Effectiveness of contingency management using transdermal alcohol monitoring to reduce heavy drinking among driving while intoxicated (DWI) arrestees: A randomized controlled trial.

BACKGROUND: Driving while intoxicated (DWI) is a serious public health problem. However, treatment for DWI arrestees is not readily available. This study examines the effectiveness of a contingency management (CM) procedure using transdermal alcohol concentration (TAC) monitoring to reduce drinking among DWI arrestees. METHOD: The study participants were 216 DWI arrestees under pretrial and included both Mandated participants undergoing court-ordered TAC monitoring and Non-Mandated participants wearing a study-provided TAC monitor. Participants were randomly assigned to either a CM (Mandated = 35; Non-Mandated = 74) or a Control condition (Mandated = 37; Non-Mandated = 70) and completed the 8-week intervention. CM participants received $50/week for not exceeding a TAC of 0.02 g/dL during the previous week. Payments to Controls were yoked to the CM group. RESULTS: Among Non-Mandated participants, the probability of meeting the contingency was higher and remained stable (about 65%) over time in the CM group, whereas the probability was lower and declined in the Control group, widening the gaps in the probability between the study conditions (16.7%-24.1% greater in the CM group from visit 4 to 8, all p < 0.05). Among Mandated participants, the probability was not significantly different between conditions (p = 0.06-0.95). Furthermore, among Non-Mandated participants, the percentage of heavy drinking days remained low (9.16%-11.37%) in the CM group, whereas it was greater and increased over time (17.43%-26.59%) in the Control group. In Mandated participants, no significant differences in percent heavy drinking days were observed between conditions (p = 0.07-0.10). CONCLUSION: We found that contingency effects on alcohol use are more pronounced among frequent and heavy alcohol users, i.e., Non-Mandated DWI arrestees. However, for individuals whose drinking was already suppressed by existing contingencies (i.e., court-mandated TAC monitoring), our CM procedure did not produce additional reductions in drinking.

Conditioned Stimulus Form Does Not Explain Failures to See Pavlovian-Instrumental-Transfer With Ethanol-Paired Conditioned Stimuli.

BACKGROUND: Pavlovian-Instrumental-Transfer (PIT) examines the effects of associative learning upon instrumental responding. Previous studies examining PIT with ethanol (EtOH)-maintained responding showed increases in responding following presentation of an EtOH-paired conditioned stimulus (CS). Recently, we conducted 2 studies examining PIT with an EtOH-paired CS. One of these found increases in responding, while the other did not. This less robust demonstration of PIT may have resulted from the form of the CS used, as we used a 120-second light stimulus as a CS, while the previous studies used either a 120-second auditory stimulus or a 10-second light stimulus. This study examined whether using conditions similar to our earlier study, but with either a 120-second auditory or a 10-second light stimulus as a CS, resulted in more robust PIT. We also examined the reliability of our previous failure to observe PIT. METHODS: Three experiments were conducted examining whether PIT was obtained using (i) a 120-second light stimulus, (ii) a 10-second light stimulus, or (iii) a 120-second auditory stimulus as CSs. RESULTS: We found PIT was not obtained using (i) a 120-second light stimulus as a CS, (ii) a 10-second light stimulus as a CS, or (iii) a 120-second auditory stimulus as a CS. CONCLUSIONS: These results suggest that CS form does not account for our earlier failure to see PIT. Rather, factors like rat strain or how EtOH drinking is induced may account for when PIT is or is not observed.

Behavioral Impulsivity Does Not Predict Naturalistic Alcohol Consumption or Treatment Outcomes.

OBJECTIVE: The purpose of this study was to determine if behavioral impulsivity under multiple conditions (baseline, after alcohol consumption or after serotonin depletion) predicted naturalistic alcohol use or treatment outcomes from a moderation-based contingency management intervention. METHOD: The current data analysis pulls information from three phases of a large study: 1) Phase 1 examined baseline and the effects of alcohol use and serotonin depletion on three types of behavioral impulsivity: response initiation (IMT task), response inhibition (GoStop task), and delay discounting (SKIP task); 2) Phase 2 involved 28 days of naturalistic drinking; and 3) Phase 3 involved 3 months of contingency management. During phases 2 and 3 alcohol use was measured objectively using transdermal alcohol monitors. The results of each individual phase has been previously published showing that at a group level the effects of alcohol consumption on impulsivity were dependent on the component of impulsivity being measured and the dose of alcohol consumed but serotonin depletion had no effect on impulsivity, and that a moderation-based contingency management intervention reduced heavy drinking. RESULTS: The current analysis combining data from those who completed all three phases (n = 67) showed that impulsivity measured at baseline, after alcohol consumption, or after serotonin depletion did not predict naturalistic drinking or treatment outcomes from a moderation-based CM treatment. CONCLUSIONS: Contingency management interventions may prove to be an effective intervention for impulsive individuals, however, normal variations in measured impulsivity do not seem to relate to normal variations in drinking pattern or response to moderation-based contingency management.

