Overview of Methamphetamine-Associated Pulmonary Arterial Hypertension.

TOPIC IMPORTANCE: The global surge in methamphetamine use is a critical public health concern, particularly due to its robust correlation with methamphetamine-associated pulmonary arterial hypertension (MA-PAH). This association raises urgent alarms about the potential escalation of MA-PAH incidence, posing a significant and imminent challenge to global public health. REVIEW FINDINGS: This comprehensive review meticulously explores MA-PAH, offering insights into its epidemiology, pathophysiology, clinical presentation, diagnostic intricacies, and management strategies. The pathogenesis, yet to be fully described, involves complex molecular interactions, including alterations in serotonin signaling, reduced activity of carboxylesterase 1, oxidative stress, and dysregulation of pulmonary vasoconstrictors and vasodilators. These processes culminate in the structural remodeling of the pulmonary vasculature, resulting in pulmonary arterial hypertension. MA-PAH exhibits a more severe clinical profile in functional class and hemodynamics compared with idiopathic pulmonary arterial hypertension. Management involves a multifaceted approach, integrating pulmonary vasodilators, cessation of methamphetamine use, and implementing social and rehabilitation programs. These measures aim to enhance patient outcomes and detect potential relapses for timely intervention. SUMMARY: This review consolidates our understanding of MA-PAH, pinpointing knowledge gaps for future studies. Addressing these gaps is crucial for advancing diagnostic accuracy, unraveling mechanisms, and optimizing treatment for MA-PAH, thereby addressing the evolving landscape of this complex health concern.

Effects of a methamphetamine vaccine, IXT-v100, on methamphetamine-related behaviors.

RATIONALE: Vaccines have been developed as a potential treatment for methamphetamine (meth) use disorder (MUD). Immunization with the meth vaccine IXT-v100 has previously been shown to elicit antibodies with high affinity for meth and thus may be an effective treatment for MUD. OBJECTIVES: These studies were designed to determine the efficacy of IXT-v100 on meth-taking and meth-seeking behaviors in rats. METHODS: In the acquisition and maintenance study, male and female rats were trained to self-administer meth (0.06 mg/kg/infusion) over an 8-week period following vaccination. In the last 4 weeks, the dose of meth was increased or decreased each week. To assess meth-seeking behavior, the meth-primed reactivity model was used. Rats were trained to self-administer meth for 5 weeks, followed by a 5-week or 11-week forced abstinence period during which the animals were vaccinated. Rats were then placed back into the self-administration chamber immediately after being injected with meth (1 mg/kg, i.p.) but did not receive meth during the session. Responses were recorded and used as a measure of meth seeking. RESULTS: Results from the acquisition and maintenance study in Wistar rats show that vaccination with IXT-v100 adjuvanted with glucopyranosyl lipid A stable emulsion decreases the percentage of animals that will self-administer a moderate level of meth. In the meth-primed reactivity studies, results from males showed that vaccination significantly attenuates meth-seeking behavior. CONCLUSION: Together, these results suggest vaccination with IXT-v100 may be effective at decreasing meth-taking and meth-seeking behaviors in humans suffering with MUD.

Lack of effect of the combination of metyrapone and oxazepam on brain dopamine.

The combination of metyrapone and oxazepam (Met-Ox) has recently shown promise as a pharmacotherapy for cocaine use disorder. Metyrapone is available clinically and is typically used to diagnose adrenal insufficiency, while oxazepam is often prescribed to treat anxiety. The combination of low doses of metyrapone and oxazepam has been shown to significantly attenuate cocaine self-administration and cue-reactivity in rats, as well as decrease the number of subjects that used cocaine in a pilot clinical trial. Previous studies in rats suggest that the combination of these two drugs may decrease drug-related behaviors by reducing corticosterone synthesis in the medial prefrontal cortex. Since corticosterone has been associated with increased brain dopamine, these reductions in central corticosterone produced by Met-Ox might be accompanied by a concomitant decrease in dopamine to thereby attenuate drug taking and seeking. Thus, these studies were designed to determine the effects of Met-Ox on dopamine in rats. In vivo microdialysis studies in the medial prefrontal cortex and nucleus accumbens revealed that Met-Ox produced no measurable effects on cocaine-induced increases in dopamine. Further, the combination of these two drugs produced no effect on dopamine in the absence of cocaine. Together, these studies demonstrate that Met-Ox does not exert its effects by altering dopamine, suggesting that it might be possible to treat cocaine use disorder without affecting dopamine, which would lead to reduced side effects and increased compliance.

Effects of the combination of metyrapone and oxazepam on cocaine-induced increases in corticosterone in the medial prefrontal cortex and nucleus accumbens.

