Effect of Bile Duct Ligation-induced Liver Dysfunction on Methamphetamine Pharmacokinetics and Locomotor Activity in Rats

Abstract

Purpose: Methamphetamine (METH) abuse is associated with hepatic dysfunction related comorbidities such as HIV, hepatitis C, and polysubstance abuse with acetaminophen-containing opioid formulations. We aimed to develop a bile duct ligation (BDL)-induced hepatic dysfunction model for studying both METH and experimental treatments for METH abuse in this comorbidity. Methods: Sham or BDL surgery was performed in male Wistar rats on day 0. Liver function was measured throughout the study. On days 7 and 19, serum pharmacokinetics studies were performed with 1 mg/kg subcutaneous (sc) METH. On day 21, this dose was repeated to determine 2 h post-METH brain concentrations. METH-induced open field behaviors were measured every other day (days 12 -16) with ascending sc doses (0.3 -3 mg/kg). Results: BDL transiently increased alanine aminotransferase levels and altered liver structure, which resulted in significantly greater METH serum and brain exposure. In the BDL compared to sham group, there was a longer duration of METH-induced locomotor activity (after 1 and 3 mg/kg) and stereotypy (after 3 mg/kg). Conclusions: In rats, liver dysfunction reduced METH clearance, increased brain METH concentrations, and enhanced METH effects on locomotor activity in a dose dependent manner. In addition, this model could be further developed to simulate the associated hepatic dysfunction of key METH abuse comorbidities for preclinical testing of novel pharmacotherapies for effectiveness and/or toxicity in vulnerable populations.

Identification of Serum Biomarkers to Distinguish Hazardous and Benign Aminotransferase Elevations

“…To do that, we subjected rats to sham surgery or BDL to induce cholestasis and collected serum 7 days later. Consistent with earlier studies (Fickert et al, 2013;Hambuchen et al, 2019;Woolbright et al, 2013), BDL caused persistent ALT elevations similar in magnitude to the Dex model (Figure 7A) and clear evidence of bile duct proliferation and liver injury (Figure 7B). Interestingly, there was no obvious increase in Aldh1a1 and Adh1 in serum from the BDL rats compared with the sham group (Figure 7C), even though liver homogenates revealed that the antibody recognized the rat forms in addition to the mouse proteins (Figure 7D).…”

“…Male Wistar rats were purchased from Charles River (Wilmington, Massachusetts) and allowed free access to food and water. The rats were subjected to either sham surgery or bile duct ligation (BDL) to induce cholestasis, as previously described (Hambuchen et al, 2019). Blood was collected by venipuncture 7 days postsurgery.…”

Psychiatric Comorbidities and Liver Injury Are Associated With Unbalanced Plasma Bile Acid Profile During Methamphetamine Withdrawal

“…More recently, epidemiological studies have shown that patients with psychosis areat greater risk of presenting with damaged liver function ( 31 ), and are at increased risk of chronic liver diseases ( 32 ), even during early stages of psychosis ( 33 ). Studies using animal modelssuggested that liver dysfunction could reduce METH clearance, increase brain drugconcentrations, and therefore enhance its psychotropic effects on locomotor activityin a dose-dependent manner ( 34 ).Hyperthermia-dependent liver damage has been observed in mice after acuteadministration of METH, accompanied by increased plasma aspartate, ALT, and plasmaammonia concentrations ( 12 ). Theco-occurrence of liver injury and psychiatric comorbidities was validated in twoindependent cohorts, with ALT and AST concentrations being associated with theseverity of symptoms of anxiety and depression.…”

The Association between Hepatic Encephalopathy and Diabetic Encephalopathy: The Brain-Liver Axis

“…HE shows neuropsychiatric symptoms by increasing brain edema and intracranial hypertension [ 40 ]. In chronic liver injury, the bile duct ligation (BDL) model demonstrates showing the pathology of chronic liver failure, including impaired liver function and fibrosis, that contributes to impaired brain functions and motor activity [ 41 ]. Abnormal liver function caused by hepatic damage results in multiple neurological symptoms including brain edema, changes to neuronal cell morphology, and neuron and glia cell function [ 42 ].…”