may lead to drug dependence in those patients.

Suggested approach

Twice daily dosing for 20 days + 8 days withdrawal (Low dose at upper end of therapeutic range, High dose = NOAEL)

Non-specific somatic measures ( E.g. food intake, body weight, body temperature)

Telemetry recording

We have been exploring the use of telemetry to examine additional parameters and to allow monitoring over 24 hours, during both treatment and withdrawal phases. This approach appears to be more sensitive and gives a more complete picture of the state of the animal during  the withdrawal phase.