The Impact of a Mobile Diabetes Health Intervention on Diabetes Distress and Depression Among Adults: Secondary Analysis of a Cluster Randomized Controlled Trial.

BACKGROUND: Diabetes is a complex, demanding disease that requires the constant attention of patients. The burden of self-management, including different medication regimens, routine self-care activities, and provider visits, has an impact on patients' emotional well-being. Diabetes distress and depression are two important components of emotional well-being that may negatively affect diabetes outcomes. OBJECTIVE: The aim was to determine the impact of the 1-year Mobile Diabetes Intervention Study cluster randomized clinical trial on emotional well-being measured by diabetes distress and depression among adults with type 2 diabetes (T2D). METHODS: A total of 163 adults with not-well-managed T2D were enrolled from community primary care practices. Primary care practices were cluster randomized into either a usual care control group or intervention group. Intervention participants were given a mobile phone with coaching software including a Web portal to communicate with providers. A priori established secondary outcomes included distress measured by the Diabetes Distress Scale (DDS), with subscales measuring emotional burden, interpersonal distress, physician-related distress, and regimen-related distress, as well as depression measured by the Patient Health Questionnaire (PHQ-9). Linear mixed models were used to calculate the effect of the intervention on diabetes distress levels over time, both overall and separately by sex, and to determine if the intervention affected distress or depression. The impact of total DDS on changes in HbA1c was also studied. RESULTS: There were no significant treatment group effects for DDS total (baseline: P=.07; differences over time: P=.38) or for depression (P=.06 over time). Significant declines in total DDS were observed over the 12-month intervention period (P=.01). Regimen-related distress significantly decreased for all study participants (P<.001), but no significant change over time was observed for emotional burden (P=.83), interpersonal distress (P=.64), or physician-related distress (P=.73). Women in both the usual care and intervention groups were more likely to have higher overall DDS, emotional burden, physician-related distress, and regimen-related distress, but not interpersonal distress. Women also reported higher baseline depression compared to men (P=.006). Overall, depression decreased over the treatment period (P=.007), but remained unaffected by group assignment (P=.06) or by sex (P=.97). Diabetes distress had no effect on the change in HbA1c (P=.91) over the treatment period. CONCLUSIONS: Although we found no definitive overall or sex-specific effect of the intervention on diabetes distress or depression, this study makes an important contribution to the understanding of mobile health interventions and the impact on emotional health. Our study verified previous work that although diabetes distress and depression are highly correlated, these measures are not evaluating the same construct. Design of future mobile technology provides an opportunity to personalize, contextualize, and intervene in the emotional well-being of persons with diabetes. TRIAL REGISTRATION: Clinicaltrials.gov NCT01107015; https://clinicaltrials.gov/ct2/show/NCT01107015 (Archived by WebCite at http://www.webcitation.org/6vVgRCLAF).

Gene Targeting Studies of Hyperexcitability and Affective States of Alcohol Withdrawal in Rodents.

Genetically engineered rodents can be used to examine the influence of single genes on alcoholism-related phenotypes. We review studies that employed gene targeting with a focus on ethanol withdrawal-associated behaviors. Earlier studies targeted the glutamate and GABA systems as contributors to the underlying hyperexcitable state of convulsions or similar signs of ethanol withdrawal. Over the past decade, many gene-targeting studies have continued to focus on the glutamatergic and GABAergic systems; however, an increasing number of these studies have focused on other withdrawal outcomes such as anxiety-like behavior and escalated ethanol consumption. Although negative affective states may drive escalated ethanol drinking, few reported studies examined the phenotypes together. However, there is significant overlap in the systems that were manipulated in relation to studying the phenotypes individually. These studies reveal common genetic influences on withdrawal-associated anxiety, convulsions, and escalated drinking that may contribute to relapse, setting the stage for the identification of novel medications to jointly target these effects.

Nest building is a novel method for indexing severity of alcohol withdrawal in mice.

