Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations.

Aims: Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α-adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations.

Methods: Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles.

Prazosin + Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in P Rats with a Protracted History of Extensive Voluntary Alcohol Drinking, Dependence, and Multiple Withdrawals.

Background: Prazosin (PRZ; an α1 -adrenergic receptor antagonist) and naltrexone (NTX; a nonspecific opioid receptor antagonist) each decrease alcohol drinking when administered to rats selectively bred for high voluntary alcohol drinking (alcohol-preferring or "P"), and the combination of PRZ + NTX decreases alcohol drinking more effectively than does either drug alone. As drug responsiveness can depend on history of alcohol drinking and dependence, we investigated whether various schedules of PRZ and NTX administration, alone or in combination, are effective in decreasing alcohol drinking in male P rats with a history of protracted voluntary alcohol drinking, dependence, and repeated withdrawals closely resembling human alcoholism.

Methods: Male P rats became alcohol-dependent during 1 year of ad libitum 24 h/d access to food, water, and 20% alcohol with repetitive temporary alcohol withdrawals.

Prazosin Reduces Alcohol Intake in an Animal Model of Alcohol Relapse.

Background: Many alcoholics and heavy drinkers undergo repeated cycles of alcohol abstinence followed by relapse to alcohol drinking; a pattern that contributes to escalated alcohol intake over time. In rodents, alcohol drinking that is interspersed with periods of alcohol deprivation (imposed abstinence) increases alcohol intake during reaccess to alcohol. This is termed the "alcohol deprivation effect" or "ADE" and is a model of alcohol relapse in humans.

Acoustic startle in alcohol-naïve male rats predicts subsequent voluntary alcohol intake and alcohol preference.

Aims: Acoustic startle response in rats is used to model sensorimotor reactivity. The aim of the study was to determine whether acoustic startle response in alcohol-naïve rats predicts subsequent increased voluntary alcohol drinking or alcohol preference.

Methods: Startle responses to 90, 95 and 100 decibel (dB) white noise stimuli presented in counterbalanced semi-randomized order were tested in alcohol-naïve young adult male Wistar rats before voluntary alcohol intake was established with an intermittent alcohol access (IAA) model.

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats.

Evidence suggests that noradrenergic signaling may play a role in mediating alcohol-drinking behavior in both rodents and humans. We have investigated this possibility by administering clonidine to alcohol-drinking rats selectively bred for alcohol preference (P line). Clonidine is an α2-adrenergic receptor agonist which, at low doses, inhibits noradrenergic signaling by decreasing norepinephrine release from presynaptic noradrenergic neurons.

Combining the α1 -adrenergic receptor antagonist, prazosin, with the β-adrenergic receptor antagonist, propranolol, reduces alcohol drinking more effectively than either drug alone.

Background: Evidence suggests that activation of the noradrenergic system may contribute to alcohol drinking in animals and humans. Our previous studies demonstrated that blocking α1 -adrenergic receptors with the antagonist, prazosin, decreased alcohol drinking in rats under various conditions. As noradrenergic activation is also regulated by β-adrenergic receptors, we now examine the effects of the β-adrenergic receptor antagonist, propranolol, alone or in combination with prazosin, on alcohol drinking in rats selectively bred for high voluntary alcohol intake and alcohol preference (P line).

Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone.

Background: Naltrexone (NTX) is underutilized in clinical treatment settings because its efficacy is modest, and it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community, and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring "P" rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone.

Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake.

Background: This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks the initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, that is alcohol-preferring (P) rats.

Methods: In study one, alcohol-experienced P rats that had been drinking alcohol for 2 h/d for several months were treated daily with prazosin (0, 0.5, 1.

The α1-adrenergic receptor antagonist, doxazosin, reduces alcohol drinking in alcohol-preferring (P) Rats.

Background: Evidence supports a role for the noradrenergic system in alcohol drinking in animals and humans. Our previous studies demonstrated the efficacy of prazosin, an α1-adrenergic antagonist, in decreasing alcohol drinking in rat models of alcohol dependence. Prazosin has also been shown to decrease alcohol drinking in treatment-seeking alcohol-dependent men.

