The role of release of endocannabinoids is less clear, however, as we have reported that URB597 unmasks some THC-like discriminative effects of nicotine , whereas another study found that URB597 did not potentiate the discriminative effects of nicotine itself. Importantly, unpublished results from company-sponsored clinical trials suggest that blockade of CB1 receptors may be effective in promoting smoking cessation and abstinence . Finally, the few studies available have not supported a role of CB1 receptors in the primary reinforcing effects of cocaine. In addition, in vivo micro-dialysis studies have found that neither anandamide nor 2-AG is formed in the shell of the NAcc during active self administration of cocaine . However, CB1 receptors appear to be required for the incentive motivational effects of cocaine, as measured by self-administration under progressive-ratio schedules and by reinstatement of extinguished cocaine self-administration .Food reward also clearly depends on CB1 receptors and almost every aspect of food reward is affected by activation or inactivation of CB1 receptors . Again, data from clinical trials appear to support the preclinical findings that CB1 blockade is effective in promoting weight loss, although the peripheral and hormonal effects of rimonabant may be more important that the central effects on reward . However,growing systems the involvement of released endocannabinoids may be limited to appetitive aspects of food reward, as concentrations of both anandamide and 2-AG increase in the NAcc during fasting but not during consumption of food.
In addition, inhibitors of anandamide uptake do not increase food intake , further indicating that endogenous anandamide, at least, may be insufficient to drive food intake. In contrast to other neurotransmitter systems involved in brain stimulation reward functions, such as dopaminergic and opioid systems , the effects of endocannabinoid system alterations in different studies have been contradictory and, in fact, activation of the endocannabinoid system appears to reduce the rewarding effects of electrical brain stimulation. Further studies are needed, but it is worth noting that in some instances dopaminergic systems and CB systems appear to have opposite antagonistic effects. For example, dopamine D2 receptor activation in the dorsal striatum releases anandamide, which might act to modulate or counterbalance the effects of dopamine . Also, glutamate release in the VTA activates dopaminergic neurons and, at the same time, leads to the release of 2-AG that in turn reduces glutamate release . On the other hand, CB agonists induce release of dopamine in the shell of the NAcc and have rewarding effects when administered locally both in the NAcc and the VTA . Thus, it is possible that, depending on the balance between endocannabinoids and dopamine and the intensity of stimulation of the region, the systems facilitate or oppose each other. This could be a mechanism for fine-tuning of dopaminergic activity. As electrical brain stimulation is a very strong excitatory stimulus, it is possible that the endocannabinoid system acts to counteract and oppose such stimulation.Alcohol consumption accounts for 5.9%, or roughly 3.3 million, deaths globally each year . Although alcohol use alone represents a serious public health concern, high comorbidity rates have been observed at an epidemiological level between alcohol and nicotine use , such that 6.2 million adults in the United States endorsed both an alcohol use disorder and dependence on nicotine .
Moreover, an individual is three times more likely to be a smoker if he/she is dependent on alcohol and those who are dependent on nicotine are four times more likely to be dependent on alcohol . Given these statistics, it is evident that heavy drinking smokers comprise a distinct sub-population of substance users that warrant unique investigation. Magnetic resonance imaging studies that have focused specifically on the effects that alcohol use may have on brain morphometry have investigated the relationship between drinking variables, such as lifetime duration of alcohol use or lifetime alcohol intake and brain structure in current alcohol users. For example, Fein et al. found lifetime duration of alcohol use was negatively associated with total cortical gray matter volume in alcohol dependent males, but not in light drinkers. Moreover, findings from Taki et al. suggest a significant negative association between lifetime alcohol intake and gray matter volume reductions in the bilateral middle frontal gyri among non-alcohol dependent Japanese men. A recent study , however, found no significant relationship between lifetime alcohol consumption and gray matter volumes in a sample of 367 non-alcohol dependent individuals. Given these contrasting findings, it is uncertain whether quantity variables, such as lifetime alcohol intake or duration of alcohol use account for many of the gray matter volume reductions observed with continued alcohol use. Various studies have implicated several different regions of gray matter atrophy in alcohol dependent individuals, such as the thalamus, middle frontal gyrus, insula, cerebellum, anterior cingulate cortex , and several prefrontal cortical areas . Due to these heterogeneous results, a meta-analysis was conducted, which concluded that there were significant gray matter decreases in the ACC and left dorsal striatum/insula , right dorsal striatum/insula , and the posterior cingulate cortex in alcohol dependent users relative to healthy controls . This suggests that brain areas implicated in processes such as reward and cognition show the most consistent gray matter atrophy in alcohol dependent individuals, but it is unclear whether overall amount of alcohol consumption or aspects of dependence severity explain these findings. Furthermore, some of the neuroimaging studies focusing on alcohol users have not mentioned whether the alcohol users also used nicotine , did not examine the effects of nicotine use on brain structure , did not control for nicotine use in their analyses , assessed nicotine use with a dichotomous questionnaire , or simply mentioned the number of smokers in the study .
