Oral alprazolam acutely increases nucleus accumbens perfusion

Abstract

Benzodiazepines treat anxiety, but can also produce euphoric effects, contributing to abuse. Using perfusion magnetic resonance imaging, we provide the first direct evidence in humans that alprazolam (Xanax) acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction.

Benzodiazepines exert therapeutic anxiolytic effects but also undesirable side effects by enhancing GABA signaling through receptors expressed widely in the brain. Benzodiazepine receptors are enriched in human ventral striatum/nucleus accumbens,¹ a critical region for normal and pathological motivational processes. Recent non-human studies demonstrated that benzodiazepines activate accumbens through alpha-1 GABA receptor-mediated disinhibition of mesolimbic dopamine projections to accumbens,² as well as through direct effects on alpha-2 GABA receptors.³ However, there is no direct evidence of benzodiazepine effects on accumbens in humans.

Pharmacological effects on regional brain function are coupled to changes in regional cerebral blood flow (CBF) and can be detected using arterial spin labeled (ASL) perfusion MRI. We used pulsed ASL (PASL) with previously described acquisition and analysis methods⁴ to examine the effects of oral alprazolam (1 mg) administered 1 hour prior to MRI in a balanced crossover placebo-controlled double-blind design (see ⁵ for details of study procedures, sample, and fMRI results; PASL was performed prior to fMRI). All procedures were performed with written informed consent and Penn IRB approval.

Usable PASL data were obtained from 45 of 47 healthy adult subjects including 19 unaffected relatives of patients with schizophrenia. Since alprazolam-induced perfusion changes did not differ by family history, subjects were pooled in a combined analysis. To localize the effects of alprazolam on regional brain function, we examined relative CBF changes, normalized by whole brain mean CBF.⁶ Alprazolam did not significantly change global CBF,⁵ and absolute regional CBF results were qualitatively similar to these normalized results.

A single dose of oral alprazolam increased CBF in accumbens (Figure 1), compared to placebo. Furthermore, subjects with higher accumbens perfusion on alprazolam showed faster (r=−0.35, p=0.020) and less accurate (r=−0.30, p=0.045) responses in a memory task following the perfusion scan.⁵ In contrast, CBF was reduced in a cluster spanning posterior thalamus and posterior midbrain. Subjects with lower thalamus perfusion after alprazolam had slower reaction times (r =−0.31, p=0.040) with no relationship to accuracy (r=0.004, p=0.98). Drug effects in accumbens and thalamus/midbrain were not correlated (r=0.12, p=0.43), suggesting they may reflect different aspects of drug action.

Figure 1.

Brain regions showing significant effects of alprazolam vs. placebo were identified using voxelwise t-tests after ruling out significant sequence or carryover confounds. Cluster-based multiple comparisons correction was performed with Monte Carlo simulation in AlphaSim (gray matter mask volume 1309392 mm3, two-tailed cluster p<0.05, minimum voxel activation height Z>2.33). Alprazolam (1mg oral dose) increased CBF in nucleus accumbens (red color bar; right cluster p=0.002, 184 voxels, peak Z 3.49 at MNI 10,8,−2; left cluster p=0.003, 168 voxels, peak Z 2.91 at MNI −12, 10, −6). This cluster also extended into white matter of the anterior limb of the internal capsule, the medial border of the ventral putamen and the ventromedial border of the caudate head. In contrast, CBF was reduced by alprazolam in posterior thalamus and midbrain (blue color bar; cluster p<.001, 1474 voxels, peak Z 3.81 at MNI 6, −30, −4). Further details regarding cluster localization, t-tests for treatment effects, and exclusion of potential sequence or carryover effects are available in Supplementary Materials.

These results provide the first direct demonstration in humans of selective benzodiazepine effects on accumbens, consistent with GABAergic activation of the mesolimbic dopamine system. However, identifying the precise neuronal source of this effect requires further investigation (see Supplementary Discussion). Anxiolytic effects of benzodiazepines have been linked to reduced amygdala activity. We suggest that increased accumbens perfusion reflects known effects of benzodiazepines including euphoria, disinhibition, impulsivity, risk-taking, and addiction. The observed relationship between greater alprazolam-induced accumbens resting perfusion and more impulsive responding in a subsequent cognitive task supports this interpretation. Alprazolam may also have antidepressant effects,⁷ and may produce transient benefits on negative symptoms of schizophrenia.⁸ Ventral striatum hypofunction is implicated in both depression and negative symptoms, suggesting that increased accumbens perfusion might also be relevant to mechanisms of therapeutic benefit. Future studies can determine whether alprazolam’s effect on accumbens perfusion is shared with other benzodiazepine and non-benzodiazepine anxiolytics that vary in abuse potential, and if this effect predicts treatment responses.

Alprazolam also reduced thalamic and midbrain perfusion. In prior PET studies, thalamic and midbrain metabolism correlated with sedative effects of benzodiazepines and general anesthetics,^{9, 10} a relationship potentially reflected here in slowed task reaction times.

This is the first study using ASL perfusion MRI to characterize benzodiazepine effects in human brain. Notably, prior PET studies did not reveal increased accumbens perfusion. The current study likely has greater sensitivity due to its larger sample size, although other methodological factors may also contribute (see Supplementary Discussion). ASL perfusion MRI provides unique advantages as a biomarker of drug actions in the brain: it is noninvasive, non-radioactive, and easily included in multimodal MRI protocols.^4–6 Our findings suggest a plausible neurobiological mechanism for some of the most commonly observed effects of benzodiazepines, supporting the use of ASL perfusion in developing drugs targeting specific neural circuits to ameliorate psychiatric symptoms.