Neuroadaptive Changes in 5-HT1A Autoreceptor Sensitivity Following High-Dose MDMA Treatment

<p>Rationale: There is evidence that the serotonin (5-HT) deficits and related cognitive and mood impairments caused by +/-3,4- methylenedioxymethamphetamine (MDMA) may be mediated by neuroadaptations of the 5-HT1A autoreceptor. Objectives: The increase in sensitivity of the 5-HT1A autoreceptor caused by highdose, repeated MDMA treatment was assessed neurochemically, by measuring 5- HTP accumulation, and physiologically, via changes in body temperature. Methods: Experiment 1 confirmed the effects of 8-hydroxy-2-(di-npropylamino) tetralin (8-OH-DPAT) (0, 0.025, 0.05, 0.1 mg/kg s.c.) on 5- hydroxytryptophan (5-HTP) accumulation following 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015) administration as a valid measure of 5-HT synthesis and hence 5-HT1A autoreceptor sensitivity in rats. Experiment 2 performed these procedures in additional animals, with half receiving MDMA (4x 10 mg/kg i.p. at 2 hour intervals) two weeks before testing. Body temperature changes due to the 8-OH-DPAT hypothermic response were tested using a rectal probe. Experiment 2b repeated the procedures in additional groups with lower doses of 8-OH-DPAT (0.0125 and 0.00625 mg/kg s.c.). Results: No significant changes in 5-HTP accumulation levels or changes in the hypothermic response to 8-OH-DPAT were found between MDMA pretreated rats and controls in Experiments 2 and 2b. Moreover, there was no substantial evidence of expected 5-HT deficits due to high-dose MDMA treatment. Conclusion: The results do not indicate an increase in sensitivity of the 5-HT1A autoreceptor, and hence the original hypothesis is not supported. However, there were a number of methodological issues, as indicated by the lack of MDMAinduced 5-HT deficits, which prevent a firm conclusion from being drawn. Future research is outlined to overcome these issues.</p>

Neuroadaptive Changes in 5-HT1A Autoreceptor Sensitivity Following High-Dose MDMA Treatment

<p>Rationale: There is evidence that the serotonin (5-HT) deficits and related cognitive and mood impairments caused by +/-3,4- methylenedioxymethamphetamine (MDMA) may be mediated by neuroadaptations of the 5-HT1A autoreceptor. Objectives: The increase in sensitivity of the 5-HT1A autoreceptor caused by highdose, repeated MDMA treatment was assessed neurochemically, by measuring 5- HTP accumulation, and physiologically, via changes in body temperature. Methods: Experiment 1 confirmed the effects of 8-hydroxy-2-(di-npropylamino) tetralin (8-OH-DPAT) (0, 0.025, 0.05, 0.1 mg/kg s.c.) on 5- hydroxytryptophan (5-HTP) accumulation following 3-hydroxybenzylhydrazine dihydrochloride (NSD-1015) administration as a valid measure of 5-HT synthesis and hence 5-HT1A autoreceptor sensitivity in rats. Experiment 2 performed these procedures in additional animals, with half receiving MDMA (4x 10 mg/kg i.p. at 2 hour intervals) two weeks before testing. Body temperature changes due to the 8-OH-DPAT hypothermic response were tested using a rectal probe. Experiment 2b repeated the procedures in additional groups with lower doses of 8-OH-DPAT (0.0125 and 0.00625 mg/kg s.c.). Results: No significant changes in 5-HTP accumulation levels or changes in the hypothermic response to 8-OH-DPAT were found between MDMA pretreated rats and controls in Experiments 2 and 2b. Moreover, there was no substantial evidence of expected 5-HT deficits due to high-dose MDMA treatment. Conclusion: The results do not indicate an increase in sensitivity of the 5-HT1A autoreceptor, and hence the original hypothesis is not supported. However, there were a number of methodological issues, as indicated by the lack of MDMAinduced 5-HT deficits, which prevent a firm conclusion from being drawn. Future research is outlined to overcome these issues.</p>

Hypoxic Preconditioning Ameliorates Amyloid-β Pathology and Longterm Cognitive Decline in AβPP/PS1 Transgenic Mice

Background and Objective: Hypoxic Preconditioning (HPC) has been well established to trigger endogenous mechanisms of neuroprotection basing on models of hypoxic and ischemic diseases in the Central Nervous System (CNS). However, its effects against Alzheimer's Disease (AD) still lack substantial evidence and in-depth exploration. The present study aimed to investigate the impacts of HPC on AD-related memory decline and amyloid-β (Aβ) pathology in AβPP/PS1 transgenic mice. Methods: Seven-week-old AβPP/PS1 transgenic mice were randomized into HPC and non-HPC groups. The HPC groups were treated with early and repetitive HPC for four weeks, while the non-HPC group was raised under normoxia condition. All the animals were then raised until the age of 28 weeks when Morris water maze tests were conducted to examine the animals’ spatial memory. Indicators for Aβ pathology (soluble Aβ levels and numbers of Aβ plaques) and the expression of relevant proteins were measured to explore potential mechanisms. Results: The results showed that HPC ameliorated memory decline and Aβ pathology in AβPP/PS1 mice. The protein levels of Amyloid-β Precursor Protein (AβPP) and β-site APP Cleaving Enzyme 1 (BACE1) were reduced while that of Hypoxic inducible factor 1α (HIF-1α) was elevated in HPC groups. Conclusion: HPC might be a promising strategy for AD intervention. Its potential protection might be realized via downregulating the expressions of AβPP and BACE1 and hence inhibiting Aβ pathology. Notably, HIF-1α might play a key role in mediating subsequent neuroadaptive changes following HPC.

Preprint: Altered subjective reward valuation among drug-deprived heavy marijuana users: Aversion to uncertainty

Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision-making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in responses to uncertainty have been observed in response to intoxication and deprivation from various drugs of abuse. To assess for these potential neuroadaptive changes in reward valuation associated with marijuana deprivation, we examined the subjective value of uncertain and certain rewards among deprived and non-deprived heavy marijuana users in a behavioral economics decision-making task. Deprived users displayed reduced valuation of uncertain rewards, particularly when these rewards were more objectively valuable. This uncertainty aversion increased with increasing quantity of marijuana use. These results suggest comparable decision-making vulnerability from marijuana use as other drugs of abuse, and highlights targets for intervention.