Ethanol self-administration in mice under a second-order schedule.

Long Fixed-Interval (FI) schedules, particularly second-order schedules, can engender substantial responding before drug or ethanol delivery that is uninfluenced by the direct effects of the drug or ethanol. Thus, these schedules can be used to study the effects of medications upon drug- or ethanol-seeking, uninfluenced by the direct effects of the self-administered drug or ethanol. Long FI second-order schedules are frequently used in primates and occasionally in rats. Under second-order schedules, completion of one response requirement, e.g., a Fixed Ratio 10 (FR10:S), produces a brief stimulus presentation, e.g., a 1-s 80-dB 4-kHZ tone, and this FR10:S serves as the response unit under another schedule, e.g., an FI 1800-s. Thus, the first FR10 completed after 1800 s would result in delivery both of the tone and of reinforcement, e.g., 10 × 0.01 mL 16% (w/v) ethanol. To examine if such schedules could be effectively used in mice, which have advantages in neurobiological and genetic studies, we trained eight C57BL/6J mice to respond under the schedule just described. This schedule maintained substantial responding. The temporal pattern of behavior was typical of an FI schedule with responding accelerating across the interval. We also examined the effects of acute and chronic administration of fluvoxamine on this responding, and these were modest. Finally, we examined responding when alcohol and/or tone deliveries were withheld, and found that extinction occurred most rapidly when both were withheld. This work demonstrates that long FI schedules of ethanol delivery may be useful in studying ethanol seeking in mice.

Using Transdermal Alcohol Monitoring to Detect Low-Level Drinking.

BACKGROUND: Several studies demonstrate the utility of Alcohol Monitoring Systems' (AMS) transdermal alcohol concentration (TAC) monitor to objectively quantify drinking. AMS standard criteria (i.e., TAC >0.02 g/dl) used for drinking detection are deliberately conservative, but consequently only detect drinking equivalent to 5 or more standard drinks. Our study sought to characterize the sensitivity of TAC measurement to detect low-level drinking defined as the consumption of 1 to 3 beers. METHODS: Data were pooled from 3 studies giving controlled doses of 1, 2, 3, 4, and 5 Corona© beers (12 oz = 0.92 standard units) to 32 male and 29 female research volunteers wearing TAC monitors under controlled conditions. Analyses describe the sensitivity to detect drinking at various peak TAC thresholds beginning with any positive reading >0 g/dl, and then using TAC thresholds of 0.02 and 0.03 g/dl. RESULTS: Nearly 40% of participants drinking 1 beer did not have a positive TAC reading. However, positive TAC readings were observed in more than 95 and in 100% of participants drinking 2 and 3 or more beers, respectively. The probability of peak TAC detection was a positive function of the number of beers consumed and a negative function of the minimum TAC threshold for detection. Drinking was somewhat more likely to be detected in females than males drinking 2 to 5 beers, but not after 1 beer. Use of AMS standard criteria only reliably detected the consumption of 5 beers, and 45.9% of all occasions of drinking 1 to 3 beers were undetected using 0.02 g/dl as a threshold. CONCLUSIONS: Peak TAC levels between 0 and 0.02 g/dl must be considered to detect the low-level drinking of 1 to 3 standard drinks, and such thresholds are necessary when researchers and clinicians want to detect low-level drinking.

Relative potency of varenicline or fluvoxamine to reduce responding for ethanol versus food depends on the presence or absence of concurrently earned food.

