Cortisol stress response predicts 9-year risky driving convictions in male first-time driving-while-impaired offenders.

BACKGROUND: With driving while impaired by alcohol (DWI) representing a persistent burden on global health, better understanding and prevention of recidivism following a first-time DWI conviction are needed. Progress towards these goals is challenged by the marked heterogeneity in offender characteristics and a traffic safety literature that relies on subjective self-report measures and cross-sectional study designs. The present study tested the hypothesis that an objective neurobiological marker of behavioural maladjustment, the cortisol stress response (CSR), predicts future DWI and other traffic convictions over a 9-year follow-up period. METHODS: One hundred thirty-two male first-time DWI offenders and 31 non-offender comparators were recruited and assessed at intake for their substance use, psychosocial and psychological characteristics and CSR. Traffic conviction data were obtained from provincial driving records. Survival analysis estimated the association between CSR and risk of a traffic conviction over time. RESULTS: In support of our hypothesis, blunted CSR predicted traffic convictions during the follow-up duration. This effect generalized to both DWI offenders and non-DWI drivers. While CSR was lower in DWI offenders compared to non-offenders, it did not specifically predict recidivism in DWI offenders. Modelling results indicated that blunted CSR, along with DWI offender group membership, experience seeking and drug use frequency, may demarcate a high-risk driver phenotype. CONCLUSIONS: CSR is a neurobiological marker of a driver phenotype with elevated generalized driving risk. For drivers with characteristics consistent with this phenotype, expanding the focus of intervention to address multiple forms of risky driving may be necessary to curb their overall threat to traffic safety.

Role of exercise in the treatment of alcohol use disorders.

Excessive alcohol use can cause harmful effects on the human body, which are associated with serious health problems, and it can also lead to the development of alcohol use disorders (AUDs). There is certain evidence that physical exercise positively affects excessive alcohol use and the associated problems by leading to reduced alcohol intake. A literature search was conducted using the databases PubMed, Medline and Web of Science. The search terms used as keywords were: Addiction, abuse, alcohol use disorders, exercise training, ß-endorphin, opioids, brain, ethanol and alcohol. The current study presents the studies that reported on the use of exercise in the treatment of AUDs between 1970 and 2015. The potential psychological and physiological mechanisms that contribute to the action of exercise were also reviewed, highlighting the role of ß-endorphin and the hypothalamic-pituitary-adrenal axis in AUDs and the possible association among physical activity, the endogenous opioid system and the desire for alcohol. Only 11 studies were identified that refer to the effect of exercise on alcohol consumption and/or the associated outcomes. Six of those studies concluded that exercise may have a positive impact towards alcohol consumption, abstinence rates or the urge to drink. One of those studies also indicated that a bout of exercise affects the endogenous opioids, which may be associated with the urge to drink. Another 3 studies indicated that responses to acute exercise in individuals with AUDs are different compared to those in healthy ones. Generally, despite limited research data and often contradictory results, there is certain early promising evidence for the role of exercise as an adjunctive tool in the treatment of AUDs. Physiological and biochemical parameters that would confirm that exercise is safe for individuals with AUDs should be examined in future studies.

Lower Cortisol Activity is Associated with First-Time Driving while Impaired.

Driving while impaired (DWI) is a grave and persistent high-risk behavior. Previous work demonstrated that DWI recidivists had attenuated cortisol reactivity compared to non-DWI drivers. This suggests that cortisol is a neurobiological marker of high-risk driving. The present study tested the hypothesis that this initial finding would extend to first-time DWI (fDWI) offenders compared to non-DWI drivers. Male fDWI offenders (n = 139) and non-DWI drivers (n = 31) were exposed to a stress task, and their salivary cortisol activity (total output and reactivity) was measured. Participants also completed questionnaires on sensation seeking, impulsivity, substance use, and engagement in risky and criminal behaviors. As hypothesized, fDWI offenders, compared to non-DWI drivers, had lower cortisol reactivity; fDWI offenders also showed lower total output. In addition, cortisol activity was the most important predictor of group membership, after accounting for alcohol misuse patterns and consequences and other personality and problem behavior characteristics. The findings indicate that attenuated cortisol activity is an independent factor associated with DWI offending risk at an earlier stage in the DWI trajectory than previously detected.

