Given that low LR participants reported a higher number of drinks per typical drinking occasion than high LR participants in the six months preceding the study, and since other groups have reported that recent heavy drinking influences subjective perceptions of alcohol along the ascending and descending limbs of the BrAC curve , this variable was used as a covariate in our analyses.These analyses are the first to directly examine the potential relationship between the low level of response to alcohol and acute tolerance. The results offered no support for Hypothesis 1, which had predicted that the low LR to alcohol would be explained, at least in part, by a more robust acute adaptation to alcohol’s effect in participants with low LR. None of the measures tested here supported that prediction including results from the SHAS-7, the subjective report of feeling sleepy, or the body sway measures. These negative results regarding acute tolerance complement the evaluation of light drinkers with lower LR who were evaluated in their early teens but who were unlikely to have developed chronic tolerance . The combination of the current results and the prior data regarding drinking 13-year-old UK sample is not consistent with a conclusion that either form of functional tolerance is central to the low LR phenomenon. The current results actually indicated the opposite of Hypothesis 1 in that low LR participants had significantly lower acute tolerance responses on the SHAS-7 in response to the alcohol challenge than high LR individuals.That finding of a relative resistance to change in the presence of alcohol is consistent with the less intense alcohol reaction seen for most measures of alcohol response including those related to EEG , ERP , hormonal , and fMRI measures . As reported elsewhere , some data indicate that the low LR might reflect a general need for greater cognitive effort to recognize relatively subtle differences in some sensory inputs,marijuana drying a phenomenon that might relate to sensitivity rather than tolerance. Prior to the current analysis it was not possible to evaluate whether acute tolerance also contributed to the low LR phenomenon.
In addition to the hypothesis that low LR reflects a diminished sensitivity to interoceptive cues that does not highly correlate with intra-session tolerance per se , the present results shine new light on several older theories intended to explain the relationship between an individual’s initial sensitivity to a drug and the development of acute tolerance. Regardless of whether these models evoked theories involving classical Pavlovian conditioning principles , the opponent-process theory of acquired motivation , theregulatory model of addictive vulnerability or Koob’s and Le Moal’s allostatic model of addiction , a key element that cuts across these four models is the view that acute tolerance likely represents an individual’s counter-regulatory response to a drug’s pharmacodynamic effects. Viewed through this lens, another interpretation of our results might be that low LR individuals exhibit diminished acute tolerance compared with the high LR group because their compensatory physiological responses underwent more rapid, long lasting, or intense adaptation after their initial exposures to alcohol earlier in their histories. Alternatively, at the moderate dosage of alcohol tested, the magnitude of the pharmacodynamic stimulus may be diminished in low LR individuals, thus, eliciting an attenuated counter-regulatory response in LR participants compared with high LR individuals. While the present results cannot answer these considerations, our current studies are probing alcohol’s pharmacodynamic effects at higher dosages. We are also currently examining the drug’s effects on the stress axis and in relation to functional connectivity networks governing stress and reward processing to further explore the relationship between alcohol sensitivity and tolerance. The finding that at least high LR individuals demonstrated acute within-session tolerance to a single dose of alcohol is consistent with a large body of literature over the past 70 years. Both Holland and Ferner and Comley and Dry in their systematic reviews of the topic reported that 63% to 81% of the dozens of studies they reviewed found evidence for acute tolerance to alcohol.
What is novel about the present study, however, is our demonstration that LR groups differed in their development of acute tolerance such that intra-session adaptation to alcohol effects was not related to the low LR phenotype. Also consistent with the literature, self-ratings of intoxication were more closely linked to acute tolerance than a performance-based measure such as of body sway is also consistent with the broader literature . In contrast to the results observed on the SHAS-7, while low LR individuals reported lower rating of sleepiness overall, acute tolerance was not observed for this subjective measure of a sedating effect of alcohol, sleepiness. Similar to the data on sleepiness, while low LR subjects tended to demonstrate lower body sway data than high LR subjects our data did not reveal evidence of acute tolerance for standing steadiness for either LR group. Finally, also consistent with the bulk of the literature , we did not find sex differences or level of response by sex interaction effects in the development of acute tolerance or sensitization to alcohol’s effects. As is true of almost all research, the results presented here must be interpreted in light of the study limitations. First, the laboratory-based alcohol challenge session from which the current data were extracted was structured to verify participants’ LR status and the safety of testing these subjects in an fMRI scanner, goals that did not require a placebo laboratory session. Thus, no placebo data were available for these analyses and we cannot rule out that other aspects of the experimental paradigm influenced the results. Additionally, since demonstrations of acute tolerance using the Mellanby effect typically require a placebo condition to rule out practice effects along the descending limb, it is important to replicate these results in other datasets that had a placebo control group. Second, for reasons relevant to the original protocol, all subjects reported Anglo or White Hispanic ethnicities and it is not clear if the current results will generalize to other ethnicities including Asian American and African American groups. Third, similar caveats relate to the fact that the 120 participants were originally selected from a Southern California university population. Fourth, the lower intensity of the alcohol response in participants with low LR might have produced a “floor effect” making it more difficult to observe differences between rising and falling BrAC time points for lower LR subjects.