BACKGROUND: Varenicline, a nicotinic partial agonist, selectively reduces ethanol (EtOH)- versus sucrose-maintained behavior when tested in separate groups, yet like the indirect agonist fluvoxamine, this selectively inverts when EtOH and food are concurrently available. METHODS: Here, we extend these findings by examining varenicline and fluvoxamine effects under a multiple concurrent schedule where food and EtOH are concurrently available in different components: Component 1 where the food fixed-ratio was 25 and Component 2 where the food fixed-ratio was 75. The EtOH fixed-ratio was always 5. Food-maintained responding predominated in Component 1, while EtOH-maintained responding predominated in Component 2. In a second experiment, varenicline effects were assessed under a multiple schedule where food, then EtOH, then again food were available in separate 5-minute components with fixed-ratios of 5 for each reinforcement. RESULTS: In the multiple concurrent schedule, varenicline was more potent at reducing food- versus EtOH-maintained responding in both components and reduced EtOH-maintained responding more potently during Component 1 (when food was almost never earned) than in Component 2 (where food was often earned). Fluvoxamine was similarly potent at reducing food- and EtOH-maintained responding. Under the multiple schedule, varenicline, like fluvoxamine, more potently decreases EtOH- versus food maintained responding when only food or EtOH is available in separate components. CONCLUSIONS: These results demonstrate that selective effects on drug- versus alternative-maintained behavior depend on the schedule arrangement, and assays in which EtOH or an alternative is the only programmed reinforcement may overestimate the selectivity of treatments to decrease EtOH self-administration. Thus selective effects obtained under one assay may not generalize to another. Better understanding the behavioral mechanisms responsible for these results may help to guide pharmaco-therapeutic development for substance use disorders.

Reinforcer magnitude and rate dependency: evaluation of resistance-to-change mechanisms.

Under many circumstances, reinforcer magnitude appears to modulate the rate-dependent effects of drugs such that when schedules arrange for relatively larger reinforcer magnitudes rate dependency is attenuated compared with behavior maintained by smaller magnitudes. The current literature on resistance to change suggests that increased reinforcer density strengthens operant behavior, and such strengthening effects appear to extend to the temporal control of behavior. As rate dependency may be understood as a loss of temporal control, the effects of reinforcer magnitude on rate dependency may be due to increased resistance to disruption of temporally controlled behavior. In the present experiments, pigeons earned different magnitudes of grain during signaled components of a multiple FI schedule. Three drugs, clonidine, haloperidol, and morphine, were examined. All three decreased overall rates of key pecking; however, only the effects of clonidine were attenuated as reinforcer magnitude increased. An analysis of within-interval performance found rate-dependent effects for clonidine and morphine; however, these effects were not modulated by reinforcer magnitude. In addition, we included prefeeding and extinction conditions, standard tests used to measure resistance to change. In general, rate-decreasing effects of prefeeding and extinction were attenuated by increasing reinforcer magnitudes. Rate-dependent analyses of prefeeding showed rate-dependency following those tests, but in no case were these effects modulated by reinforcer magnitude. The results suggest that a resistance-to-change interpretation of the effects of reinforcer magnitude on rate dependency is not viable.

Ethanol effects on multiple fixed-interval, fixed-ratio responding in mice with deletions of the serotonin transporter gene.

Serotonin transporter knockout (KO) mice self-administer less ethanol than either heterozygous or wild-type mice; however, the mechanistic basis for this difference remains unclear. Here we examine the possibility that ethanol more readily decreases responding in KO mice, thereby limiting ethanol self-administration. To examine whether KO mice were more sensitive to the response-decreasing effects of ethanol, we administered ethanol (0.2-3.2 g/kg) to mice responding under a multiple fixed-ratio 30-response, fixed-interval 300-s schedule of milk presentation. Ethanol decreased responding similarly in all three genotypes. Fixed-ratio responding tended to be decreased at lower doses than fixed-interval responding. The decreased level of ethanol self-administration in serotonin transporter KO mice is not explained by an increased sensitivity to the response-decreasing effects of ethanol in KO mice, as sensitivity to the response-decreasing effects of ethanol was similar in the KO, heterozygous, and wild-type mice.

Effects of varenicline on ethanol- and food-maintained responding in a concurrent access procedure.