Higher crash and near-crash rates in teenaged drivers with lower cortisol response: an 18-month longitudinal, naturalistic study.

IMPORTANCE: Road traffic crashes are one of the leading causes of injury and death among teenagers worldwide. Better understanding of the individual pathways to driving risk may lead to better-targeted intervention in this vulnerable group. OBJECTIVE: To examine the relationship between cortisol, a neurobiological marker of stress regulation linked to risky behavior, and driving risk. DESIGN, SETTING, AND PARTICIPANTS: The Naturalistic Teenage Driving Study was designed to continuously monitor the driving behavior of teenagers by instrumenting vehicles with kinematic sensors, cameras, and a global positioning system. During 2006-2008, a community sample of 42 newly licensed 16-year-old volunteer participants in the United States was recruited and driving behavior monitored. It was hypothesized in teenagers that higher cortisol response to stress is associated with (1) lower crash and near-crash (CNC) rates during their first 18 months of licensure and (2) faster reduction in CNC rates over time. MAIN OUTCOMES AND MEASURES: Participants' cortisol response during a stress-inducing task was assessed at baseline, followed by measurement of their involvement in CNCs and driving exposure during their first 18 months of licensure. Mixed-effect Poisson longitudinal regression models were used to examine the association between baseline cortisol response and CNC rates during the follow-up period. RESULTS: Participants with a higher baseline cortisol response had lower CNC rates during the follow-up period (exponential of the regression coefficient, 0.93; 95% CI, 0.88-0.98) and faster decrease in CNC rates over time (exponential of the regression coefficient, 0.98; 95%, CI, 0.96-0.99). CONCLUSIONS AND RELEVANCE: Cortisol is a neurobiological marker associated with teenaged-driving risk. As in other problem-behavior fields, identification of an objective marker of teenaged-driving risk promises the development of more personalized intervention approaches.

Effects of corticotropin-releasing hormone receptor antagonists on the ethanol-induced increase of dynorphin A1-8 release in the rat central amygdala.

Neurons in the central amygdala (CeA) co-express dynorphin and corticotropin-releasing hormone (CRH). Moreover, the activity of both the CRH and dynorphin systems in CeA is altered by alcohol treatments, effects suggesting interactions between the CRH and dynorphin systems. Thus, the objectives of the present study were to investigate the effects of (1) activating CRH receptors (CRHRs) by microinjection of CRH in CeA and (2) blocking CRHRs by local microinjections of CRHR antagonists in the CeA on the alcohol-induced changes in the extracellular concentrations of dynorphin A1-8 with in vivo microdialysis experiments. Microdialysis probes with a microinjection port were implanted in the CeA of alcohol-naïve Sprague-Dawley rats. Microinjections of CRH or antalarmin, a CRH receptor type 1 (CRHR1) antagonist, or anti-sauvagine-30, a CRH receptor type 2 (CRHR2) antagonist, at the level of CeA were followed by an intraperitoneal injection of either saline or 2.8 g ethanol/kg body weight. The content of dynorphin A1-8 was determined in dialyzate samples obtained prior to and following the various treatments using a specific radioimmunoassay. Activation of CRHRs in CeA induced an increase in the extracellular concentrations of dynorphin A1-8. Moreover, acute alcohol administration increased the extracellular concentrations of dynorphin A1-8 in CeA, an effect that was attenuated by blocking CRHR2 with anti-sauvagine-30 microinjection but not blocking CRHR1 with antalarmin microinjection. Therefore, the findings suggest an interaction between the CRH and dynorphin A1-8 systems at the level of CeA in response to acute alcohol exposure.

Effects of acute ethanol on corticotropin-releasing hormone and ß-endorphin systems at the level of the rat central amygdala.