Finally, all of the participants in these secondary analyses were 18- to 25-year-old, right-handed individuals who had no alcohol or other substance use disorder diagnoses. While this step was important from a matching and fMRI methodologic standpoint, the homogeneity of the sample might have also reduced the generalizability of the results. In summary, we found that the development of more robust acute tolerance to alcohol is unlikely to contribute significantly to the low LR. Second, the results regarding acute tolerance were not significantly different in males and females. Finally, while acute tolerance was observed for high LR subjects for alcohol’s intoxicating effects, this adaptation was not significant for alcohol-related sleepiness or for body sway,how to dry cannabis an observation that underscores how acute tolerance differs for different effects of alcohol. It is relevant that minority groups most at risk for poor asthma management and subsequent disease progression are more likely to live in areas failing to meet the NAAQS. This includes 80% of Hispanics and 65% of Blacks compared with 57% of Whites in the United States . Asthma has been defined as having three phenotypic characteristics: intermittent and reversible airway obstruction; increased airway responsiveness to contractile stimuli; and airway inflammation. Pulmonary inflammation is a hallmark of asthma and is directly related to asthma severity as a function of acute and chronic airflow obstruction. One potential mechanism of action for air toxics is through enhancement of airway inflammation. Inflammation in asthma, however, has diverse pathways, mirroring the complexity of the disease. Three general mechanisms of inflammation in asthma include immunoglobulin E -mediated, neurogenic, and irritant induced. The principal inflammatory mechanism in asthma is an IgE-mediated reaction whereby an antigen cross-links with an IgE antibody specific to that antigen on the surface of mast cells and other immune cells. Commonly recognized antigens that induce acute exacerbations of asthma are high molecular weight allergens such as pollen, fungal and animal proteins. Low molecular weight agents involved in IgE-mediated reactions, including certain air toxics, act as haptens.IgE-mediated mechanisms are key in early-phase asthmatic reactions . Other processes follow over several hours and involve the recruitment of eosinophils, CD4+T cells, neutrophils, basophils, and macrophages, and the release of proinflammatory mediators and cytokines. T-cell activation leads to the release of Thelper cell type 2 -like cytokines, which may be involved in a more prolonged chronic phase of inflammatory response over days .
The involvement of TH2 cells is important because a key pathway to the development of the asthma phenotype is believed to be the early differentiation of T-helper lymphocytes into TH2 rather than TH1 cells, although this is still controversial . TH1 cells participate in delayed-type hypersensitivity reactions. TH2 cells promote antibody immune responses, and because they secrete eosinophil-active cytokines and enhance IgE synthesis, they are implicated in the genesis of allergic inflammation. Putative progenitor T cells develop into early TH0 cells with the first antigen encounter. TH0 cells then differentiate into TH1- or TH2-type lymphocytes after repetitive antigen stimulation . Interleukin -4 shifts the differentiation from TH1 to TH2. The balance toward TH2 cells may be tipped by early environmental influences, including exposure to air pollutants , coupled with genetic susceptibilities. This is presumed to be key in the development of asthma. Neurogenic inflammation involves a spread of the inflammatory response via the release of neurotransmitters or activation of afferent nerves by the action of inflammatory mediators . Inflammatory mediators can trigger the activation of nonadrenergic, noncholinergic nerves to release tachykinins. A cascade of bronchoconstrictive reflexes and of inflammatory events can follow. Reactive airways dysfunction syndrome is a primary example of a type of asthma where toxic irritant-induced inflammation is a key mechanism. RADS has been identified in occupational settings and is defined as an irritant-induced nonimmunologic asthma with no latency period. RADS is nonimmunologic in the sense that bronchial epithelial injury is the primary causal event and typical phases of the immune response are absent, namely, sensitization, latent period, episode of elicitation of an immune response to antigen, and repetitive elicitation . RADS is an example of an inflammatory mechanism of air toxics, but it is rare and its relevance to nonoccupational asthma is unclear. There is hypothesized to be a feedback loop between inflammatory processes and neuronal processes that trigger inflammation . The inflammatory processes can be either immune mediated or triggered by irritant-induced airway injury. For RADS , and to some extent oxidant pollutants such as O3 , the initiation of bronchial epithelial injury could initiate the release of inflammatory mediators. This inflammation could then trigger neurogenic inflammation. Chemical irritants may also act as neuronal triggers directly . Irritant-induced induction of tachykinin release could serve to enhance ongoing inflammation in the asthmatic lung caused by known immune triggers. Examples consistent with this hypothetical mechanism include the putative interaction between ozone and pollen in asthma exacerbations , and the finding in subjects with mild asthma that airway responsiveness to inhaled allergen increases after ozone challenge . Airborne irritants could also indirectly enhance neuroinflammation by inhibition of neutral endopeptidase . NEP degrades tachykinins and its levels are decreased following exposure to oxidants , cigarette smoke , and an agent responsible for a form of occupational asthma, toluene diisocyanate . PAHs are found in relatively high concentrations in automobile and DE, along with other potentially important chemicals including nitroaromatics, aldehydes, alcohols, ketones, quinones, phenols, and other organic compounds, as well as volatile co-pollutants— oxides of nitrogen and of sulfur, CO, and numerous VOCs such as formaldehyde, benzene, and 1,3-butadiene. Diesel exhaust particles have a sub-micrometer elemental carbon core coated with organic compounds , nitrites, sulfites, and trace metals. The most common type of PAH compound in DEPs includes the phenanthrenes, followed by fluorenes, fluoranthrenes, naphthalenes, and pyrenes . However, PAHs are semivolatile, and so much of the PAHs emitted from motor vehicles is not particle bound.