A Preliminary Study of Acute Responses to Clamped Alcohol Concentration and Family History of Alcoholism

Ramchandani, Vijay A.; O’Connor, Sean; Blekher, Tanya; Kareken, David A.; Morzorati, Sandra L.; Nürnberger, John I.; Li, Ting Kai

doi:10.1111/j.1530-0277.1999.tb04353.x

Cited by 66 publications

(28 citation statements)

References 39 publications

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“…Other research has shown indications for acute tolerance to stable alcohol levels in a small subject sample [32], but the obtained average alcohol level was less constant than the pseudo-steady state concentrations presented here. A few groups were able to generate accurate and stable alcohol levels by clamping the BrAC according to the original O'Connor procedure [2], and reported acute tolerance to constant alcohol levels, particularly for subjective measurements [33][34][35]. However, these findings were based on only two measurements throughout the steady-state periods.…”

Section: Figure 10mentioning

confidence: 58%

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Zoethout¹,

Schoemaker²,

Zuurman³

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The acute effects of alcohol are often studied after oral administration, and alcohol exposure is controlled by adaptation of the dose to weight, and sometimes to sex or demographic variables.• Measurements of the alcohol effects are usually performed at fixed time intervals after intake.• In only a few studies has alcohol been administered intravenously to by-pass the variability in absorption, but plasma levels often vary after administration and efforts to maintain constant levels are rare. WHAT THIS STUDY ADDS• The pharmacodynamic central nervous system (CNS) effects of alcohol or drug-alcohol interactions can be more accurately investigated if alcohol is administered intravenously and alcohol levels are kept within tightly controlled limits.• In the current study we introduce a clamping procedure to study the acute effects of a constant alcohol level of 0.6 g l -1 for 5 h on a wide range of CNS domains.• The obtained pseudo-steady-state levels with very little inter-and intravariability allow the separation of concentration-and time-dependent changes in alcohol effects. AIMIn determining the acute effects of alcohol, it is helpful if alcohol concentrations are maintained at stable levels, to facilitate the interpretation of the results. Recently, an alcohol clamping method was developed that resulted in stable alcohol concentrations for hours. The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. METHODSTo achieve a pseudo-steady state of 0.6 g l -1 , breath alcohol concentrations (BrAC) were frequently measured and fed back into a spreadsheet-based program to guide intravenous dosing. CNS effects were frequently measured throughout the clamp. RESULTSThe clamping paradigm resulted in a pseudo-steady-state BrAC of 0.61 g l -1(coefficient of variation 6.2%). A plateau was maintained from 25 to 300 min and caused significant effects on smooth pursuit eye movements [-9.7%, 95% confidence interval (CI) -12.4, -7.1], adaptive tracking (-3.4%, 95% CI -4.5, -2.2), visual analogue scale (VAS) alertness (-13 mm, 95% CI -20, -6), VAS alcohol effects (16 mm, 95% CI 7, 25) and body sway (21.3%, 95% CI 1.8, 45). Some effects (like smooth pursuit eye movements) closely followed the relatively stable alcohol concentrations, whereas others (such as body sway and VAS alcohol effects) fluctuated during the plateau phase. CONCLUSIONSMost CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions. The intravenous clamping method provides precise control over BrAC levels and allows frequent repetition of different CNS measurements. These features make this technique eminently suitable to study the complex pharmacodynamic effects of acute alcohol administration.

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Section: Figure 10mentioning

confidence: 58%

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Zoethout¹,

Schoemaker²,

Zuurman³

et al. 2009

Brit J Clinical Pharma

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“…Furthermore, venous blood measurements of the drug concentration often do not reflect the drug concentration in the brain (Wu et al 2001;. To circumvent these methodological problems, a compelling rationale has been made for measuring acute tolerance at steady-state drug concentrations for ethanol (Ramchandani et al 1999;Froehlich et al 2001) and for other drugs as well (Kissin et al 1996;Kaiyala et al 2001). Measuring a dependent variable continuously at steady-state drug concentrations facilitates the measurement of initial sensitivity and acute tolerance.…”

Section: Discussionmentioning

confidence: 99%

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

2005

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Rationale: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations.Objectives: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops.Methods: During an initial 3-h administration of 60% nitrous oxide (N 2 O), male Long-Evans rats were screened for N 2 O's hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N 2 O or placebo gas. Core temperature was measured telemetrically.Results: Rats that exhibited a comparable degree of hypothermia during an initial N 2 O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N 2 O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N 2 O exposure, the II group breathing N 2 O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N 2 O exposures.Conclusions: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent adaptive responses may mediate this relationship.

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“…A return of the measured variable toward pre-drug baseline (or control) values during a steady-state drug administration indicates acute tolerance development (Ramchandani et al, 1999;Ramsay and Woods, 1997). N 2 O is well suited for research requiring steady-state concentrations.…”

Section: Acute Tolerance and Reboundmentioning

confidence: 99%

Nitrous oxide analgesia in humans: acute and chronic tolerance

Ramsay¹,

Rothen²,

Prall³

et al. 2005

Pain

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Electrical tooth stimulation was used to investigate whether humans develop tolerance to nitrous oxide (N 2 O) analgesia within a single administration as well as over repeated administrations. In a double-blind cross-over experiment, 77 subjects received a 40-minute administration of 38% N 2 O at one session and placebo gas at the other. The sessions were separated by 1 week and the order of gas administration was counterbalanced. Acute analgesic tolerance developed for pain threshold but not for detection threshold. There was no evidence of a hyperalgesic rebound effect following cessation of the N 2 O administration. In a second double-blind experiment, 64 subjects received both 30-min of placebo gas and 30-min of 35% N 2 O, separated by a 35-min gas wash-out period, during each of 5 sessions. Sensory thresholds were assessed prior to drug or placebo administration (baseline) and between 7-12 min and 25-30 min of gas administration. A control group of 16 subjects received only placebo gas at these 5 sessions. During a sixth session, the experimental procedures were similar to the previous sessions except that the control group received N 2 O for the first time and the experimental group was sub-divided to test for conditioned drug effects. For both detection and pain threshold measures, acute tolerance developed during the initial N 2 O exposure and chronic tolerance developed over repeated administrations. Although chronic tolerance developed, a test for Pavlovian drug conditioning found no evidence of conditioned effects on sensory thresholds. In conclusion, acute and chronic tolerance develop to N 2 O's analgesic effects in humans.

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A Preliminary Study of Acute Responses to Clamped Alcohol Concentration and Family History of Alcoholism

Abstract: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.

Cited by 66 publications

References 39 publications

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

Individual differences in initial sensitivity and acute tolerance predict patterns of chronic drug tolerance to nitrous-oxide-induced hypothermia in rats

Nitrous oxide analgesia in humans: acute and chronic tolerance

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