Noncontingent and Response-Contingent Intravenous Ethanol Attenuates the Effect of Naltrexone on Hypothalamic-Pituitary-Adrenal Activity in Rhesus Monkeys

Background : The mechanism by which the opioid antagonist naltrexone suppresses overconsumption of ethanol is unclear. Oral ethanol consumption in humans increases hypothalamic-pituitary-adrenal (HPA) activity, and recent studies suggest that naltrexone may reduce ethanol consumption by modifying the HPA-stimulating effects of ethanol. The purpose of this study was to measure in rhesus monkeys the effects of ethanol and naltrexone, alone and in combination, on plasma levels of adrenocorticotropin hormone (ACTH). Methods : Nine adult male and female rhesus monkeys with chronic, indwelling intravenous catheters were maintained on tethers that allowed ethanol delivery and blood sampling. In one study, the monkeys received intramuscular injections of saline or 0.32 mg/kg naltrexone followed by noncontingent intravenous bolus infusions of saline or 0.3 to 1.8 g/kg ethanol. In a second study, other monkeys were given intramuscular injections of saline or 0.01 to 0.3 mg/kg naltrexone and subsequently responded on levers to receive intravenous saline or ethanol 0.03 g/kg per injection. Results : Ethanol, delivered either response contingently or noncontingently, did not produce systematic changes in ACTH plasma levels. Naltrexone alone produced increases in plasma ACTH that were attenuated by the subsequent administration of noncontingent or response-contingent ethanol. Naltrexone also produced dose-dependent reductions in intravenous ethanol self-administration. Linear regression analysis indicated that ethanol intake was negatively correlated with the plasma levels of ACTH over time. Conclusions : The route of administration may modulate ethanol's effects on HPA activity. Ethanol may attenuate naltrexone's effect on the HPA axis by impairing HPA axis sensitivity to other stimuli. The negative correlation between ethanol intake and ACTH levels supports the notion that naltrexone's effect of increasing HPA axis activity may be related to its ability to suppress ethanol consumption.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66078/1/01.ALC.0000121655.48922.C4.pd

Self-administration of fentanyl, cocaine and ketamine: effects on the pituitary–adrenal axis in rhesus monkeys

Drugs of abuse can affect the functioning of the hypothalamic–pituitary–adrenal (HPA) axis. Acute administration of drugs that serve as reinforcers have been observed to stimulate the rat HPA axis, leading to the suggestion that these stimulatory effects may contribute to the development of drug-maintained behaviors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46362/1/213_2004_Article_1891.pd

Self-administration of methohexital, midazolam and ethanol: effects on the pituitary–adrenal axis in rhesus monkeys

There is disagreement in the literature with respect to how drugs of abuse affect the functioning of the hypothalamic–pituitary–adrenal (HPA) axis, and whether these changes in endocrine function may be related to the rewarding effects of these drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46363/1/213_2004_Article_1986.pd

Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on κ-opioid agonists in the mouse writhing assay

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-depend-ently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kg β -FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone. Hence, SC administered nor-BNI selectively antagonized agonist activity mediated through kappaopioid receptors without differentiating between kappa subtypes. Nor-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46343/1/213_2005_Article_BF02245071.pd

Glucocorticoid-reinforced responding in the rhesus monkey

Rationale: Glucocorticoids have been reported to have rewarding effects in rats and may lead to drug-seeking behavior in humans under some circumstances. Objectives: The present study investigated whether glucocorticoids would be self-administered intravenously by rhesus monkeys (Macaca mulatta). Methods: Ten monkeys, 7 male and 3 female, were maintained on a fixed ratio 10 (30 or 100), time-out 10-s schedule for 0.1 mg/kg methohexital or saline injections. Dexamethasone (0.03–0.3 mg/kg), methylprednisolone (0.1–1.0 mg/kg) and hydrocortisone (0.3–3.0 mg/kg) were periodically substituted for methohexital or saline. Results: Dexamethasone (0.3 mg/kg) was self-administered by all of the male monkeys on the first, but not on subsequent occasions. It was hypothesized that suppression of hypothalamic–pituitary–adrenal (HPA) activity by these exogenous glucocorticoids following their first presentation may have interfered with their reinforcing effects on subsequent evaluation. Subsequently, plasma adrenocorticotropin and cortisol were measured in four male monkeys to ascertain that normal basal HPA activity had resumed prior to each glucocorticoid substitution. Of the ten monkeys that were tested, only one reliably self-administered dexamethasone, methylprednisolone and hydrocortisone, and he did so regardless of whether his basal HPA activity was suppressed. This monkey differed from some of the other monkeys both behaviorally and in his response to intravenous corticotropin releasing hormone. None of the three female monkeys that were tested with selected glucocorticoid doses showed any evidence of glucocorticoid reinforcement on any occasion. Conclusions: The results indicate that glucocorticoids were not reinforcing to the majority of monkeys in this study; nevertheless, large individual differences may exist in proclivity of monkeys to self-inject these compounds.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41967/1/213-147-1-46_91470046.pd

Guest editorial: the role of oxytocin in positive affect and drug related reward

Our insight regarding the effects of oxytocin on our brain and behaviour is growing at an astronomical pace. Oxytocin is principally known for its regulatory roles in birth, lactation, and social behaviours. Recent evidence suggests that oxytocin may also be an important modulator of endogenous mood, as well as the rewarding and entactogenic effects of some drugs of abuse. The special issue was built on the research presented in a plenary session at the 2012 Annual Conference of the International Behavioral Neuroscience Society in Hawaii chaired by Femke T.A. Buisman-Pijlman and Jillian H. Broadbear. This special issue will highlight recent developments in our understanding of the role of oxytocin in drug and social rewards and other behaviours related to drug abuse. Additionally, it highlights potential roles for the endogenous oxytocin system, how these might be affected by drug use and how this could affect the susceptibility to drug abuse and dependence. The special issue will present research findings, from animal and human studies, along with current reviews. Together these provide a comprehensive overview of how interactions between oxytocin, neurotransmitters and the stress axis may produce long-term effects on behaviour

Antalarmin, a putative CRH-RI antagonist, has transient reinforcing effects in rhesus monkeys

AbstractPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41983/1/s00213-002-1187-y.pd

Ecstasy use and self-reported disturbances in sleep

Objective Ecstasy users report a number of complaints after its use including disturbed sleep. However, little is known regarding which attributes of ecstasy use are associated with sleep disturbances, which domains of sleep are affected or which factors may predict those ecstasy users likely to have poor sleep quality and/or excessive daytime sleepiness. Methods This study examined questionnaire responses of social drug users (n = 395) to the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. Results A significant proportion of ecstasy users (69.5%) had Pittsburgh Sleep Quality Index scores above the threshold used to identify sleep disturbance. Although frequency of ecstasy use did not affect the degree of reported sleep disturbance, participants who used larger amounts of ecstasy had poorer sleep. In addition, participants who perceived harmful consequences arising from their ecstasy use or had experienced remorse following ecstasy use had poorer sleep. Clinically relevant levels of sleep disturbance were still evident after controlling for polydrug use. Risk factors for poor sleep quality were younger age, injury post-ecstasy use and having been told to cut down on ecstasy use. Conclusions Many ecstasy users report poor sleep quality, which likely contributes to the negative effects reported following ecstasy use