Journal of Drug and Alcohol Research最新文献

Background: Heavy use of alcohol is commonly associated with heavy smoking (nicotine intake). Although many factors, including mood effects of these two drugs may contribute to their co-use, the exact neurobiological underpinnings are far from clear. It is well known that chronic alcohol exposure induces neuroinflammation that may precipitate depressive-like behavior, which is considered an important factor in alcohol relapse. Nicotine, on the other hand, possesses anti-inflammatory and antidepressant effects.

Purpose: In this study, we sought to determine which proinflammatory markers may be associated with the depressogenic effects of chronic alcohol and whether nicotine pretreatment may normalize these changes.

Study design: For this purpose, we treated adult male Wistar rats with alcohol (1.0 g/kg, IP), nicotine (0.3 mg/kg, IP) or their combination once daily for 14 days. Two prominent proinflammatory cytokines (IL-1β and TNF-α) in two primary brain regions, namely the hippocampus and frontal cortex that are intimately involved in mood regulation, were evaluated.

Results: Chronic alcohol resulted in increases in both cytokines in both regions as determined by Western blot. Nicotine completely blocked alcohol-induced effects in the hippocampus, but not in the frontal cortex. These data suggest that nicotine may mitigate the inflammatory effects of alcohol in brain-selective region. Hence, the previously observed depressogenic effects of alcohol and the antidepressant effects of nicotine may at least be partially mediated through manipulations of proinflammatory cytokines in the hippocampus.

Conclusion: These findings suggest possible therapeutic potential of anti-inflammatory cytokines in combating alcohol-induced depression and/or relapse.

Alcohol-induced white matter (WM) degeneration is linked to cognitive-motor deficits and impairs insulin/insulin-like growth factor (IGF) and Notch networks regulating oligodendrocyte function. Ethanol downregulates Aspartyl-Asparaginyl-β-Hydroxylase (ASPH) which drives Notch. These experiments determined if alcohol-related WM degeneration was linked to inhibition of ASPH and Notch. Adult Long Evans rats were fed for 3, 6 or 8 weeks with liquid diets containing 26% ethanol (caloric) and in the last two weeks prior to each endpoint they were binged with 2 g/kg ethanol, 3×/week. Controls were studied in parallel. Histological sections of the frontal lobe and cerebellar vermis were used for image analysis. Frontal WM proteins were used for Western blotting and duplex ELISAs. The ethanol exposures caused progressive reductions in frontal and cerebellar WM. Ethanol-mediated frontal WM atrophy was associated with reduced expression of ASPH, Jagged 1, HES-1, and HIF-1α. These findings link ethanol-induced WM atrophy to inhibition of ASPH expression and signaling through Notch networks, including HIF-1α.

Background: In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants.

Purpose: We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH).

Study design: Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively.

Results: Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated increased motor activity when given either a subsequent challenge of MDPV (0.5 mg/kg i.p.) or METH (0.5 mg/kg), indicating the development of behavioral sensitization and cross-sensitization, respectively. Moreover, rats repeatedly administered METH (1 mg/kg) every 48 hours did not exhibit cross-sensitization to the motor stimulating effects of a subsequent challenge with MDPV (0.5 mg/kg).

Conclusion: These results suggest that specific patterns of MDPV administration may lead to lasting changes in behavioral responses to subsequent METH exposure.

The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum membrane protein that involves a wide range of physiological functions. The Sig-1R has been shown to bind psychostimulants including cocaine and methamphetamine (METH) and thus has been implicated in the actions of those psychostimulants. For example, it has been demonstrated that the Sig-1R antagonists mitigate certain behavioral and cellular effects of psychostimulants including hyperactivity and neurotoxicity. Thus, the Sig-1R has become a potential therapeutic target of medication development against drug abuse that differs from traditional monoamine-related strategies. In this review, we will focus on the molecular mechanisms of the Sig-1R and discuss in such a manner with a hope to further understand or unveil unexplored relations between the Sig-1R and the actions of cocaine and METH, particularly in the context of cellular biological relevance.

Purpose: The purpose of this paper is to better understand the relationship between substance abuse counselors' personal recovery status, self-schemas, and willingness to use empirically supported treatments for substance use disorders.

Methods: A phenomenological qualitative study enrolled 12 practicing substance abuse counselors.

Results: Within this sample, recovering counselors tended to see those who suffer from addiction as qualitatively different from those who do not and hence themselves as similar to their patients, while nonrecovering counselors tended to see patients as experiencing a specific variety of the same basic human struggles everyone experiences, and hence also felt able to relate to their patients' struggles.

Discussion: Since empirically supported treatments may fit more or less neatly within one or the other of these viewpoints, this finding suggests that counselors' recovery status and corresponding self-schemas may be related to counselor willingness to learn and practice specific treatments.

Earlier studies suggesting an involvement of cocaine and amphetamine regulated transcript peptide (CARTp) in the actions of drugs of abuse are confirmed in the most recent publications. This seems especially true for the psychostimulants where CARTp in the nucleus accumbens inhibits or regulates the actions of these drugs; the regulation is lost after repeated drug use which may be an important mechanism in addiction. The other drugs, including nicotine, alcohol, opiates, and perhaps caffeine can affect CARTp or CART mRNA levels. While the exact mechanism is not always clear, the hope is that these findings may provide some insight for the development of medications. While binding studies indicate the existence of specific G-protein coupled receptors (GPCR) receptors for CARTp, major work to be done is the cloning of these receptors.

Background: Age has been recognized as an important contributor into susceptibility to alcohol-driven pathology.

Purpose: We aimed at determining whether alcohol-induced constriction of cerebral arteries was age-dependent.

Study design: We used rat middle cerebral artery (MCA) in vitro diameter monitoring, patch-clamping and fluorescence labeling of myocytes to study an age-dependent increase in the susceptibility to alcohol in 3 (50 g), 8 (250 g), and 15 (440 g) weeks-old rats.

Results: An age-dependent increase in alcohol-induced constriction of MCA could be observed in absence of endothelium, which is paralleled by an age-dependent increase in both protein level of the calcium-/voltage-gated potassium channel of large conductance (BK) accessory β1 subunit and basal BK channel activity. Ethanol-induced BK channel inhibition is increased with age.

Conclusions: We demonstrate an increased susceptibility of MCA to ethanol-induced constriction in a period equivalent to adolescence and early adulthood when compared to pre-adolescence. Our work suggests that BK β1 constitutes a significant contributor to age-dependent changes in the susceptibility of cerebral arteries to ethanol.

Background: Modafinil and its enantiomer R-modafinil are approved for the treatment of various sleep disorders, and may also be efficacious in the treatment of psychostimulant abuse. However, the ability of modafinil and R-modafinil to alter brain reward function has not yet been assessed.

Purpose: This study assessed the effects of modafinil and R-modafinil on brain reward function using the intracranial self-stimulation (ICSS) paradigm.

Study design: Male Sprague-Dawley rats were trained to respond for ICSS using current-intensity threshold determination procedures. Changes in ICSS thresholds were then assessed following administration of modafinil and R-modafinil (50, 100, and 150 mg/kg), or cocaine (2.5 - 20 mg/kg) as a positive control.

Results: ICSS thresholds were reduced by modafinil at the 150 mg/kg dose, as well as by cocaine at the 10 and 20 mg/kg doses. R-modafinil only produced non-significant trends towards reducing ICSS thresholds.

Conclusion: Modafinil and R-modafinil have limited effects on brain reward function in otherwise drug-naïve subjects. Additional assessments of these effects in the context of psychostimulant dependence are needed.