Background: Recent cannabis use is associated with an approximate two-fold increase in automobile crash risk, but detecting cannabis-impaired driving remains a challenge.
Objectives and Methods: In ...this perspective, the pros and cons of two types of assessments arising from those used to detect alcohol-impaired driving are discussed in the context of cannabis-impaired driving.
Results: Some laws rely on tests to detect whether blood or breath levels exceed a legally defined (per se) threshold. These laws rely on clear and consistent relationships across individuals between detectable drug concentrations and the amount consumed, crash risk, or degree of driver impairment. However, unlike alcohol, there is poor correspondence between detected levels of the primary active constituent of cannabis or its metabolites and the amount consumed or its behavioral effects. Field sobriety tests assess impairment on functional tests calibrated to reflect actual driving-impairment and validated to predict traffic safety risk. However, functional tests for cannabis-impaired driving have not been developed or validated, and the degree of impairment resulting from recent cannabis use is difficult to distinguish from other conditions such as advancing age or use of certain medications.
Conclusions: Although standard field sobriety tests have advantages over per se tests for cannabis-impaired driving, limitations of both leave cannabis users and law enforcement officials little guidance in assessing an individual's driving fitness after recent cannabis use. General strategies for detecting and preventing impaired driving regardless of the cause would be preferable to establishing specific methods for every situation or substance that could impair driving.
Periods of engaging in an alternative behavior diminishes behavioral control by stimuli occasioning alcohol use. This increase in relapse resistance with increasing recovery suggests that changing ...stimulus control over substance use may be a mechanism responsible for decreased relapse rates with longer recovery. However, the generality of this phenomenon to other drugs of abuse, including opioid self-administration, remains unclear. This study tests the generality of these findings with etonitazene to determine whether the shift in attention represents a behavioral process that generalizes from conditions we previously reported.
Five adult male Lewis rats were trained to respond on levers under two stimulus conditions; high-cost food (food FR150 and etonitazene FR5) and low-cost food (both food and etonitazene FR 5). Next, only the high-cost food stimulus (occasioning etonitazene responding) was presented for 20 sessions (Use Phase) followed by 9 sessions in which only the low-cost food stimulus (occasioning food responding) was presented (Recovery Phase). During the Recovery Phase, testing occurred during the first component of sessions 0, 1, 2, 4, and 8 when rats were re-exposed to the high-cost food stimulus. The number of food responses prior to completing the etonitazene response requirement during this stimulus exposure was the primary measure.
Food responses during stimulus re-exposure increased significantly as a function of recovery sessions completed with a slope 95 % CI of 2.49 responses/recovery session 0.16, 4.81. The average number of etonitazene deliveries per use session was 32 ± 6.6 or an average daily dose of 48.8 ± 10.1 μg/kg. During Recovery Phase, etonitazene deliveries decreased to 2.4 ± 1 or 3.6 ± 1.5 μg/kg.
The decrease in stimulus control observed for ethanol self-administration appears to generalize to opioid self-administration, indicating this change in stimulus control may play a general role in recovery.
Conditioned stimuli (CS) associated with alcohol ingestion are thought to play a role in relapse by producing a craving that in turn increases motivation to drink which increases ethanol-seeking and ...disrupts other ongoing behavior. Alternatively, such CS may provide information indicating a likely increase in the density of the paired unconditioned stimulus and simultaneously elicit behavior that may be incompatible with other ongoing behavior, i.e., approach toward the CS. To explore these possibilities, rats were trained to respond for ethanol or food in two different components of the same session after which a light above the ethanol-lever was lighted twice during each component and each light presentation was followed by ethanol delivery. The duration of this CS was 10 s initially and then increased to 30 s, then to 100 s, and finally returned to 30 s. The change in responding for ethanol or food was compared to a matched period immediately preceding CS presentation. The CS presentation increased responding to ethanol, and this effect
increases
with longer CS presentations. In contrast, the CS presentation decreased responding to food, and this effect
decreases
with longer CS presentations. These results appear to support the informational account of CS action rather than simply a change in the motivation to seek and consume ethanol. This suggests that craving as it is commonly understood likely represents multiple behavioral processes, not simply increased desire for alcohol and that reports of craving likely reflect labeling based upon past experiences rather than a cause of future drug-taking.
