Treatment regimen and hypnotic self-administration.

RATIONALE AND OBJECTIVES: Previous studies have shown that insomniacs self-administer hypnotics at high nightly rates. This study determined whether prior experience with different treatment regimens (i.e., instructions and capsule availability) would alter the previously observed high hypnotic self-administration rates. METHODS: Sixty-four healthy men and women with (n = 32) and without (n = 32) insomnia, 21-55 years, self administered placebo or triazolam (0.25 mg) after different prior treatment regimens. They received one of three different treatment regimens enforced for 11 nights: a capsule each night, a capsule as needed, or a capsule every third night. On 14 subsequent nights they choose to self-administer a capsule or not, placebo during 1 week and triazolam (0.25 mg) the other (counterbalanced in order). RESULTS: Insomniacs self-administered more capsules than normals and triazolam was self-administered more than placebo. For both groups, treatment regimen had a minimal effect on capsule self-administration. During the treatment phase, triazolam improved self-ratings of sleep relative to placebo. During the choice phase, nightly variations in self-rated sleep predicted self-administration of a capsule on the following night, regardless of whether the capsule was active drug or placebo. CONCLUSIONS: The data of this study are consistent with the view that hypnotic self-administration by insomniacs is therapy-seeking behavior and not drug abuse.

Hypnotic self administration: forced-choice versus single-choice.

Twenty-four men and women with insomnia, age 21-50 years, self administered hypnotics under a single-choice with placebo, single-choice with triazolam (0.25 mg), or forced-choice of placebo versus triazolam (0.25 mg) paradigm. Subjects received 4- sampling nights of placebo or triazolam in the single-choice conditions or 2 nights of each in the forced-choice condition. Then on 7 choice nights they could self administer a capsule, or not, in the single-choice conditions, or were required to choose one of two color-coded capsules in the forced-choice condition. In the single-choice conditions, subjects chose placebo 80% of nights and triazolam 77% of nights, while in the forced-choice condition triazolam was chosen on 86% of nights. Thus, the self administration of triazolam did not vary significantly between single or forced choice conditions, but that of placebo did. Placebo rate was high when it was the only alternative, but low when competing with triazolam. On sampling nights, compared to placebo, triazolam produced a significant increase in total sleep time, a reduction in latency to sleep, wake after sleep onset, and percentage stage 1 sleep. Triazolam, relative to placebo, also improved mood in the morning on some sampling nights. For subjects choosing capsules < 100% of opportunities (n = 14), on nights a capsule was chosen versus nights none was chosen (regardless of whether placebo or triazolam was the choice), self-ratings 30 min before bedtime on the Profile of Mood States vigor scale were significantly higher.

Hypnotic self administration and dose escalation.

The dependence liability of benzodiazepines in the context of their use as hypnotics (i.e. by insomnia patients as pre-sleep medications) is unresolved. A recent study found that insomniacs self administer capsules at bedtime at a high rate, with triazolam (0.25 mg) taken as often as placebo. This study sought to determine if differential self administration would develop when multiple capsules are available nightly. Eighteen men and women, age 21-45 years, with insomnia complaints (nine with objective sleep disturbance and nine without) were studied, 1 week with placebo and 1 week with triazolam (0.25 mg). The two conditions were administered double-blind and presented in a counter-balanced order with a week between conditions. In each condition, after 3 consecutive sampling nights of the available single capsule for that condition, subjects could self administer 0-3 capsules before bed on the 4 subsequent nights. Triazolam was self administered as many nights as placebo, but the number of placebo capsules self administered was twice that of triazolam capsules. The objective insomniacs self administered more capsules than the subjective insomniacs and neither group differentially choose triazolam over placebo. The number of triazolam capsules taken nightly was stable and the number of placebo capsules variable. It is concluded that insomniacs show no short-term escalation of triazolam dose, but do choose an increased and variable number of placebos, a pattern which is interpreted as being insomnia relief-seeking behavior.

ATP depletion by iodoacetate and cyanide in renal distal tubular cells.