Withdrawal after chronic ethanol (EtOH) affects body temperature, goal-directed behavior and motor function in mice and increases general central nervous system excitability. Nest-building tests have been used to assay these states but to this point have not been employed as measures of EtOH withdrawal severity. We first refined nest-scoring methods using a genetically heterogeneous stock of mice (HS/Npt). Mice were then made physically dependent following three days of chronic EtOH vapor inhalation to produce average blood EtOH concentrations (BECs) of 1.89 mg/mL. EtOH withdrawal affected the progression of nest building over time when mice were tested 2-4 days after removal from three days of chronic exposure to EtOH. In a separate group of mice, chronic EtOH vapor inhalation (BECs 1.84 mg/mL) suppressed nest building over days 1-2 but not days 2-3 of withdrawal. In a following experiment, EtOH withdrawal dose-dependently slowed recovery of nest building for up to 32 h. Finally, we determined that long-lasting nest-building deficits extend to mice undergoing withdrawal from a high dose (4 g/kg) of acute EtOH. Sex differences for nest building were absent following EtOH exposure. In mice naïve to EtOH treatments, male mice had lower pre-test body temperatures and increased nest scores across a two-day testing period compared to females. These results suggest that nest building can be used to assess chronic and acute EtOH withdrawal severity in mice.

Distinct ethanol drinking microstructures in two replicate lines of mice selected for drinking to intoxication.

The High Drinking in the Dark (HDID) mice have been selectively bred for reaching high blood ethanol concentrations (BECs) following the limited access Drinking in the Dark (DID) test. We have shown previously that mice from the first HDID replicate line (HDID-1) drink in larger, but not longer, ethanol drinking bouts than the low-drinking HS/Npt control mice when consuming modest amounts in the DID test. Here, we assessed drinking microstructure in HDID-1 mice during binge-like levels of ethanol intake using a lickometer system. Mice from both HDID replicates (HDID-1 and -2) and HS mice were also given three DID tests (single-bottle ethanol, two-bottle choice and single-bottle saccharin) using a continuously recording BioDAQ system to determine whether there are selection-dependent changes in drinking microstructure. Larger ethanol bout size in the HDID-1 mice than the HS mice was found to be due to a larger lick volume in these mice. HDID-1 and HDID-2 mice were also seen to have different drinking microstructures that both resulted in high intake and high BECs. The HDID-1 mice drank in larger ethanol bouts than HS, whereas HDID-2 mice drank in more frequent bouts. This pattern was also seen in two-bottle choice DID. The HDID-2 mice had a high bout frequency for all fluid types tested, whereas the large bout size phenotype of the HDID-1 mice was specific to alcohol. These findings suggest that selection for drinking to intoxication has resulted in two distinct drinking microstructures, both of which lead to high BECs and high ethanol intake.

Secular trends, race, and geographic disparity of early-stage breast cancer incidence: 25 years of surveillance in Connecticut.

OBJECTIVES: We considered changes in the geographic distribution of early stage breast cancer among White and non-White women while secular trends in lifestyle and health care were under way. METHODS: We aggregated tumor registry and census data by age, race, place of residence, and year of diagnosis to evaluate rate variation across Connecticut census tracts between 1985 and 2009. Global and local cluster detection tests were completed. RESULTS: Age-adjusted incidence rates increased by 2.71% and 0.44% per year for White and non-White women, respectively. Significant global clustering was identified during surveillance of these populations, but the elements of clustering differed between groups. Among White women, fewer local clusters were detected after 1985 to 1989, whereas clustering increased over time among non-White women. CONCLUSIONS: Small-area variation of breast cancer incidence rates across time periods proved to be dynamic and race-specific. Incidence rates might have been affected by secular trends in lifestyle or health care. Single cross-sectional analyses might have confused our understanding of disease occurrence by not accounting for the social context in which patient preferences or provider capacity influence the numbers and locations of diagnosed cases. Serial analyses are recommended to identify "hot spots" where persistent geographic disparities in incidence occur.

Progress in a replicated selection for elevated blood ethanol concentrations in HDID mice.