RATIONALE: The endogenous opioid and corticotropin-releasing hormone (CRH) systems, present in the central amygdala (CeA), are implicated in alcohol consumption. OBJECTIVES: The purpose of this study is to investigate the hypothesis that, in CeA, alcohol stimulates CRH release, which then stimulates ß-endorphin release. MATERIALS AND METHODS: Rats were unilaterally implanted with a guide cannula to aim microdialysis probes in CeA. Experiment 1: rats received an intraperitoneal (IP) injection of various ethanol doses (0.0, 2.0, 2.4, or 2.8 g ethanol/kg body weight) and microdialysates were sampled at 30-min intervals to determine the effects over time of acute alcohol on the extracellular CRH concentrations in CeA. Experiment 2: phosphate-buffered saline, CRH, or CRH receptor (CRHR) antagonists (antalarmin or anti-sauvagine-30) was microinjected into CeA followed by a saline or 2.8 g/kg ethanol IP injection to determine the effects of CRHR activation or blockade in CeA on the basal and alcohol-stimulated release of ß-endorphin. CRH and ß-endorphin dialysate contents were determined using specific radioimmunoassays. RESULTS: Acute alcohol induced a delayed increase in the extracellular CRH levels in CeA. Behavioural data showed no difference in locomotion between alcohol- and saline-treated rats. However, a transient increase in grooming was observed which did not correspond with alcohol-induced changes in CRH. Local CRH microinjections increased the extracellular ß-endorphin concentrations in CeA. CRHR1 and CRHR2 blockade with microinjections of antalarmin and anti-sauvagine-30, respectively, attenuated the alcohol-induced increase of extracellular ß-endorphin in CeA. CONCLUSIONS: Acute alcohol exerts indirect actions on CRH release and induced interactions of the CRH and ß-endorphin systems in CeA.

The effect of naltrexone on alcohol's stimulant properties and self-administration behavior in social drinkers: influence of gender and genotype.

BACKGROUND: Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some. METHODS: To investigate potential predictors of these differential responses, 40 social drinkers (20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double-blind, counterbalanced, crossover design. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1). RESULTS: Naltrexone decreased the ethanol-induced 'euphoria' to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages on the PR task regardless of gender or genotype. CONCLUSIONS: The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use.

Effects of acute ethanol on beta-endorphin release in the nucleus accumbens of selectively bred lines of alcohol-preferring AA and alcohol-avoiding ANA rats.

RATIONALE: The selectively bred lines of alcohol-preferring alko alcohol (AA) and alcohol-avoiding alko nonalcohol (ANA) rats have been used to demonstrate differences in relevant neurotransmitters which could account for their difference in alcohol consumption. Studies have demonstrated differences in distinct components of the endogenous opioid system in various brain regions associated with the process of reinforcement between the AA and ANA lines of rats. OBJECTIVES: The goal of this current study was to investigate the hypotheses that the AA and ANA rats will show differences in the release of beta-endorphin at the level of nucleus accumbens (NAC) and in locomotor activity in response to acute systemic administration of ethanol. MATERIALS AND METHODS: AA and ANA rats were unilaterally implanted with a guide cannula to aim microdialysis probes at the level of NAC. Intraperitoneal injections of 0.0, 1.5, 2.0, and 2.5 g ethanol/kg body weight were administered. Dialysate samples were collected at 30-min intervals prior to and following the injection. Radioimmunoassay specific for beta-endorphin was used to determine the dialysate beta-endorphin content. RESULTS: The 2.5-g/kg ethanol dose induced a transient increase in extracellular beta-endorphin at the level of NAC of AA but not of ANA rats. The 2.5-g/kg ethanol dose also attenuated locomotor activity in the AA but not in the ANA rats. CONCLUSIONS: The lack of an increase in the beta-endorphin concentration in the NAC of ANA rats in response to ethanol may partially account for their lower alcohol consumption and lower alcohol-induced attenuation of locomotor activity compared to AA rats.

Endogenous opioids and addiction to alcohol and other drugs of abuse.

There is significant experimental evidence implicating the endogenous opioid system (opioid peptides and opioid receptors) with the processes of reward and reinforcement. Indeed, many behaviors associated with reward and reinforcement, for example feeding behavior, are controlled by distinct components of the endogenous opioid system located in relevant brain regions. It has also been shown that regardless of their initial site of action many drugs of abuse, such as morphine, nicotine, cocaine, alcohol and amphetamines, induce an increase in the extracellular concentration of dopamine in the nucleus accumbens. This, increased secretion of dopamine in the nucleus accumbens seems to be a common effect of many drugs of abuse, and it was proposed that may mediate their rewarding and reinforcing properties. Furthermore, activation of mu opioid receptors in the ventral tegmental area, or of mu and delta opioid receptors in the nucleus accumbens enhances the extracellular concentration of dopamine in the nucleus accumbens. Thus, stimulation of the activity of distinct components of the endogenous opioid system either by opioid or by other drugs of abuse, may mediate some of their reinforcing effects. In this review article, a brief description of the endogenous opioid system and its implication in the processes of reward and reinforcement of opioid and other drugs of abuse will be presented. Furthermore, the use of opioid antagonists in the treatment of drug addiction will be discussed. Special emphasis will be given to ethanol addiction, the drug mainly studied in my laboratory.

From the brain to bad behaviour and back again: neurocognitive and psychobiological mechanisms of driving while impaired by alcohol.

ISSUES: Driving while impaired by alcohol (DWI) is responsible for substantial mortality and injury. Significant gaps in our understanding of DWI re-offending, or recidivism, reduce our ability to practically assess recidivism probability and to match interventions to individual risk profiles. These shortcomings reflect the baffling heterogeneity in the DWI population and the limited focus of much existing DWI recidivism research to psychosocial, psychological and substance use correlates. APPROACH: This narrative review summarises the evidence for the contribution of neurocognitive and psychobiological mechanisms to DWI behaviour and recidivism. Given the nascent nature of this literature, insight into the putative contribution of these mechanisms to DWI is also drawn from other experimental literatures, particularly those on alcohol use disorders and cognitive and behavioural neuroscience. KEY FINDINGS: Alcohol-related neurotoxicity and dysregulation of hypothalamic-pituitary-adrenal axis and serotonergic systems may underlie certain offender characteristics consistently correlated with heightened DWI risk, persistence and intervention resistance. Their markers are less vulnerable to sources of bias than subjective psychosocial indices and are more far-reaching than alcohol abuse in explaining DWI behaviour and recidivism. Implications. The investigation of neurocognitive and psychobiological mechanisms in DWI research is a promising avenue for discerning clinically meaningful subgroups within the DWI population. This can lead to research and development in alternative assessment and more targeted intervention technologies. CONCLUSION: Multidimensional research in DWI and recidivism offers novel avenues for increasing road safety.

Effect of acute ethanol administration on the release of opioid peptides from the midbrain including the ventral tegmental area.

BACKGROUND: Experimental evidence suggests that ethanol alters the activity of the endogenous opioid peptide systems in a dose and brain-region dependent manner. These alterations may influence the processes of ethanol reward and reinforcement. Thus, it was the objective of this study to investigate the response of the 3 major opioid peptide systems (endorphins, enkephalins, and dynorphins) to acute ethanol administration, at the level of the midbrain including the ventral tegmental area (midbrain/VTA), a region important for drug, including ethanol reinforcement. METHODS: Using the in vivo microdialysis technique coupled with specific solid-phase radioimmunoassay for beta-endorphin, met-enkephalin, and dynorphin A(1-8,) changes in the extracellular concentration of theses peptides at the level of midbrain/VTA were determined at distinct time points following the administration of 0.0 (saline), 0.8, 1.2, 1.6, 2.0, and 2.4 g ethanol/kg B.Wt. RESULTS: A biphasic effect of ethanol on beta-endorphin release was found, with low to medium (1.2, 1.6, and 2.0 g) but not high (2.4 g) doses of ethanol, inducing a significant increase in the dialysate content of beta-endorphin. A late increase in the dialysate content of dynorphin A(1-8) was observed in response to the 1.2 g ethanol dose. However, none of the ethanol doses tested significantly altered the content of met-enkephalin in the dialysate. CONCLUSIONS: The present findings suggest that the ethanol-induced increase of beta-endorphin release at the level of midbrain/VTA may influence alcohol reinforcement.

Effects of acute ethanol on opioid peptide release in the central amygdala: an in vivo microdialysis study.

RATIONALE: There is experimental evidence that indicates that the endogenous opioid system of the central nucleus of the amygdala (CeA) may mediate some of the reinforcing effects of ethanol. However, the precise interactions of ethanol with the endogenous opioid system at the level of the CeA have not been investigated. OBJECTIVES: The aim of the current study was to investigate the hypothesis that acute systemic ethanol administration will increase the release of endogenous opioid peptides at the level of the CeA in a time- and dose-dependent manner. MATERIALS AND METHODS: Rats were implanted with a unilateral guide cannula to aim microdialysis probes at the CeA. Intraperitoneal injections of saline and various doses of ethanol (0.8, 1.6, 2.0, 2.4, and 2.8 g ethanol/kg body weight) were administered to the rats. Dialysate samples were collected at 30-min intervals at distinct time points prior to and following treatment. Radioimmunoassays specific for beta-endorphin, met-enkephalin, and dynorphin A1-8 were used to determine the effect of ethanol on the content of the opioid peptides in the dialysate. RESULTS: We report that the 2.8-g/kg dose of ethanol induced a long-lasting increase in beta-endorphin release from 60 min onwards following administration and, later, an ongoing increase in dynorphin A1-8 release. None of the ethanol doses tested elicited significant changes in dialysate met-enkephalin content compared to the saline treatment. CONCLUSIONS: Acute systemic ethanol administration induced a dose- and time-dependent increase in beta-endorphin and dynorphin A1-8 release at the level of the CeA, which may be involved in ethanol consumption.

Hypothalamic-pituitary-adrenal axis response to stress in male DUI recidivists.

Cortisol is a stress hormone mediated by the hypothalamic-pituitary-adrenal (HPA) axis and a psychobiological marker of genetic risk for alcoholism and other high-risk behavioural characteristics. In previous work with driving under the influence of alcohol (DUI) recidivists, we uncovered a significant inverse relationship between the frequency of past DUI convictions and salivary cortisol, whose strength surpassed those observed between DUI frequency and measures of alcohol abuse and other DUI-related characteristics. This finding emerged using a methodology not specifically contrived to test this relationship. The goals of this follow-up study were to (a) examine if a standardized stress-induction protocol would produce a significant inverse relationship between cortisol response and number of DUI offences; and (b) clarify whether HPA axis dysregulation could be linked to particular DUI-related behavioural correlates, such as alcohol use severity, sensation seeking, and antisocial features. Thirty male DUI recidivists were recruited as well as 11 male non-DUI drivers as a comparison group. Results indicated an inverse relationship between DUI frequency and cortisol response (r(39)=-0.36, p=0.021), as well as a lower cortisol response in DUI offenders than the comparison group (F(1,39)=5.71, p=0.022). Finally, for recidivists, hierarchical regression analyses indicated that experience seeking (R(2)=0.23, p=0.008), followed by number of cigarettes smoked daily ((Delta)R(2)=0.12, p=0.031), combined to explain 35% of the variance in cortisol (F(2,29)=7.26, p=0.003). These findings indicate that severe recidivism may have psychobiological underpinnings, and that HPA axis dysregulation appears to be a mechanism common to high-risk behaviours including DUI recidivism, sensation seeking, and cigarette smoking.

Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism.

Dysfunction of the hypothalamic-pituitary-adrenal (HPA)-axis has been observed in chronic alcoholics and in non-alcoholic sons of alcoholic parents, while genetic and environmental factors, such as stress, may play a significant role in the development of alcoholism. The present study was designed to investigate the response of the HPA-axis to alcohol and stress as a function of family history of alcoholism and chronic alcohol abuse. We determined changes in plasma adrenal corticotrophin (ACTH) and cortisol concentrations in response to a placebo or an alcohol (0.50g ethanol/kg body wt) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, four groups of healthy male individuals, low risk with no alcohol-dependence diagnosis (LRNAD), high risk with no alcohol-dependence diagnosis (HRNAD), low-risk alcohol dependent (LRAD) and high-risk alcohol dependent (HRAD), participated in the four experimental sessions given in random order. Basal plasma ACTH levels of LRNAD participants were higher from those of the other three groups of participants. Basal plasma cortisol levels of HRAD participants were higher from those of LRNAD and HRNAD but not of LRAD participants. The stress-induced increases of plasma ACTH and cortisol concentrations were more pronounced in LRNAD participants. The alcohol drink prevented the stress-induced increases in plasma ACTH and cortisol of all groups of participants. The self-ratings of anxiety were attenuated in LRNAD and LRAD participants in the alcohol only session and in HRNAD and HRAD participants in the alcohol plus stress session. In conclusion, there are differences in the activity of the HPA-axis as a function of family history and alcohol dependence, while the effect of an alcohol drink on the self-rating of anxiety may be influenced by both family history and stress.