Effects of prazosin, an α1-adrenergic receptor antagonist, on the seeking and intake of alcohol and sucrose in alcohol-preferring (P) rats.

Background: Previous studies show that prazosin, an α(1) -adrenergic receptor antagonist, decreases alcohol drinking in animal models of alcohol use and dependence [Rasmussen et al. (2009) Alcohol Clin Exp Res 3:264-272; Walker et al. (2008) Alcohol 42:91-97] and in alcohol-dependent men [Simpson et al.

The alpha1-adrenergic receptor antagonist, prazosin, reduces alcohol drinking in alcohol-preferring (P) rats.

Background: Preliminary evidence suggest that noradrenergic signaling may play a role in mediating alcohol drinking behavior in both humans and rats. Accordingly, we tested the hypothesis that blockade of alpha(1)-adrenergic receptors will suppress alcohol drinking in rats selectively bred for alcohol preference (P line).

Methods: Adult male P rats were given 24-hour access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 hours daily.

alpha1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol.

The purpose of this study was to test the hypothesis that blockade of alpha1-adrenergic receptors may suppress the excessive ethanol consumption associated with acute withdrawal in ethanol-dependent rats. Following the acquisition and stabilization of operant ethanol self-administration in male Wistar rats, dependence was induced in half the animals by subjecting them to a 4-week intermittent vapor exposure period in which animals were exposed to ethanol vapor for 14h/day. Subsequent to dependence induction, the effect of alpha1-noradrenergic receptor antagonist prazosin (0.

Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats.

Following exposure to trauma, a vulnerable sub-population of individuals develops post-traumatic stress disorder (PTSD) with characteristic persistent autonomic hyper-responsivity, associated increased startle response, and commonly altered hypothalamo-pituitary-adrenal regulation. A goal of this investigation was to identify a predictive marker for this vulnerability. Previous investigators have developed a model for PTSD in which male mice were exposed to a single brief episode of inescapable footshock followed by 1-min contextual reminders of this trauma at weekly intervals for 6 weeks.

Alcoholism, craving, and hormones: the role of leptin, ghrelin, prolactin, and the pro-opiomelanocortin system in modulating ethanol intake.

Evidence is growing that appetite regulating peptides such as leptin and ghrelin, but also other hormones including prolactin are altered in alcoholism. The brain pro-opiomelanocortin (POMC) system which has important mediating roles in alcohol intake also has important functions in prolactin regulation and energy homeostasis. Furthermore, it has been demonstrated to be functionally integrated with leptin regulation.

Chronic daily ethanol and withdrawal: 6. Effects on rat sympathoadrenal activity during "abstinence".

We have reported that repetitive daily ethanol consumption increased anxiety-like behavior in rats 4 weeks after ethanol consumption had ceased, consistent with the persistently increased anxiety exhibited by abstinent alcoholics. Increased anxiety is associated with sympathoadrenal activation, so we have now also investigated ethanol-induced persistent changes in basal and stress-induced plasma epinephrine (E) and norepinephrine (NE) levels. Male Sprague-Dawley rats received liquid diet containing ethanol versus pair-fed isocaloric control liquid diet for 9 weeks.

Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats.

The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. We asked if melatonin similarly would reverse olanzapine-induced increased weight and visceral adiposity in rats.

Chronic daily ethanol and withdrawal: 5. Diurnal effects on plasma thyroid hormone levels.

We previously demonstrated that chronic daily ethanol consumption and daily withdrawal by male rats in a modified ethanol liquid diet paradigm produced (a) chronically increased adrenal glucocorticoid activity; (b) decreased plasma testosterone; (c) decreased forebrain proopiomelanocortin gene expression; and (d) corresponding alterations in plasma leptin levels-all of which are consistent with reported changes during alcohol abuse and alcoholism. Each of these systems interact with hypothalamo-pituitary-thyroid (HPT) regulation, and links between chronic alcohol abuse and thyroid dysfunction have been suggested by both human and rat studies. Accordingly, we have begun to investigate potential HPT mediation of, or response to, alterations in these systems by investigating plasma thyroid hormone levels in the same chronic daily ethanol/ withdrawal paradigm.