Drinking in the dark (DID) is a limited access ethanol-drinking phenotype in mice. High Drinking in the Dark (HDID-1) mice have been bred for 27 selected generations (S27) for elevated blood ethanol concentrations (BECs) after a 4-h period of access to 20% ethanol. A second replicate line (HDID-2) was started later from the same founder population and is currently in S20. An initial report of response to selection in HDID-1 was published after S11. This article reports genetic and behavioral characteristics of both lines in comparison with the HS controls. Heritability is low in both replicates (h(2) = 0.09) but the lines have shown 4-5 fold increases in BEC since S0; 80% of HDID-1 and 60% of HDID-2 mice reach BECs greater than 1.0 mg/ml. Several hours after a DID test, HDID mice show mild signs of withdrawal. Although not considered during selection, intake of ethanol (g/kg) during the DID test increased by approximately 80% in HDID-1 and 60% in HDID-2. Common genetic influences were more important than environmental influences in determining the similarity between BEC and intake for HDID mice. Analysis of the partitioning of intake showed that 60% of intake is concentrated in the last 2 h of the 4 h session. However, this has not changed during selection. Hourly BECs during the DID test reach peak levels after 3 or 4 h of drinking. HDID mice do not differ from HS mice in their rate of elimination of an acute dose of alcohol.

Translational behaviour-genetic studies of alcohol: are we there yet?

In biomedical research, one key stage of translating basic science knowledge to clinical practice is the reconciliation of phenotypes employed for laboratory animal studies with those important for the clinical condition. Alcohol dependence (AD) is a prototypic complex genetic trait. There is a long history of behaviour-genetic studies of AD in both human subjects and various genetic animal models. This review assesses the state of the art in our understanding of the genetic contributions to AD. In particular, it primarily focuses on the phenotypes studied in mouse genetic animal models, comparing them to the aspects of the human condition they are intended to target. It identifies several features of AD where genetic animal models have been particularly useful, and tries to identify understudied areas where there is good promise for further genetic animal model work.

Evidence for multiple genetic factors underlying the DSM-IV criteria for alcohol dependence.

To determine the number of genetic factors underlying the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for alcohol dependence (AD), we conducted structural equation twin modeling for seven AD criteria, plus two summary screening questions, in 7133 personally interviewed male and female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, who reported lifetime alcohol consumption. The best-fit twin model required three genetic and two unique environmental common factors, and criterion-specific unique environmental factors. The first genetic factor was defined by high loadings for the probe question about quantity and frequency of alcohol consumption, and tolerance criterion. The second genetic factor loaded strongly on the probe question about self-recognition of alcohol-related problems and AD criteria for loss of control, desire to quit, preoccupation and activities given up. The third genetic factor had high loadings for withdrawal and continued use despite the problems criteria. Genetic factor scores derived from these three factors differentially predicted patterns of comorbidity, educational status and other historical/clinical features of AD. The DSM-IV syndrome of AD does not reflect a single dimension of genetic liability, rather, these criteria reflect three underlying dimensions that index risk for: (i) tolerance and heavy use; (ii) loss of control with alcohol associated social dysfunction and (iii) withdrawal and continued use despite problems. While tentative and in need of replication, these results, consistent with the rodent literature, were validated by examining predictions of the genetic factor scores and have implications for gene-finding efforts in AD.

Genetics of novelty seeking, amphetamine self-administration and reinstatement using inbred rats.

Previous research using outbred rats indicates that individual differences in activity in a novel environment predict sensitivity to the reinforcing effect of psychostimulant drugs. The current study examined if the link between responses related to novelty and amphetamine self-administration is heritable. Twelve inbred rat strains were assessed for locomotor activity in a novel environment, preference for a novel environment, and intravenous amphetamine self-administration (acquisition, extinction and amphetamine-induced reinstatement). Strain differences were observed in activity in a novel environment, novelty preference and amphetamine self-administration, indicating a genetic influence for each of these behaviors. While there was no relation between activity in an inescapable novel environment and amphetamine self-administration, strain-dependent differences in novelty preference were positively correlated with the amount of amphetamine self-administered. There was also a positive correlation between the dose-dependent rate of amphetamine self-administration and magnitude of reinstatement. These results show that the activity in an inescapable novel environment and the preference for a novel environment are different genetically, and thus likely to reflect different behavioral constructs. Moreover, these results implicate a genetic influence on the relation between novelty seeking and stimulant self-administration, as well as on the relation between stimulant reward and reinstatement.