Addiction is continued drug use despite its harm. As one always has alternatives, addiction can be construed as a decision to allocate behavior to drug use. While decision making is commonly ...discussed and studied as if it resulted from deliberative, evaluative processes, such processes are actually only rarely involved in behavior allocation. These deliberative processes are too slow, effortful and inefficient to guide behavior other than when necessary. Rather, most actions are guided by faster, more automatic processes, often labeled habits. Habits are mostly adaptive, and result from repeated reinforcement leading to over-learned behavior. Habitual behavior occurs rapidly in response to particular contexts, and the behavior occurring first is that which occurs, i.e., the behavior that is decided upon. Thus, as drug use becomes habitual, drug use is likely to be chosen over other available activities in that particular context. However, while drug use becoming habitual is necessary for addiction to develop, it is not sufficient. Typically, constraints limit even habitual drug use to safer levels. These constraints might include limiting occasions for use; and, almost always, constraints on amount consumed. However, in a minority of individuals, drug use is not sufficiently constrained and addiction develops. This review discusses the nature of these constraints, and how they might fail. These failures do not result from abnormal learning processes, but rather unfortunate interactions between a person and their environment over time. These accumulate in the maladaptive allocation of behavior to drug use. This Behavior Allocation Disorder (BAD) can be reversed; occasionally easily when the environment significantly changes, but more often by the arduous application of deliberative processes generally absent from decision making. These deliberative processes must continue until new more adaptive habits become the most probable behavior in the contexts encountered. As alternatives to drug use become the most probable behavior, relapse risk diminishes.
•Addiction is a Behavioral Allocation Disorder, a BAD.•BADs result from learning, the cumulative experiences of a person with an environment.•Of the behaviors that could occur, the most probable, the fastest one occurs.•Habitual behavior is rapid; thus as drug use becomes habitual, it becomes more likely.•Habits are naturally constrained, when habits escape constraints a BAD may occur.
Cannabinoid use has increased among aging individuals. However, little information on age-related differences in the behavioral effects of these agents is available. To explore potential differences ...in the behavioral effects of cannabinoids, we determined effects of Δ9-tetrahydrocannabinol (THC, 1–10 mg/kg) or rimonabant (0.3–3.2 mg/kg) on operant fixed-ratio responding (FR10) for food in young adult (6 months) and aged (29 months) rats. THC dose-dependently decreased responding for food. Rimonabant alone had little or no effect on responding up to 1.0 mg/kg, but disrupted responding following a 3.2 mg/kg dose. Rimonabant (1.0 mg/kg) partially antagonized response disruption by THC. These effects were similar in young adult and aged rats. However, aging has been reported to change the neurobiology of cannabinoid CB1 receptors. To confirm our rats exhibited such differences, we assessed CB1 receptor binding sites and function in six subcortical (caudate, nucleus accumbens CA1, and CA2/CA3), and three cortical regions (medial prefrontal, temporal, entorhinal) in young adult (6 months) or aged (26 months) male Lewis rats using quantitative autoradiography. CB1 receptor binding sites were reduced in cortical, but not subcortical brain regions of aged rats. CB1 receptor function, at the level of receptor-G protein interaction, was not different in any region studied. Results indicate that down-regulation of CB1 receptor binding sites observed in cortical regions of aged rats was not accompanied by a commensurate decrease in CB1 receptor-stimulated 35SGTPγS binding, suggesting a compensatory increase in receptor function in cortical areas. Together, our results provide additional evidence of age-related changes in central CB1 receptor populations. However, the functional compensation for decreased CB1 receptor binding may mitigate changes in behavioral effects of cannabinoids. With the rising use of cannabinoid-based therapeutics among aging populations, further evaluation of age-related changes in the cannabinoid system and the impact of these changes on effects of this class of drugs is warranted.