This makes it difficult to ascertain whether the observed neural effects were attributable to either alcohol and/or nicotine use and further illustrates the necessity and utility of disentangling the neural effects of each substance. Similar to studies of alcohol use effects on brain morphometry, several MR imaging studies have been conducted to specifically examine the effects of nicotine use on brain structure . As with studies of alcohol users, studies of cigarette smokers have attempted to quantify and incorporate a lifetime use variable, such as pack-year smoking history, which has been found to negatively correlate with PFC gray matter densities as well as gray matter volume in the middle frontal gyrus, temporal gyrus, and the cerebellum . Interestingly, Brody et al., found no significant association between pack-year smoking history and regions of interest determined as having significant between group differences, such as the left dorsolateral PFC, ventrolateral PFC,growing rack and left dorsal ACC. Given these conflicting findings, it is uncertain whether quantity variables, such as pack-year smoking history, account for many of the gray matter volume reductions observed in nicotine dependence. Dissimilar to studies of alcohol dependent individuals, some studies of nicotine dependent individuals have examined symptoms of dependence severity in relation to brain morphometry. For example, the Fagerström Test for Nicotine Dependence , which was not associated with pack-year smoking history, was not correlated with PFC or insular gray matter density . The lack of a significant correlation between FTND scores and pack-year smoking history suggests that quantity of use and dependence severity symptoms may be unrelated in nicotine dependence, and thus have distinct relationships with brain structure. Overall, gray matter degradation has been observed in the thalamus, medial frontal cortex, ACC, cerebellum, and nucleus accumbens in nicotine dependent individuals . Due to widespread results, a meta-analysis was conducted, which found that only the left ACC showed significant gray matter reductions in nicotine dependent individuals compared to healthy controls . While studying primarily alcohol or nicotine using populations carries unique benefits, specific investigation is needed into heavy drinking smokers as past studies have shown compounded neurocognitive effects , as well as pronounced gray matter volume reductions in heavy drinking smokers when compared to nonsmoking light drinkers . Chronic cigarette smoking has been found to have negative consequences on neurocognition during early abstinence from alcohol and in one particular study, it was found that after 8 months of abstinence, actively smoking alcohol-dependent individuals performed worse on several neurocognitive measures, such as working memory and processing speed, when compared to never-smoking alcohol-dependent individuals .
Additionally, formerly smoking alcohol users were found to perform more poorly than never-smoking alcohol users at this time point. These findings not only illustrate the contribution of smoking status on neurocognitive measures but establish the clinical relevance of nicotine use in heavy drinkers. This relevance paired with the compounded neurocognitive and morphometric effects further merit investigation into this unique sub-population of substance users. The present work aimed to ascertain the effects of alcohol and nicotine dependence severity on gray matter density in a sample of 39 non-treatment seeking heavy drinking smokers using standard voxel-based morphometry . While some imaging studies have previously investigated the relationship of FTND scores with brain structure, to our knowledge, no imaging study to date has examined how alcohol dependence severity relates to gray matter density in heavy drinking smokers. Thus, the goal of this study was to examine if alcohol or nicotine dependence severity was correlated with gray matter density in heavy drinking smokers, while controlling for age, gender, and total intracranial volume . By examining dependence severity scores in addition to quantity of use variables, we may be able to capture how dependence is related to structural changes in the brain in a way that is not captured by variables that focus singularly on quantity of use. Based on previous findings, we hypothesized that gray matter density would be negatively related to quantity of both alcohol and nicotine use, in regions such as the middle frontal gyrus. We also hypothesized that dependence severity scores would uniquely relate to gray matter atrophy in several regions previously identified across the meta-analyses of voxel-based morphometry studies, such as the ACC, dorsal striatum, and insula. The subjects for the present study are a subset of participants from a medication development study of varenicline, naltrexone, and their combination in a sample of heavy drinking smokers. Subjects participated in the medication component of the study, details of which have been described in a previous publication , and a sub-sample was invited to complete a neuroimaging session. Participants were recruited from the greater Los Angeles area through online and print advertisements with the following inclusion criteria: 1) between 21 and 55 years of age; 2) reported smoking at least 7 cigarettes per day; and 3) endorsed heavy drinking per the National Institute on Alcohol Abuse and Alcoholism guidelines: for men, >14 drinks per week or ≥5 drinks per occasion at least once per month over the last 12 months; for women, >7 drinks per week or ≥4 drinks per occasion at least once per month over the last 12 months. Participants were excluded from the study based on the following criteria: 1) had a period of smoking abstinence greater than 3 months within the past year; 2) reported use of illicit substances within the last 60 days, confirmed via positive urine toxicology screen at assessment visit ; 3) endorsed lifetime history of psychotic disorders, bipolar disorders, or major depression with suicidal ideation; 4) endorsed moderate or severe depression symptoms as measured by a score of 20 or higher on the Beck Depression Inventory-II ; 5) reported current use of psychotropic medications; 6) reported any MRI contraindications, such as any metal fragment in the body or pregnancy; and 7) reported MRI constraints, such as left-handedness or color blindness. As no Structured Clinical Interview for Diagnostic Statistical Manual 4th edition , or DSM 5th edition , Axis I Disorders was administered, drinking status for participants was determined solely via NIAAA heavy drinking guidelines . After a telephone screening to determine eligibility, participants came to the laboratory for a screening visit, during which informed, written consent was obtained. A urine cotinine test along with carbon monoxide levels verified self-reported smoking patterns and a breath alcohol concentration of 0.00 was required at the beginning of each visit. Eligible participants then came in for a physical examination and if eligible afterwards, began taking medication for nine days, previously described elsewhere . Participants received varenicline alone , naltrexone alone , their combination, or matched placebo.