Alcohol trait and transcriptional genomic analysis of C57BL/6 substrains.

C57BL/6 inbred mice have been widely used as research models; however, widespread demand has led to the creation of several B6 substrains with markedly different phenotypes. In this study, we report that two substrains of C57BL/6 mice, C57BL/6J (B6J) and C57BL/6NCrl (B6C), separated over 50 years ago at two different breeding facilities differ significantly in alcohol consumption and alcohol preference. The genomes of these two substrains are estimated to differ by only 1-2% of all gene loci, providing a unique opportunity to extract particular expression signatures between these substrains that are associated with quantifiable behavioral differences. Expression profiling of the cortex and striatum, hippocampus, cerebellum and the ventral brain region from alcohol-naïve B6C and B6J mice showed intervals on three chromosomes that are enriched in clusters of coregulated transcripts significantly divergent between the substrains. Additional analysis identified two genomic regions containing putative copy number differences between the substrains. One such region on chromosome 14 contained an estimated 3n copy number in the B6J genome compared with B6C. Within this interval, a gene of unknown function, D14Ertd449e, was found to be both associated with alcohol preference and vary in copy number across several inbred strain lineages. H2afz, Psen1, Wdfy1 and Clu were also identified as candidate genes that may be involved in influencing alcohol consumption.

Three murine anxiety models: results from multiple inbred strain comparisons.

The literature surrounding rodent models of human anxiety disorders is discrepant concerning which models reflect anxiety-like behavior distinct from general activity and whether different models are measuring the same underlying constructs. This experiment compared the responses of 15 inbred mouse strains (129S1/SvlmJ, A/J, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, C57L/J, CBA/J, CE/J, DBA/2J, FVB/NJ, NZB/B1NJ, PL/J, SJL/J and SWR/J) in three anxiety-like behavioral tasks (light/dark test, elevated zero-maze and open field) to examine whether responses were phenotypically and/or genetically correlated across tasks. Significant strain differences were found for all variables examined. Principal components analyses showed that variables associated with both activity and anxiety-like behaviors loaded onto one factor, while urination and defecation loaded onto another factor. Our findings differ from previous research by suggesting that general activity and anxiety-related behaviors are linked, negatively correlated and cannot easily be dissociated in these assays. However, these findings may not necessarily generalize to other unconditioned anxiety-like behavioral tests.

Selection for contextual fear conditioning affects anxiety-like behaviors and gene expression.

Conditioned fear and anxiety-like behaviors have many similarities at the neuroanatomical and pharmacological levels, but their genetic relationship is less well defined. We used short-term selection for contextual fear conditioning (FC) to produce outbred mouse lines with robust genetic differences in FC. The high and low selected lines showed differences in fear learning that were stable across various training parameters and were not secondary to differences in sensitivity to the unconditioned stimulus (foot shock). They also showed a divergence in fear potentiated startle, indicating that differences induced by selection generalized to another measure of fear learning. However, there were no differences in performance in a Pavlovian approach conditioning task or the Morris water maze, indicating no change in general learning ability. The high fear learning line showed greater anxiety-like behavior in the open field and zero maze, confirming a genetic relationship between FC and anxiety-like behavior. Gene expression analysis of the amygdala and hippocampus identified genes that were differentially expressed between the two lines. Quantitative trait locus (QTL) analysis identified several chromosomal regions that may underlie the behavioral response to selection; cis-acting expression QTL were identified in some of these regions, possibly identifying genes that underlie these behavioral QTL. These studies support the validity of a broad genetic construct that includes both learned fear and anxiety and provides a basis for further studies aimed at gene identification.

Mouse inbred strain differences in ethanol drinking to intoxication.