•Cannabinoid CB1 receptor agonist and antagonist behavioral effects were similar in aged versus young rats.•THC disrupted responding 24-hours after exposure in both age groups, and this effect was partially reversed by rimonabant.•CB1 receptor binding sites were reduced in cortical, but not subcortical brain regions of aged rats compared to young rats.•CB1 receptor function, at the receptor-G protein interaction level, was not different between ages in any region studied.•CB1 receptor function may compensate for age-related changes in binding sites.
Previously, we reported that recovery-like behavior decreases stimulus control over drinking, and this likely plays a role in the clinical observation that longer recovery increases relapse ...resistance. Those studies were conducted using a procedure that required repeated assessment, preventing a longitudinal analysis of the changes in stimulus control over time in each individual. Here we recapitulate those results and extend them to female rats using a more efficient procedure that allows repeated assessment of changes in stimulus control over drinking during recovery.
Under a multiple concurrent schedule, rats were trained to reliably respond predominately for ethanol (concurrent Ethanol FR5, Food FR150) in the presence of one stimulus and for food (concurrent Ethanol FR5, Food FR5) in the presence of another stimulus. Stimuli were either lights or tones, depending on the group. After that, a drinking phase in which only the stimulus occasioning ethanol responding was presented (10 or 20 sessions) followed by recovery-like sessions in which only the stimulus occasioning food responding was presented. During these sessions, rats were exposed to the ethanol stimulus under extinction during the first component on sessions 0, 1, 2, 4,8, and 16. The number of food responses during these stimulus exposures prior to the first 5 ethanol responses was the primary measure.
Consistent with the earlier procedure, the number of food responses during ethanol tests increased as a function of the number of recovery sessions completed, regardless of whether the stimuli were visual or auditory. However, there were no significant effects of extended alcohol exposure or sex.
A rapid procedure consistent with the earlier procedure and clinical evidence was developed in which stimulus control over drinking decreased following longer periods of recovery. Under conditions tested, stimulus type, length of drinking history and sex did not affect this relationship.
•Longer periods of engagement in recovery like behavior increases relapse resistance by shifting stimulus control over drinking.•Previously established animal models that reproduce this relation to study substance use disorder was time consuming and lengthy.•Current results showed an effective new model that can reproduce the previously established relationship within significantly shorter periods of time.
Background
Phosphatidylethanol 16:0/18:1 (PEth), found in whole blood, is a biomarker for alcohol consumption with high sensitivity, specificity, and a long detection window. The TASSO‐M20 device is ...used to self‐collect capillary blood from the upper arm and has advantages over finger stick methods. The purpose of this study was to (1) validate PEth measurement using the TASSO‐M20 device, (2) describe the TASSO‐M20 for blood self‐collection during a virtual intervention, and (3) characterize PEth, urinary ethyl glucuronide (uEtG) and self‐reported alcohol in a single participant over time.
Methods
PEth levels in blood samples dried on TASSO‐M20 plugs were compared to those in (1) liquid whole blood (N = 14) and (2) dried blood spot cards (DBS; N = 23). Additionally, the self‐reported drinking, positive or negative uEtG results (dip card cutoff ≥300 ng/mL), and observed self‐collection of blood with TASSO‐M20 devices for PEth levels were obtained over time during virtual interviews of a single contingency management participant. High‐performance liquid chromatography with tandem mass spectrometry detection was used to measure PEth levels for both preparations.
Results
PEth concentrations from dried blood on TASSO‐M20 plugs and liquid whole blood were correlated (0 to 1700 ng/mL; N = 14; r2 = 0.988; slope = 0.951) and in a subgroup of samples with lower concentrations (N = 7; 0 to 200 ng/mL; r2 = 0.944, slope = 0.816). PEth concentrations from dried blood on TASSO‐M20 plugs and DBS were correlated (0 to 2200 ng/mL; N = 23; r2 = 0.927; slope = 0.667) and in a subgroup of samples with lower concentrations (N = 16; 0 to 180 ng/mL; r2 = 0.978, slope = 0.749). Results of the contingency management participant indicate that changes in PEth levels (TASSO‐M20) and uEtG concentrations were consistent with each other and with changes in self‐reported alcohol use.
Conclusions
Our data support the utility, accuracy, and feasibility of using the TASSO‐M20 device for blood self‐collection during a virtual study. The TASSO‐M20 device had multiple advantages over the typical finger stick method, including consistent blood collection, participant acceptability, and less discomfort as indicated by acceptability interviews.
This study validated methods for assessing phosphatidylethanol 16:0/18:1 (PEth) levels following blood collection with the TASSO‐M20 device. PEth levels on TASSO‐M20 plugs were compared to the standard methods of liquid whole blood or dried blood spot (DBS). PEth concentrations on TASSO‐M20 plugs were highly correlated with liquid whole blood (0–200 ng/mL; r2 = 0.944, slope = 0.816) and DBS (0–180 ng/mL; r2 = 0.978, slope = 0.749). The TASSO‐M20 device is an accurate blood collection method for PEth quantification.
The influence of Pavlovian Conditioned Stimuli (CS) on ethanol self-administration and choice between ethanol and an alternative are potentially important. Ethanol-paired CS might increase ethanol ...self-administration, especially when it has been reduced during recovery, though the selectivity of these increases has been questioned. To date, one study examined the effects of an ethanol-paired CS on ethanol choice and found that the CS increased ethanol-responding more than food-responding when both were in extinction. However, it remains unclear whether ethanol-paired CS increase ethanol-choice that is not in extinction. Here, we examine the effects of an ethanol-paired CS on ethanol-choice when both food- and ethanol-responding are reinforced. Sixteen adult male Lewis rats were trained on a concurrent schedule to respond for ethanol on one lever and for food on the other lever. Ethanol was available under an FR 5 schedule, and food was available under an FR schedule that was adjusted for each rat to earn an equal number of food and ethanol deliveries. Then, 2-min light presentations were paired with an RT 25-sec schedule of ethanol delivery for 10 sessions in the absence of both levers. After this, subjects were placed back on the concurrent schedule for one session, then five sessions with the CS being present or absent on each trial of the concurrent schedule occurred. Rats learned to respond on one lever for ethanol and on the other for food and earned similar numbers of ethanol and food deliveries. During Pavlovian Conditioning, the number of head entries into the head-entry detector was higher in the presence of the CS than in its absence. In the test sessions, rats made more ethanol responses in the presence of the CS than in its absence. However, this effect was small and did not increase the amount of ethanol earned. Thus, ethanol-paired CS could increase ethanol-responding under a choice procedure but did not increase ethanol consumption meaningfully under the studied conditions.
•Ethanol-paired conditioned stimulus increased ethanol-responding when both ethanol and an alternative were reinforced.•A Pavlovian conditioned stimulus effect on drinking was not robust, and it did not increase the amount of ethanol earned.•The effects of conditioned stimulus on ethanol choice when ethanol and food stimuli were not in extinction are shown.
The aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the ...Interventions Testing Program demonstrated that the anti‐diabetes drug, Canagliflozin (Cana), a sodium‐glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30‐month‐old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana‐treated male and female mice showed significant reductions in age‐associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana‐treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30‐month‐old male but not female mice. Taken together, we demonstrate the sex‐specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.
Our findings demonstrate sex‐specific neuroprotective effects of Canagliflozin treatment that are associated with reduced neuroinflammation, improved central insulin sensitivity, and locomotor activity in aged mice.
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