Imaging the Effects of Zolpidem and Alprazolam in Healthy Volunteers at 3T

Benzodiazepines (BZs) and related drugs commonly are prescribed for treating anxiety and sleep disorders. Their clinical utility is based on their behavioral effects which are attributed to positive allosteric modulation of the GABA-A receptor. Multiple subtypes of the GABAA receptor exist, and recent research has focused on understanding the role of BZ-sensitive GABAA receptors (i.e., receptors containing alpha-1, alpha-2, alpha-3, and alpha-5 protein subunits) in the behavioral effects of BZ-type drugs. Results from a body of work suggests that the anxiolytic or anti-anxiety effects of BZ-like drugs likely involve alpha-2- and/or alpha-3-containing GABAA receptors, while their sedative-like effects are attributable to alpha-1GABAA receptors.

Compared to BZs, the BZ-like hypnotic zolpidem exhibits relative selectivity for alpha-1GABAA receptors. Although this selectivity is believed to underlie its superior hypnotic ability, zolpidem's ability to engender anxiolytic-like effects has been inconsistent. Zolpidem's primary effects should not include anxiolysis given its preference for interacting with alpha-1GABAA receptors and their abundant distribution in sensorimotor cortex and extrapyramidal motor areas relative to the more enriched distribution of the other receptor subtypes throughout the limbic system, anterior thalamus, and caudate nucleus. However, in the amygdala, a brain region that has been shown to be intricately involved in anxiety-related neuronal processes, high levels of alpha-1 GABAA receptors as well as alpha-2 and alpha-3GABAA receptors are expressed.

Among the anxiety-related processes typically studied empirically, the ability to recognize emotion is an important proxy for psychopathology. Neuroimaging studies have shown that the ability to process emotional stimuli requires coordinated activity between the amygdala, insula, and prefrontal cortical regions. Individuals who suffer from anxiety disorders exhibit an impaired ability to recognize facial emotion, which has been associated with aberrant amygdala activation. Importantly with respect to pharmacological manipulation of anxiety-related brain function, functional magnetic resonance imaging (fMRI) studies examining the neural correlates of emotional processing by employing acute challenge with potent anxiolytics have demonstrated significant reductions in the blood oxygen level-dependent (BOLD) signal within the amygdala and insula.

The primary aim of the study outlined in this protocol is to demonstrate drug-induced differences in limbic activation during an fMRI-based emotional face recognition task following acute administration of zolpidem, alprazolam, and the positive control caffeine in healthy volunteers. Although zolpidem may exhibit a similar behavioral pharmacological profile to the conventional BZs in many instances, its relative GABAA receptor selectivity distinguishes it from its non-selective counterparts. Thus it is hypothesized that the anxiolytic alprazolam (1 mg) will reduce the BOLD response to emotional faces within the amygdala and insula similar to other anxiolytics (e.g., lorazepam, diazepam, and pregabalin), while the hypnotic zolpidem (10 mg) will not cause such a reduction. It is hypothesized further that because adenosine receptors have been localized to the amygdala and caffeine has been shown to be anxiogenic, an acute challenge with a moderate dose of caffeine (200 mg) will enhance the BOLD response in the amygdala and/or insula during the face recognition task. The data that will be collected in this aim will provide the first in vivo brain imaging evidence for different actions based on the different GABAA receptor pharmacological profiles of zolpidem and alprazolam, and will support their clinical roles in the treatment of insomnia and anxiety, respectively.

The secondary aim of this project is to collect information regarding the subjective drug effects of each of the four interventions. This information, in conjunction with data showing how each treatment affects brain activity, permits the visualization of the neurobiological substrates of drug action. For instance, in a previous study we found that zolpidem-induced increases in self-reported ratings of "like", "high", and intoxication were related to increased brain activity in specific limbic networks. Our data were consistent with those areas shown previously to undergo hemodynamic or metabolic alterations in association with the subjective states of intoxication following administration of cocaine, alcohol, and hydromorphone, and they speak to a body of literature implicating limbic, paralimbic, and mesocortical regions in mediating the actions of psychotropic drugs. Because alprazolam is known to possess more abuse potential in general, results from the present study may confirm our previous findings while also demonstrating that investigating pharmacological effects on brain activity may help identify the neural correlates of drug action and behavior, thereby revealing the functional significance of GABAergic modulation on intrinsic brain activity.