DEPENDENCE POTENTIAL

Identifying abuse and dependence liability is an important issue for CNS safety pharmacology.  Regulatory bodies in the US and Europe are in the process of developing standard guidelines, based on looking for similarities with known drugs of abuse.

At Porsolt , we provide fully GLP compliant models for evaluating drug dependence and liability:

> Spontaneous withdrawal effects, including telemetry assessment

> Precipitated withdrawal (naloxone, flumazenil)

> Place preference

> Drug discrimination

> Self-administration

Assessment of withdrawal symptoms

In addition to assessing abuse liability, regulatory agencies have indicated how the problem of withdrawal symptoms should be addressed. 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.

SUGGESTED APPROACH

• Twice a day 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.

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.

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).

Recent Porsolt publications: