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Melior Pharmaceuticals

melior melior melior discovery melior pharmaceuticals preclinical services pre-clinical services in vivo pharmacology in vivo efficacy efficacy models pharmacokinetics indications discovery specialized animal models bioanalytical services theratrace exton pennsylvania cro contract research drug discovery drug development metabolic disease alzheimer’s alzheimers diabetes reprofiling

Melior Discovery drug abuse liability

Drug Discrimination
The actions of psychoactive agents as discriminative stimuli are closely related to their ‘subjective’ effects in humans. In this sense, it is believed that analysis of discriminative properties of drugs in animals is of considerable value in predicting which specific drugs may be prone to abuse.  However, a second major reason for the popularity of drug discrimination procedures is the remarkable pharmacological specificity of the discriminative stimulus properties of compounds.  Thus, the paradigm may also be used to elucidate pharmacological mechanisms of novel compounds depending on their discriminative stimulus similarities in comparison to a given training drug with known pharmacology.

Drug discrimination is a well-established technique for measuring the in vivo pharmacology of drugs of abuse.  The technique can be used as a means of determining the abuse liablity of test compounds when compared with a known drug of abuse.  Rats can be trained daily during 15 minute sessions, during which lever pressing is reinforced by the presentation of a sucrose pellet.  Prior to each traning ession, rats are injected with either a training drug or vehicle.  Responses on the "drug lever" are reinforced during drug training sessions and responses on the other, "vehicle lever" are reinforced during vehicle training days. 

Rats can be tested twice weekly, with training sessions conducted on the remaining days of the week.  Tests can be used to determine whether a compound mimics the training drug or whether a compound alters the effects of the training drugs. 

 

Drugs eliciting 80% or greater responding on the drug-trained lever are classified as producing full generalization to the training compound.  This is a measure of the abuse liability of a new compound.  Full generalization to a known drug of abuse can mean a high risk of abuse potential.  Compounds producing 20-80% drug lever responding are said to partially generalize to the training days, indicating a lower abuse liablity than compounds eliciting full generalization.

 

Figure 1: Drug Discrimination- Active Lever Presses

                   Drug Discrimination: Active Lever Presses - Amphetamine and Modafinil

Percent Drug Lever Responding.  Percent drug lever responding in Sprague Dawley rats trained to discriminate Amephetamine, a full generalization drug of abuse, at 1mpk dose from saline.  Amphetamine completely generalized to the 1mpk training dose at doses of 0.7mpk and 1mpk.  When saline or vehicle for test compounds were tested, near zero levels of amphetamine-lever responding occured (not shown).  Modafinil produced partial generalization to the amphetamine descriminative stimulus cue (60%), which is in line with published literature (Quisenberry AJ, 2013).

 

Figure 2: Drug Discrimination- Response Rates per Second

                         Drug Discrimination: Response rates per second- Amphetamine and Modafinil

Response Rates per Second. This figure depicts mean response rates produced after dosing with amphetamine or modafinil.  Higher doses of amphetamine do not produce a response.                     

 

If you are interested in learning more about Drug Discrimination and Abuse Liability, please contact models@meliordiscovery.com to start the conversation.