Chronic daily ethanol and withdrawal: 4. Long-term changes in plasma testosterone regulation, but no effect on GnRH gene expression or plasma LH concentrations.

Although ethanol has been repeatedly demonstrated to inhibit the hypothalamo-pituitary-testes axis by multiple mechanisms, plasma testosterone levels can be normal in alcoholics who do not exhibit severely compromised liver function and even increased in some abstinent alcoholics, suggesting that adaptive changes to chronic alcohol abuse may alter these regulatory mechanisms. To address this variability, we have investigated the effects of chronic ethanol and withdrawal on rat testosterone regulation using a well-characterized liquid diet model that we have previously demonstrated to (1) provide daily oral ethanol consumption that produces behaviorally relevant plasma ethanol levels during the active (awake) stage of the photoperiod; (2) establish physical dependence on ethanol; and (3) produce not only hypothalamo-pituitary-adrenal axis, but also behavioral (anxiety-like behavior, response to novelty, sucrose preference) changes consistent with those of actively drinking and subsequently abstinent alcoholics. The results demonstrate that chronic daily episodes of ethanol consumption and withdrawal by male Sprague-Dawley rats decreased (p < 0.

Melatonin effects on metabolism independent of gonad function.

We previously demonstrated that daily melatonin administration to middle-aged rats, restoring nocturnal plasma melatonin to young adult levels, decreased body weight and suppressed visceral fat and plasma leptin. In some species, metabolic and some neuronal responses to melatonin are mediated or dependent at least in part on gonadal steroid levels. Thus, melatonin-induced changes in gonadal steroid secretion may have mediated the aging-dependent melatonin-induced metabolic responses in our previous studies.

Melatonin effect on rat body weight regulation in response to high-fat diet at middle age.

We previously demonstrated that daily melatonin administration to middle-aged rats to restore youthful plasma melatonin levels also decreased body weight, visceral fat, plasma leptin, and plasma insulin to more youthful levels, without detectable changes in consumption of chow diet. We now evaluate: (a) whether melatonin alters consumption of a more precisely quantifiable liquid diet similar in high-fat content to the typical American diet; (b) differences between melatonin-induced endocrine responses in the fasted vs fed state; and (c) time course of these responses. Ten-month-old male Sprague- Dawley rats received liquid diet containing either 0.

Suppression of hypothalamic pro-opiomelanocortin (POMC) gene expression by daily melatonin supplementation in aging rats.

Both plasma melatonin levels and hypothalamic arcuate nucleus pro-opiomelanocortin (POMC) (biosynthetic precursor to the endogenous opioid ss-endorphin and other opiomelanocortins) mRNA content decrease with aging. To test whether the decline in melatonin is responsible for the decline in POMC mRNA, we investigated the effects of daily melatonin treatment on hypothalamic POMC mRNA content in middle-aged and older Sprague-Dawley rats. Daily nocturnal melatonin treatment (50 microg kg bw(-1) night(-1), in the night-time drinking water) for 7 months, starting at 13 months of age, did not significantly alter female arcuate nucleus POMC mRNA content determined at the end of the light period (i.

Chronic daily ethanol and withdrawal: 3. Forebrain pro-opiomelanocortin gene expression and implications for dependence, relapse, and deprivation effect.

Background: Although forebrain pro-opiomelanocortin (POMC)-producing neurons seem to mediate or modulate many responses to ethanol consumption, changes in activity of this opiomelanocortinergic system in response to chronic ethanol consumption, withdrawal, and subsequent abstinence remain unresolved.

Methods: We investigated the effects of chronic daily ethanol consumption, withdrawal, and subsequent abstinence on adult male Sprague-Dawley rat forebrain opiomelanocortinergic activity as reflected by changes in hypothalamic POMC messenger RNA (mRNA) content by using a well characterized liquid diet model that we have previously demonstrated to accurately simulate not only daily oral ethanol consumption quantity and pattern, but also both neuroendocrine and behavioral changes characteristic of actively drinking and subsequently abstinent alcoholics.

Results: After 7 weeks of daily ethanol consumption at night and withdrawal during the day, evening mediobasal hypothalamus POMC mRNA concentrations were suppressed versus both ad libitum-fed and pair-fed controls.