BACKGROUND: Varenicline has been reported to reduce drinking in smokers and to selectively decrease responding for ethanol (EtOH) versus alternatives in preclinical studies. Such selectivity may reflect potential therapeutic effects and the involvement of nicotinic receptors in EtOH reinforcement. However, these studies have been conducted with EtOH and an alternative available in isolation or in separate groups, and selectivity can depend on the context in which reinforcement occurs. Whether varenicline selectivity is maintained when EtOH and an alternative are concurrently available has not been reported. To examine the effects of varenicline on EtOH self-administration when an alternative is concurrently available, male Lewis rats (n = 5) were trained to respond for EtOH and food under a concurrent FR5 FRX schedule where the fixed ratio (FR) for food was adjusted (FR = 25 or 35 for each subject) to provide similar numbers of EtOH and food deliveries during a 30-minute session. METHODS: Doses of varenicline (0.56 to 5.6 mg/kg, i.p.) or vehicle were administered 30 minutes before sessions. Effects of varenicline on responding across the session and during each tenth of the session were compared to responding following vehicle treatment. RESULTS: Lower doses (0.56 to 1.0 mg/kg) of varenicline increased responding for EtOH without affecting responding for food. Higher doses disrupted responding for EtOH and food similarly. CONCLUSIONS: Previous reports of varenicline selectivity on EtOH-maintained responding do not generalize to other experimental conditions such as a concurrent schedule. The increase in responding for EtOH following lower doses might be due to enhanced EtOH reinforcement, decreased food reinforcement, rate dependency, or greater perseverance on the initial, EtOH response.

Shifts in discriminative control with increasing periods of recovery in the rat.

BACKGROUND: During recovery from alcoholism, other behavior likely increases. The development of alternative behavior may reduce attention to alcohol-associated stimuli. This could result in greater persistence of the alternative behavior when individuals again encounter alcohol-associated stimuli that might precipitate relapse. Developing animal models of this process could facilitate a better understanding of the mechanisms involved in relapse and recovery. However, current preclinical models of recovery and relapse rarely measure alternative behavior. Thus, our objective was to establish a procedure in rats in which an increase in alternative behavior (responding for food) reduced responding for ethanol (EtOH). The amount of responding for food and EtOH was then assessed after re-exposure to the alcohol-associated stimulus after varying the number of preceding sessions of increased responding for food and reduced responding for EtOH. These results were compared with those from a parallel group responding for saccharin solution instead of EtOH. METHODS: The solution (EtOH or saccharin) was always available following 5 responses. Presentation of flashing stimulus lights indicated food delivery followed 150 responses and resulted in responding predominately for the solution (84 to 86% of total responses). Presentation of solid stimulus lights indicated food delivery followed 5 responses and resulted in responding predominately for food (1 to 3% of total responses were for the solution). Rats were exposed to solid light conditions for 0, 1, 2, 4, or 16 consecutive sessions before being re-exposed to the flashing stimulus lights in extinction. RESULTS: Responding for either solution resumed when rats were re-exposed to the flashing stimulus lights (associated with solution-predominate responding). However, more responses occurred on the food lever with longer recent histories of responding for food instead of the solution. CONCLUSIONS: These results suggest that the longer alternative behavior replaces drinking, the more that attention to stimuli associated with drinking decreases. These results are consistent with the notion that the risk of relapse declines with longer periods of recovery because alternative behavior comes to predominate even in the presence of stimuli associated with drinking.

The potency of fluvoxamine to reduce ethanol self-administration decreases with concurrent availability of food.

The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigated further the impact that concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions in which food and ethanol were available concurrently and response rates were equal [average variable intervals (VIs) 405 and 14 s for food and ethanol, respectively], as well as when density of food delivery was increased (average VI 60 s for food and VI 14 s for ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14 s for ethanol) and under multiple VIs (VI 30 s for food and ethanol) wherein either food or ethanol was the only programmed reinforcement available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently {ED50 [95% confidence limit (CL): 8.2 (6.5-10.3) and 10.7 (7.9-14.4)]} versus when ethanol was available in isolation [ED50: 4.0 (2.7-5.9) and 5.1 (4.3-6.0)]. Effects on food were similar under each condition in which food was available. The results demonstrate that the potency of fluvoxamine in reducing ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement.

Reinforcement magnitude modulation of rate-dependent effects of fluvoxamine and desipramine in the rat.