We have previously demonstrated that a combination of drugs (i.e., metyrapone and oxazepam) known to attenuate HPA-axis activity effectively decreases cocaine self-administration and cue reactivity in rats. However, we did not find changes in plasma corticosterone that matched the behavioral effects we observed, indicating that a different mechanism of action must be involved. Therefore, we hypothesized that the combination of metyrapone and oxazepam attenuates cocaine taking and seeking by decreasing cocaine-induced increases in corticosterone in the brain. Male rats were implanted with guide cannulae targeting the medial prefrontal cortex or nucleus accumbens. After the rats recovered from surgery, the microdialysis session was conducted. Rats were housed in the experimental chamber and the dialysis probes inserted into the guide cannulae the night before the session. The following day, dialysate samples were collected over a five-hour session. Baseline samples were collected for the first two hours, every 20min. Samples were then collected following administration of cocaine (15mg/kg, ip). Before injections of cocaine, rats were pretreated with either vehicle or the combination of metyrapone (50mg/kg, ip) and oxazepam (10mg/kg, ip). The administration of cocaine resulted in an increase in corticosterone in the medial prefrontal cortex following vehicle pretreatment, which was not observed in the nucleus accumbens. This cocaine-induced increase in corticosterone was attenuated by metyrapone/oxazepam. Reducing cocaine-induced increases in corticosterone in the medial prefrontal cortex might represent a novel mechanism through which the combination of metyrapone/oxazepam produces its behavioral effects.

Combinations of oxazepam and metyrapone attenuate cocaine and methamphetamine cue reactivity.

BACKGROUND: We have previously reported that combining low doses of oxazepam and metyrapone (OX/MET) reduces intravenous cocaine self-administration without affecting stress-hormone levels. We hypothesized that the combination of OX/MET would also inhibit the reinstatement of cocaine or methamphetamine seeking induced by the presentation of a conditioned reinforcer and that stress hormone levels would not be influenced by this treatment. METHODS: Male rats were implanted with jugular catheters and trained to self-administer cocaine or methamphetamine during daily 2-h sessions. During training, cocaine or methamphetamine delivery was paired with the presentation of a tone and the illumination of a house light. Following stable self-administration, rats were placed into forced abstinence. During cue-reactivity testing, rats were placed back into the operant chambers and responding only resulted in the presentation of the conditioned reinforcer; no cocaine or methamphetamine was delivered. Blood was collected on the last day of self-administration and on the day of cue-reactivity testing (either 15-min or 2-h session) to assess plasma corticosterone. RESULTS: The response-contingent presentation of the conditioned reinforcer reliably maintained cocaine or methamphetamine seeking following vehicle pretreatment. Pretreatment with OX/MET resulted in a dose-related attenuation of both cocaine and methamphetamine seeking. Corticosterone levels were significantly different at the end of the 15-min session, but not following the 2-h session. CONCLUSION: These data suggest that OX/MET may be useful in blocking the ability of environmental cues to stimulate both cocaine and methamphetamine seeking and that this effect is not entirely dependent on stress hormone levels.

Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat.

RATIONALE: Methamphetamine (MA) increases extracellular dopamine (DA) and at chronic high doses induces toxicity as indicated by decreased expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Notably, rats will self-administer MA in escalating quantities producing such toxicity. However, the impact of MA at sub-toxic doses on DA regulation is not well established. OBJECTIVE: The temporal dynamics of DA regulation following cessation of sub-toxic escalating and binge doses of non-contingent MA were investigated as changes therein may be associated with escalation of MA intake. MATERIALS AND METHODS: MA was administered 3×/day using an established 14-day escalating-dose regimen (0.1-4.0 mg/kg) or a single-day binge-style administration (3 × 4 mg/kg). DA tissue content, DA turnover, TH protein, TH phosphorylation, DAT, and vesicular monoamine transporter 2 were measured in nigrostriatal and mesoaccumbens pathways 48 h and 2 weeks after MA cessation. RESULTS: Changes in striatal DA regulation were limited to increased DA turnover. However, in the mesoaccumbens pathway, escalating MA had biphasic effects. DA was increased in ventral tegmental area (VTA) and decreased in nucleus accumbens at 48 h post-MA while the reverse was seen at 2 weeks. These changes were matched by similar changes in TH protein and, in the VTA, by changes in DAT. CONCLUSION: Escalation of MA intake produces both transient and long-lasting effects upon DA, TH, and DAT in the mesoaccumbens pathway. The eventual decrease of DA in the VTA is speculated to contribute to craving for MA and, thus, may be associated with MA escalation and resulting dopaminergic toxicity.