Neurocognitive characteristics of DUI recidivists.

Individuals who drive under the influence (DUI) of alcohol may be at greater risk for neurocognitive impairment because of their exposure to multiple sources of neurological risk. This could contribute to the persistence of DUI behaviour and influence the effectiveness of remedial interventions. The objectives of this study were to clarify the neurocognitive characteristics of DUI recidivists and the nature of potential impairments, and to explore relationships between these characteristics and the frequency of past DUI convictions. One hundred male recidivists were evaluated for visuospatial constructional abilities and visual memory, verbal fluency, attention skills, cognitive flexibility, spatial planning, and verbal and movement inhibition. Results indicated that a majority of recidivists showed signs of neurocognitive impairment on several dimensions. Impairment was most marked on visuospatial constructional abilities and visual memory. In contrast to previous studies, no participants were found to have impulse control problems. Measures of memory and cognitive efficiency were significantly associated with the frequency of past convictions. Finally, exploratory analyses of two potential sources of impairment, alcohol exposure and head trauma, suggested the role of excessive alcohol use as the most obvious associated factor. Overall, the findings indicate that neurocognitive impairments are a common feature in recidivists and may contribute to DUI persistence. Development of a DUI-specific neurocognitive assessment and greater understanding of how neurocognitive status influences DUI risk could lead to remediation strategies better adapted to the individual characteristics of recidivists.

Differential effects of naltrexone on cardiac, subjective and behavioural reactions to acute ethanol intoxication.

OBJECTIVE: Alcohol may have psychomotor stimulant properties during the rising limb of the blood alcohol curve at commonly self-administered doses. Increased heart rate (HR) immediately after alcohol consumption may serve as an indicator or marker of such properties, which appear to be potentially opiate-mediated and dopamine-dependent. Naltrexone, an opiate antagonist, has been used successfully in the treatment of alcoholism and may produce its therapeutic effects through its effects on alcohol metabolism or by blocking alcohol's rewarding effects. We hypothesized that, if naltrexone blocks the psychomotor stimulant properties of ethanol, then it would decrease or eliminate the HR increase associated with acute alcohol intoxication and that this would be independent of any effect on alcohol metabolism. METHODS: Twenty male subjects were administered placebo and alcohol (1.0 mL 95% USP ethanol/kg body weight) in a laboratory setting on one day and naltrexone (50 mg) and alcohol on another (counterbalanced). We assessed all subjects for a change in HR and for a subjective and behavioural response from 35 to 170 minutes after drug or alcohol administration. RESULTS: The placebo and alcohol mix produced a significant mean HR increase from baseline (F(1,95) = 46.01, p < 0.0001, Cohen's d = 0.62), while naltrexone and alcohol did not (nonsignificant). The significant effects of naltrexone on blood alcohol level did not account for the effect of naltrexone on alcohol-induced HR change but did account for alterations in subjective and behavioural response to alcohol. CONCLUSIONS: Naltrexone appears to substantially reduce the HR increase that is characteristic of alcohol intoxication. This finding appears to lend moderate support to the notions that, first, naltrexone has differential effects on alcohol reactions and, second, that it specifically blocks the acute psychomotor stimulant properties of alcohol.

A microdialysis profile of dynorphin A(1-8) release in the rat nucleus accumbens following alcohol administration.