Reinforcement magnitude modulates the effects of the antidepressants fluvoxamine and desipramine in the pigeon. Increasing reinforcement magnitude diminishes the rate-dependent effects of these drugs. Whether this is also the case in other species is unknown. Rats were trained to respond under a multiple fixed-interval (FI 300 s) schedule of reinforcement. In one FI component, rats earned two food pellets, and in the other component they earned 10 food pellets when they completed the FI requirement. The effects of fluvoxamine (3, 5.6, 10, and 17.8 mg/kg) or desipramine (1, 3, 5.6, 10, 30 mg/kg) given 30 min presession (intraperitoneally) on overall response rate were examined. Local rates of responding (during each 10th of the component) increased throughout the FI as is typical, and were higher during the component reinforced with 10 pellets. Fluvoxamine and desipramine decreased overall response rates similarly in both components. Both drugs exerted limited rate-dependent effects, shown by a negative slope for the regression of log (drug rate/control rate) on log (control rate) using data from each 10th of the FI. The slope for the two-pellet condition was, however, significantly steeper than the slope for the 10-pellet condition after 3 and 10 mg/kg fluvoxamine and after 30 mg/kg desipramine. This result is consistent with those obtained in pigeons and shows that reinforcement magnitude can modulate rate-dependent effects of fluvoxamine and perhaps desipramine in rats.

Mouse breathalyzer.

BACKGROUND: The development of a relatively simple, noninvasive method for estimating blood ethanol concentrations in mice will be useful in behavioral studies related to alcoholism. This study validated such a method. METHODS: The apparatus consists of a body chamber fitted with a head stock through which the mouse head protrudes. This was fitted against a water-jacketed head-space chamber surrounding the mouse's head. Rebreathed air maintained at 37 degrees C in the head-space chamber was removed using a peristaltic pump and loaded into a 1-ml injection loop. Ethanol in the sample was quantified using gas chromatography. To validate this method, ethanol levels in breath samples were compared against those in tail blood samples collected immediately after the breath samples. Breath samples were collected at 5, 10, 20, 40, 80, 120, and 160 minutes after ethanol (0.4, 0.8, 1.2, 1.6, 2.4, and 3.2 g/kg) was administered to male C57BL/6J mice. RESULTS: Breath and blood ethanol levels were well correlated (r(2) = 0.96) across time points on the descending ethanol-time curve at doses below 2.4 g/kg. Correlation for these doses on the ascending portion of the curve had greater variance, but was still well correlated (r(2) = 0.92). CONCLUSIONS: The mouse breathalyzer is an accurate, convenient, noninvasive and well-tolerated method for estimating blood ethanol concentrations in mice across a range of behaviorally relevant concentrations below 2.4 g/kg, especially on the descending limb of the ethanol-time curve. Although this procedure requires a gas chromatograph in the animal facility, the ability to estimate ethanol concentrations quickly and easily will be especially useful in behavioral studies where repeated blood sampling is not feasible.

Reinforcement magnitude modulates the rate-dependent effects of fluvoxamine and desipramine on fixed-interval responding in the pigeon.

Some doses of fluvoxamine can decrease ethanol-maintained behavior more than food-maintained behavior. This might be explained by differences in reinforcement magnitude. In a previous study, the effects of fluvoxamine on fixed-ratio responding did not depend upon reinforcement magnitude. Response rates, however, differed with reinforcement magnitude. These differences in response rates might explain the failure to observe differences in the potency of fluvoxamine with changes in reinforcement magnitude. In this study, we examined whether the effects of fluvoxamine and desipramine depended on the reinforcement magnitude and response rate, by administering these drugs to pigeons responding under a multiple fixed-interval schedule, in which responding in three components was maintained by differing durations of food presentation (2, 4, and 8 s). The effects of fluvoxamine and desipramine depended jointly on control rate, reinforcement magnitude, and dose. Low fluvoxamine doses had rate-dependent effects in all three components, increasing lower rates more than higher rates: as dose increased, these rate-dependent effects became greater in the components maintained by the 2-s or 4-s food presentation; whereas, in the component maintained by the 8-s presentations, they declined. Low desipramine doses had rate-dependent effects only in the component maintained by the 2-s presentations, whereas higher doses had rate-dependent effects in components maintained by 2-s or 4-s presentations. Still higher doses had rate-dependent effects in all the three components. Although the effects of fluvoxamine and desipramine might not depend on reinforcement magnitude when studied under fixed-ratio schedules, reinforcement magnitude can modulate their effects when they are studied over a wider range of control response rates.

