A Three-Way Drug Discrimination Study: A Role for DA-Mediated Effects in MDMA's Discriminative Cue Properties

<p>While 3,4-methylenedioxymethamphetamine (MDMA) shares many similarities with amphetamine, previous two choice drug discrimination procedures have shown that substitution between the two substances is inconsistent. Three choice drug discrimination procedures have revealed that MDMA can be discriminated from amphetamine, due to MDMA’s primary influence in releasing 5-HT. Neurochemical evidence had previously suggested that at doses >3.0mg/kg MDMA-induced dopamine (DA) release will increase significantly. In the current study rats were trained to discriminate MDMA from amphetamine and saline. As the dose of MDMA increased beyond the training dose (>1.5mg/kg) MDMA-appropriate responding decreased, while the proportion of amphetamine lever responding increased and eventually surpassed MDMA-appropriate responding at the highest dose (4.5mg/kg). This would indicate an important role for DA mediated influences in MDMA’s discriminative cue properties. Further evidence for this conclusion comes from tests with the D1 antagonist SCH23390 and the D2 antagonist eticlopride which attenuated this effect and also led to a nonsignificant increase in the proportion of saline lever responding. Subsequent tests with the 5-HT2c antagonist RS102221resulted in no significant dose dependent changes, but appeared to reduce MDMA-appropriate responding especially at the training dose. The current findings would suggest that low doses of MDMA are discriminable from amphetamine, however with increasing doses MDMA will be perceived as more “amphetamine-like”. These findings could suggest that at relatively high doses MDMA produces effects that are typically associated with dopamine-releasing drugs, such as high abuse potential.</p>

A Three-Way Drug Discrimination Study: A Role for DA-Mediated Effects in MDMA's Discriminative Cue Properties

<p>While 3,4-methylenedioxymethamphetamine (MDMA) shares many similarities with amphetamine, previous two choice drug discrimination procedures have shown that substitution between the two substances is inconsistent. Three choice drug discrimination procedures have revealed that MDMA can be discriminated from amphetamine, due to MDMA’s primary influence in releasing 5-HT. Neurochemical evidence had previously suggested that at doses >3.0mg/kg MDMA-induced dopamine (DA) release will increase significantly. In the current study rats were trained to discriminate MDMA from amphetamine and saline. As the dose of MDMA increased beyond the training dose (>1.5mg/kg) MDMA-appropriate responding decreased, while the proportion of amphetamine lever responding increased and eventually surpassed MDMA-appropriate responding at the highest dose (4.5mg/kg). This would indicate an important role for DA mediated influences in MDMA’s discriminative cue properties. Further evidence for this conclusion comes from tests with the D1 antagonist SCH23390 and the D2 antagonist eticlopride which attenuated this effect and also led to a nonsignificant increase in the proportion of saline lever responding. Subsequent tests with the 5-HT2c antagonist RS102221resulted in no significant dose dependent changes, but appeared to reduce MDMA-appropriate responding especially at the training dose. The current findings would suggest that low doses of MDMA are discriminable from amphetamine, however with increasing doses MDMA will be perceived as more “amphetamine-like”. These findings could suggest that at relatively high doses MDMA produces effects that are typically associated with dopamine-releasing drugs, such as high abuse potential.</p>

Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

Background: Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Aims/methods: Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Results/outcomes: The MIA rats’ discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. Conclusion: These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

Preclinical Models of Substance Use Disorder

The foundational premise for all preclinical biomedical research is that results generated from nonhumans would be predictive of and consistent with results generated in humans. Preclinical procedures have been developed to model various aspects of substance use disorder (SUD) in almost every nonhuman species, but the predominant species utilized are mice, rats, and nonhuman primates. Three common preclinical procedures that have been utilized to determine the abuse liability of novel or emerging psychoactive compounds include intracranial self-stimulation (ICSS), drug discrimination, and drug self-administration. Although all three procedures model slightly different aspects of substance abuse, all three have shown good translational concordance to predicting substance abuse potential in humans. Where these three preclinical procedures differentiate is in their utility to evaluate candidate medications for the treatment of SUDs, and preclinical drug self-administration procedures have shown to be more predictive of candidate medication treatment effects than drug discrimination endpoints. Candidate medication treatment effects on ICSS have only recently been published. Two preclinical experimental design attributes that enhance translational concordance with clinical evaluation of candidate pharmacotherapies for SUD include repeated dosing of the candidate medication over several days and assessment of behavioral selectivity for candidate medication effects to decrease drug-maintained behavior and increase behavior maintained by nondrug reinforcers such as food.