Suspensions of proximal tubular and distal tubular (DT) cells from rat kidney were treated with iodoacetate and potassium cyanide (IAA+KCN) as a model to assess injury from ATP depletion. Cells were also incubated under N2/CO2 to assess if they respond similarly to ATP depletion due to hypoxia. Based on cytotoxic effects of IAA (lactate dehydrogenase [LDH] release, protein sulfhydryl depletion) and inhibition of lactate formation, 20 microM IAA was chosen with 1 mM KCN to inhibit cellular ATP generation. DT cells exhibited significantly greater LDH release due to both IAA + KCN and hypoxia than PT cells. Mechanisms of cellular injury and the ability of various strategies to protect against (IAA+KCN)-induced injury were then studied in isolated renal DT cells to investigate factors responsible for the enhanced susceptibility of this renal cell population, about which little metabolic and toxicological information is known. IAA+KCN produced marked depletion of ATP, only minimal changes in cellular content of glutathione, but significantly decreased cellular content of glutathione disulfide, suggesting generation of a proreductant environment. Extracellular acidosis (pH 6.2 vs. 7.4) completely prevented the increase in LDH release during 2-hr incubations with IAA+KCN and partially prevented ATP depletion. Similarly, preincubation with glutathione, glycine, ATP, or adenosine significantly protected DT cells from injury. Complete restoration of cellular ATP content was not required for protection, although viability correlated better with cellular content of total adenine nucleotides. These studies are the first to explore cellular energetics and cytotoxicity in renal DT cells and demonstrate that these cells are highly sensitive to injury from ATP depletion due to either IAA+KCN or hypoxia.

Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD).

Forty-nine men, 25 with obstructive sleep apnea syndrome (OSAS) and 24 with chronic obstructive pulmonary disease (COPD), were evaluated with a standard 8-hour nocturnal polysomnogram, multiple sleep latency test the following day and a neuropsychological test battery. The OSAS patients had more respiratory disturbances per hour of sleep, more stage 1 sleep and greater daytime sleepiness than COPD patients. The OSAS patients were as impaired as the COPD patients in neuropsychological test functioning, with the pattern of impairment nonspecific as to hypoxemic-sensitive versus sleepiness-sensitive tasks, with two exceptions. The OSAS patients performed more poorly on a test requiring sustained attention and considered sensitive to sleepiness, whereas the COPD patients performed more poorly on a test requiring motor skills and sensitive to hypoxemia. These deficits in psychomotor and attention appear to be specifically related to patients group (OSAS vs. COPD), but the other deficits found in complex reasoning and memory are nonspecific.

Hypoxia and oxygen dependence of cytotoxicity in renal proximal tubular and distal tubular cells.

Ischemia and hypoxia are major causes of renal failure and altered oxygen supply may affect renal responses to toxic chemicals. In vitro experiments were designed to evaluate the susceptibility of isolated proximal tubular (PT) and distal tubular (DT) cells from rat kidney to brief periods of oxygen deprivation and to assess how variations in oxygen supply affect chemical-induced cytotoxicity. Isolated cells were incubated for 1 hr in either oxygen (95% O2/5% CO2), air (21% O2), or nitrogen (95% N2/5% CO2) atmosphere. PT cells exhibited no injury due to brief oxygen deprivation whereas DT cells exhibited moderate, but significant injury, indicating that DT cells are more susceptible than PT cells to hypoxic injury. The cytotoxicity of chemicals that alter cellular redox status [i.e. tert-butyl hydroperoxide (tBH), menadione, methyl vinyl ketone] and the cytotoxicity of "chemical hypoxia" [i.e. KCN + iodoacetic acid] were greatest in air, intermediate in oxygen, and lowest in nitrogen. In contrast, the cytotoxicity of the alkylating agent N-dimethylnitrosamine was independent of oxygen concentration and the cytotoxicity of p-aminophenol was related directly to oxygen concentration. The mechanism of the oxygen dependence of chemical injury was investigated further, employing tBH as a model toxicant. tBH metabolism was oxygen independent in both PT and DT cells. Depletion of cellular protein sulfhydryl groups by tBH increased with increasing oxygen concentration and lipid peroxidation due to tBH was inhibited in nitrogen but was not different in air as compared with oxygen. Although these processes may contribute to the much lower toxicity in nitrogen as compared with oxygen, it does not explain the higher toxicity in air as compared with that in oxygen. Other processes that predominate at lower oxygen concentrations but that only produce injury if enough oxygen is present are likely to be responsible for the enhanced susceptibility of both PT and DT cells to oxidants in air as compared with oxygen.