Taurine and ethanol interactions: behavioral effects in mice.

Taurine is an abundant amino acid in the brain that shares pharmacological effects and similar potency with ethanol. Recently, taurine-containing beverages have been reported to enhance the euphoric effects of ethanol, though the extent of this effect and the role of taurine remain speculative. The present study was designed to explore interactions between taurine and ethanol on several behaviors including locomotion, ataxia, and loss of righting. Two strains of mice, C57BL/6J and DBA/2J mice, were used to examine potential strain differences. In the first experiment, effects of various doses of taurine (0.3-3.0 g/kg), ethanol (1.0-4.2 g/kg), or taurine in combination with ethanol were assessed in a within-subjects design. Although taurine did not appear to alter effects of ethanol on any measure in either strain, the development of tolerance to locomotor effects and sensitization to ataxic effects of ethanol in DBA/2J mice complicated interpretation of these results. In a second experiment, drug-naïve mice were assigned to one of four treatment groups: saline+saline, saline+ethanol (1.78 g/kg), taurine (1.78 g/kg)+saline, or ethanol+taurine. In this experiment, taurine pretreatment significantly attenuated the locomotor-stimulating effect of ethanol in both strains (but to a greater extent in C57BL/6J mice) and appeared to reduce the ataxic effects of ethanol in C57BL/6J mice. In conclusion, the interaction between taurine and ethanol is subtle. Further, results are inconsistent with the notion that taurine plays a major role in the locomotor, ataxic, or loss of righting effects of ethanol.

Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Delta9-THC or (R)-methanandamide (AM-356).

OBJECTIVE: To characterize in vivo the high-affinity cannabinoid CB1 receptor (CB1R) selective anandamide analog AM-1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination procedures. D-amphetamine and also morphine in the (R)-methanandamide-trained group (see below) were examined to assess pharmacological specificity. METHODS: Three groups of rats were trained to discriminate between vehicle and (1) 1.8 mg/kg Delta9-tetrahydrocannabinol (Delta9-THC); (2) 5.6 mg/kg Delta9-THC; and (3) 10 mg/kg (R)-methanandamide (AM-356; a metabolically stable analog of anandamide). Delta9-THC was given i.p. 30 min and (R)-methanandamide 15 min before training. RESULTS: AM-1346 generalized to all three training conditions, both at 15 and 30 min after administration. The rank order potency was: Delta9-THC > AM-1346 > (R)-methanandamide. AM-1346 appeared slightly more potent 30 min compared to 15 min postadministration. In the presence of 0.3 mg/kg of the CB1R antagonist/inverse agonist SR-141716A, the dose generalization curves of Delta9-THC and AM-1346 resulted in parallel shifts to the right in the 1.8 mg/kg Delta9-THC-trained group. A long duration of action for AM-1346 (relative to AM-356) was indicated in tests where AM-1346 was examined in the 5.6 mg/kg Delta9-THC-trained group. Neither D-amphetamine, nor morphine generalized in either of the groups, suggesting pharmacological specificity. CONCLUSION: Unlike (R)-methanandamide, the surmountable antagonism between SR-141716A and AM-1346 shows that the structural features of anandamide can be modified in ways that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB1R agonists derived from an anandamide template.

Cannabinoid effects on behaviors maintained by ethanol or food: a within-subjects comparison.

The cannabinoid CB1 antagonist rimonabant (SR141716A) has been proposed as a therapeutic agent for several addictive disorders, including alcoholism. Rimonabant may selectively reduce responding for an ethanol solution compared with an alternative. While this could represent a specific effect of CB1 inhibition on ethanol reinforcement, this could also result from differences in the baseline rates of behavior or experiences between comparison groups. We developed a procedure in rats that allows a within-subject comparison of ethanol and food-maintained responding and provides well matched baseline response rates. We determined the effects of acute doses of rimonabant (0.3-5.6 mg/kg, intraperitoneal) and the CB1 agonist Delta-9-tetrahydrocannabinol (1.0-5.6 mg/kg, intraperitoneal) on responding for food and ethanol under a multiple fixed-ratio schedule. To confirm that rimonabant blocked cannabinoid receptors, the ability of rimonabant to antagonize Delta-9-tetrahydrocannabinol effects in the same subjects under the same reinforcement schedule was also determined. In contrast with previous reports, rimonabant did not significantly alter responding for ethanol or food. The effects of Delta-9-tetrahydrocannabinol on responding for food were completely antagonized by rimonabant, whereas Delta-9-tetrahydrocannabinol effects on responding for ethanol were not. These results suggest that there may be neuroadaptation of the cannabinoid system following aging or chronic self-administration of ethanol.