BACKGROUND: Pharmacological studies have implicated the endogenous opioid system in mediating alcohol intake. Other evidence has shown that alcohol administration can influence endorphinergic and enkephalinergic activity, while very few studies have examined its effect on dynorphinergic systems. The aim of the present study was to investigate the effect of alcohol administration or a mechanical stressor on extracellular levels of dynorphin A(1-8) in the rat nucleus accumbens-a brain region that plays a significant role in the processes underlying reinforcement and stress. METHODS: Male Sprague-Dawley rats were implanted with a microdialysis probe aimed at the shell region of the nucleus accumbens. Artificial cerebrospinal fluid was pumped at a rate of 1.5 microL/min in awake and freely moving animals and the dialysate was collected at 30-minute intervals. In one experiment, following a baseline period, rats were injected intraperitoneally with either physiological saline or 1 of 3 doses of alcohol, 0.8, 1.6, or 3.2 g ethanol/kg body weight. In a second experiment, following a baseline period, rats were applied a clothespin to the base of their tail for 20 minutes. The levels of dynorphin A(1-8) in the dialysate were analyzed with solid-phase radioimmunoassay. RESULTS: Relative to saline-treated controls, an alcohol dose of 1.6 and 3.2 g/kg caused a transient increase in the extracellular levels of dynorphin A(1-8) in the first 30 minutes of alcohol administration. However, the effect resulting from the high 3.2 g/kg dose was far more pronounced and more significant than with the moderate dose. There was no effect of tail pinch on dynorphin A(1-8) levels in the nucleus accumbens. CONCLUSIONS: In this experiment, a very high dose of alcohol was especially capable of stimulating dynorphin A(1-8) release in the nucleus accumbens. Dynorphin release in the accumbens has been previously associated with aversive stimuli and may thus reflect a system underlying the aversive properties of high-dose alcohol administration. However, the lack of effect of tail-pinch stress in the present study suggests that dynorphin A(1-8) is not released in response to all forms of stressful/aversive stimuli.

Differences in the peripheral levels of beta-endorphin in response to alcohol and stress as a function of alcohol dependence and family history of alcoholism.

BACKGROUND: Evidence indicates that both genetic and environmental factors, such as stress, may play an important role for the development of alcoholism, while beta-endorphin may be implicated in the control of alcohol consumption. The objective of the present studies was to test the hypothesis that there are differences in the response of the pituitary beta-endorphin system to stress as a function of family history of alcoholism and alcohol dependence. METHODS: The response of the pituitary beta-endorphin to a placebo or an alcohol (0.50 g ethanol/kg) drink and to a stress task performed 30 min following ingestion of either the placebo or the alcohol drink was measured in social and heavy drinkers with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism. Thus, each subject participated in 4 experimental sessions given on different days in a randomized order. Four groups of subjects were investigated: 1) low risk nonalcoholics (LRNA); 2) high risk nonalcoholics (HRNA), 3) low risk alcoholics (LRA); and 4) high risk alcoholics (HRA). Plasma beta-endorphin was estimated prior to and for 3.5 hr post-stress. Changes in the concentration of plasma beta-endorphin following ingestion of either the placebo or alcohol drink without performance of the stress task served as controls to compare the stress-induced changes. RESULTS: Basal plasma beta-endorphin levels were higher in LRNA than LRA, HRNA and HRA participants, while basal plasma beta-endorphin levels were higher in LRA than those in HRNA and HRA participants. Furthermore, there was no significant difference in the plasma beta-endorphin levels between HRNA and HRA participants. Stress, induced a significant increase in plasma beta-endorphin concentration in all four groups of participants. However, the stress-induced increase in plasma beta-endorphin levels was more pronounced in LRNA than HRNA, LRA and HRA participants. Thus, alcohol dependence decreased the basal plasma beta-endorphin levels in LR only, as well as the stress induced increase in plasma beta-endorphin levels of participants without, but not of those with, a family history of alcoholism. Alcohol prior to stress attenuated the stress-induced increase in plasma beta-endorphin levels of all four groups of participants. CONCLUSIONS: The present data indicates that there are differences in both, the basal plasma beta-endorphin levels as well as the response of the pituitary beta-endorphin to stress as a function of family history of alcoholism and alcohol dependence. Thus, in HR individuals a dysfunction in the activity of the pituitary beta-endorphin system predates the development of alcoholism, while in LR individuals it develops following alcohol dependence. Furthermore, alcohol dependence did not alter the alcohol-induced attenuation of beta-endorphin response to stress.

