Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol

Abstract

The progress on understanding the pharmacological basis of ethanol’s discriminative stimulus effects has been substantial, but appears to have plateaued in the past decade. Further, the cross-species translational efforts are clear in laboratory animals, but have been minimal in human subject studies. Research findings clearly demonstrate that ethanol produces a compound stimulus with primary activity through GABA and glutamate receptor systems, particularly ionotropic receptors, with additional contribution from serotonergic mechanisms. Further progress should capitalize on chemogenetic and optogenetic techniques in laboratory animals to identify the neural circuitry involved in mediating the discriminative stimulus effects of ethanol. These infrahuman studies can be guided by in vivo imaging of human brain circuitry mediating ethanol’s subjective effects. Ultimately, identifying receptors systems, as well as where they are located within brain circuitry, will transform the use of drug discrimination procedures to help identify possible treatment or prevention strategies for alcohol use disorder.

Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys

“…Interestingly, however, MK‐801 fully substituted for EtOH in this monkey, suggesting that the glutamatergic cue was guiding the discrimination. This finding is contrary to several other published reports on EtOH discrimination in cynomolgus macaques that have concluded that the GABAergic component is more prominent in macaques relative to rodents across several training doses (Allen et al., ; Grant et al., , ; Stolerman et al., ). One explanation is the relatively large sample size (8 subjects relative to groups of 4 monkeys in previous studies) and choosing the monkeys to be relatively genetically heterogeneous (no common grandparents) allowed this individual difference to be captured.…”

“…In conclusion, the data presented here demonstrate that EtOH's discriminative stimulus effects in rhesus monkeys are largely consistent with reports in many other species including pigeons (Grant and Barrett, ), rats (Shelton and Balster, ), mice (Shelton and Grant, ), squirrel monkeys (Platt et al., ), cynomolgus macaques (Grant, ; Grant et al., ; Vivian et al., ; Helms and Grant, ), and humans (Duka et al., ) (for reviews, see Allen et al., ; Grant and Bennett, ; Stolerman et al., ). Additionally, we have conducted a thorough blood EtOH time course with 15‐minute sampling intervals during the rising phase of BEC to capture the time and value of peak BEC following low and moderate EtOH doses.…”

“…The current study is the first study to our knowledge that has characterized the absorption and clearance rates of low‐to‐moderate EtOH doses and determined the GABA A and NMDA receptor involvement in moderate EtOH doses. These data fill an important gap in understanding the psychopharmacology of EtOH in the rhesus monkey, which is used in translational studies of alcohol drinking relevant to alcohol use disorders (Allen et al., ; Baker et al., ; Grant et al., ; Jimenez and Grant, ). The pharmacokinetic data indicate that the time to peak BEC following 1.0 g/kg (i.g.)…”

“…The relative contribution of each of these receptor systems to EtOH's discriminative stimulus effects is dependent on EtOH training dose in rodents, with lower EtOH doses being most similar to GABA A receptor positive modulators, and higher EtOH doses being most similar to NMDA receptor antagonists (Stolerman et al., ). However, this dose relationship does not directly translate to macaque monkeys, with GABA A receptor positive modulation and NMDA receptor antagonism remaining prominent at both low and high EtOH doses in cynomolgus macaques (Allen et al., ; Grant et al., , ; Vivian et al., ).…”

Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies

“…Taken together, these studies suggest that mGlu receptor signaling can modulate (but not mediate) the interoceptive effects of ethanol, as ligands for these receptors neither substitute nor abolish ethanol’s discriminative stimulus. 177 In contrast, NMDA receptor antagonists and GABAa receptor agonists can completely substitute for the discriminative stimulus effects of ethanol. 178 Interestingly, mGlu 5 may modulate the discriminative stimulus effects of ethanol through downstream interactions with the GABAa receptor.…”