Rat breathalyzer.

BACKGROUND: The purpose of this study was to characterize the estimation of blood alcohol (ethanol) concentration (BAC) in laboratory rats by measuring ethanol concentration in breath (BrAC) using a specialized apparatus in combination with a gas chromatography system. METHODS: The apparatus consisted of a body chamber, a plastic cylinder, from which the head of the rat protruded, a head chamber, and a water-jacketed cylinder, in which the rat's head was placed while the breath sample was collected. The breath sample was withdrawn from the head chamber through a sample loop by a Minipuls pump and then injected directly into the gas chromatography system that was equipped with a flame ionization detector for the quantification of ethanol. For these experiments, Lewis rats were catheterized 1 week before the commencement of the experiments so that blood samples were collected at exactly the same time as the breath samples. RESULTS: Our results show that Lewis rats can be trained to enter and be secured in the body chamber and that they appear to be comfortable for periods as long as 150 min. The profiles of the pharmacokinetic curves for BrAC and BAC were essentially identical. Cmax for BrAC and BAC at 8 min after the intraperitoneal injection of ethanol was directly proportional to the doses of ethanol. The ratio of BrAC expressed as peak area to BAC (expressed as mM) was calculated to be 3282. This conversion factor can be used to directly estimate the BAC from the BrAC. CONCLUSIONS: The principal conclusion of this study was that the rat breathalyzer is an accurate and convenient laboratory method to estimate BAC in a noninvasive manner. This procedure will be particularly useful for studies requiring repeated assessment of alcohol levels.

Adamantyl cannabinoids: a novel class of cannabinergic ligands.

Structure-activity relationship studies have established that the aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have now synthesized a series of analogues in which a variety of adamantyl substituents were introduced at the C3 position of Delta(8)-THC. Our lead compound, (-)-3-(1-adamantyl)-Delta(8)-tetrahydrocannabinol (1a, AM411), was found to have robust affinity and selectivity for the CB1 receptor as well as high in vivo potency. The X-ray crystal structure of 1a was determined. Exploration of the side chain conformational space using molecular modeling approaches has allowed us to develop cannabinoid side chain pharmacophore models for the CB1 and CB2 receptors. Our results suggest that although a bulky group at the C3 position of classical cannabinoids could be tolerated by both CB1 and CB2 binding sites, the relative orientation of that group with respect to the tricyclic component can lead to receptor subtype selectivity.

Cut-off levels for breath carbon monoxide as a marker for cigarette smoking.

AIMS: Current clinical studies often use a breath carbon monoxide (BCO) cut-off level of 8 parts per million (p.p.m.) or higher to identify smoking. In this study, the cut-off level of BCO as an indicator of smoking over the past 24 hours was re-examined. DESIGN: BCO and self-reported smoking were obtained each weekday for up to 14 weeks in 213 subjects paid to deliver reduced BCO values. Analysis of 12 386 paired values for reported smoking and BCO were analyzed. FINDINGS: The 25% quartile, median and 75% quartile values for BCO were 1, 1 and 2 p.p.m. on non-smoking days and 2, 5 and 12 p.p.m. on smoking days, respectively. Receiver-operating characteristic (ROC) analysis indicated that BCO provided high diagnostic accuracy to distinguish between smoking and non-smoking days [area under the curve (AUC) = 0.853, P < 0.0001]. The highest combined sensitivity and specificity was observed at a BCO cut-off level of 3 p.p.m. (sensitivity = 71.5%; specificity = 84.8%). At a BCO cut-off of 8 p.p.m. sensitivity and specificity were 40.6% and 98.2%, respectively, indicating that many smokers would be falsely classified as abstinent. Finally, the percentage of true tests (positive and negative) was highest at a BCO cut-off of 2 p.p.m. (80.2%). CONCLUSIONS: BCO cut-off levels well below 8 p.p.m and as low as 2-3 p.p.m. may be more useful when it is important to maximize identification of smoking abstinence with a high degree of certainty.