A microdialysis profile of Met-enkephalin release in the rat nucleus accumbens following alcohol administration.

BACKGROUND: Pharmacological studies have implicated the endogenous opioid system in mediating alcohol intake. Other evidence has shown that alcohol administration can influence opioid activity. In this regard, the majority of studies have concentrated on endorphinergic systems, whereas other opioid systems have been granted comparably less attention. This is the case despite some compelling evidence that has implicated enkephalinergic peptide systems, particularly Met-enkephalin, in mediating alcohol preference. The aim of the present study was to investigate the effect of alcohol administration on extracellular levels of Met-enkephalin in the rat nucleus accumbens--a brain region that plays a significant role in the processes underlying reinforcement and stress. METHODS: Male Sprague-Dawley rats were implanted with a microdialysis probe aimed at the shell region of the nucleus accumbens. Artificial cerebrospinal fluid was pumped at a rate of 1.75 mul/min in awake and freely moving rats and dialysates were collected at 30-minute intervals. After several baseline collections, rats were injected intraperitoneally with either physiological saline or one of four doses of alcohol: 0.8, 1.6, 2.4, or 3.2 g/kg ethanol body weight. The levels of Met-enkephalin in the dialysates were analyzed with solid-phase radioimmunoassay. RESULTS: Within the first 30 minutes of administration, an alcohol dose of 1.6 g/kg caused a significant and prolonged elevation in the extracellular levels of Met-enkephalin. Alcohol did not have a major effect on the release of Met-enkephalin at any other dose. CONCLUSIONS: In this experiment, only a moderate dose of alcohol was capable of stimulating Met-enkephalin release in the nucleus accumbens. Enkephalins may modulate local neurotransmitter release by binding to presynaptic Delta-opioid receptors, or, they may inhibit effector cells by binding to postsynaptic Delta- or mu-opioid receptors. This may be one of multiple neurological mechanisms that modulate alcohol-drinking behavior.

Levels and circadian rhythmicity of plasma ACTH, cortisol, and beta-endorphin as a function of family history of alcoholism.

RATIONALE: Individuals with a family history of alcoholism may present a dysfunction in the activity of the hypothalamic-pituitary-adrenal (HPA) axis that predates the development of alcoholism. OBJECTIVE: The present study investigated the hypothesis that this HPA-axis dysfunction is associated with alterations in the pattern of the circadian (24 h) secretions of adrenal corticotropic hormone (ACTH), cortisol, and beta-endorphin. METHODS: Men with [high risk (HR)] or without [low risk (LR)] family history of alcoholism participated in the study. Blood samples were drawn every 30 min for 24 h for estimation of the plasma hormone levels. Participants ingested meals at predetermined intervals and filled out mood questionnaires prior to the placement of the catheter and 1 h after each meal. RESULTS: The circadian peaks for beta-endorphin, ACTH, and cortisol occurred between 0800 and 0830 hours in both LR and HR participants. The plasma ACTH and beta-endorphin concentrations were lower in HR than LR participants, while the plasma cortisol concentrations were similar between HR and LR participants. For each hormone, the total 24-h secretion was estimated from the area under the 24-h time-concentration curve (AUC). For ACTH and beta-endorphin, but not the cortisol, AUC were lower in HR than LR participants. LR participants reported being more nervous than HR participants. For the LR participants, but not HR participants, the initial mood ratings of "nervous" were positively correlated with the initial plasma cortisol and beta-endorphin concentrations as well as with the cortisol and beta-endorphin AUC. CONCLUSIONS: HR participants presented lower plasma concentrations as well as lower AUC for beta-endorphin and ACTH but not for cortisol. This suggests a dysfunction of the HPA-axis in HR participants that predates the development of alcoholism and a dissociation between plasma ACTH and cortisol levels as a function of family history of alcoholism.