Recently, we described a simple procedure, Drinking in the Dark (DID), in which C57BL/6J mice self-administer ethanol to a blood ethanol concentration (BEC) above 1 mg/ml. The test consists of replacing the water with 20% ethanol in the home cage for 4 h early during the dark phase of the light/dark cycle. Three experiments were conducted to explore this high ethanol drinking model further. In experiment 1, a microanalysis of C57BL/6J behavior showed that the pattern of ethanol drinking was different from routine water intake. In experiment 2, drinking impaired performance of C57BL/6J on the accelerating rotarod and balance beam. In experiment 3, 12 inbred strains were screened to estimate genetic influences on DID and correlations with other traits. Large, reliable differences in intake and BEC were detected among the strains, with C57BL/6J showing the highest values. Strain means were positively correlated with intake and BEC in the standard (24 h) and a limited (4 h) two-bottle ethanol vs. water test, but BECs reached higher levels for DID. Strain mean correlations with other traits in the Mouse Phenome Project database supported previously reported genetic relationships of high ethanol drinking with low chronic ethanol withdrawal severity and low ethanol-conditioned taste aversion. We extend these findings by showing that the correlation estimates remain relatively unchanged even after correcting for phylogenetic relatedness among the strains, thus relaxing the assumption that the strain means are statistically independent. We discuss applications of the model for finding genes that predispose pharmacologically significant drinking in mice.

Drug reward and intake in lines of mice selectively bred for divergent exploration of a hole board apparatus.

Individuals characterized as high-novelty seekers are more likely to abuse drugs than are low-novelty seekers, and it is possible that the biological substrates underlying novelty seeking and drug abuse are similar. We selectively bred replicate lines of mice from a B6D2 F3 hybrid stock for high exploratory behavior (HEB) or low exploratory behavior (LEB) as measured by the number of head dips on a hole board. To determine whether common genes might influence exploratory behavior and behaviors relevant to drug abuse, we tested HEB and LEB mice for conditioned place preference produced by ethanol and d-amphetamine and also examined oral methamphetamine intake. After four generations of selection, HEB and LEB mice did not differ in the magnitude of place preference for ethanol, but LEB mice showed a greater place preference for an amphetamine-paired location than did HEB mice. However, this difference did not replicate in mice tested from the fifth generation of selection. The selected lines also did not differ in sensitization to the locomotor stimulant effects of d-amphetamine that developed across the conditioning trials. Finally, HEB and LEB mice consumed equivalently low amounts of methamphetamine. These results suggest that common genes do not influence head dipping and several behaviors potentially relevant to drug abuse.

Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11.

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABA(A) receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABA(A) receptor gamma2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for alpha1 subunit containing GABA(A) receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.

Selected line difference in sensitivity to a GABAergic neurosteroid during ethanol withdrawal.

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. Earlier work indicates that sensitivity to the anticonvulsant effect of ALLO was enhanced during ethanol (EtOH) withdrawal in rats and in C57BL/6 mice, an inbred strain with mild EtOH withdrawal. In contrast, ALLO sensitivity was reduced during EtOH withdrawal in DBA/2 mice, an inbred strain with severe EtOH withdrawal. Thus, the present studies examined ALLO sensitivity during EtOH withdrawal in another animal model of EtOH withdrawal severity, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines. Male mice were exposed to EtOH vapor or air for 72 h. During peak withdrawal, animals were injected with ALLO [0, 3.2, 5, 10 or 17 mg/kg, intraperitoneally (i.p.)] and tested for their sensitivity to the anticonvulsant effect. In separate studies, potentiation of GABA-stimulated chloride uptake by ALLO (10 nm to 10 microm) was assessed in microsacs prepared from mouse brain mice during peak withdrawal. Notably, WSP mice were cross-tolerant to the anticonvulsant effect of ALLO during EtOH withdrawal (i.e. significant decrease in the efficacy of ALLO) when compared with values in air-exposed mice. In contrast, sensitivity to the anticonvulsant effect of ALLO was unchanged during EtOH withdrawal in the WSR line. Functional sensitivity of GABA(A) receptors to ALLO was significantly decreased during EtOH withdrawal in WSP mice in a manner consistent with the change in behavioral sensitivity to ALLO. These findings suggest that mice selectively bred for differences in EtOH withdrawal severity are differentially sensitive to ALLO during EtOH withdrawal.

MRI bone oedema predicts eight year tendon function at the wrist but not the requirement for orthopaedic surgery in rheumatoid arthritis.

OBJECTIVE: To investigate the role of early magnetic resonance imaging (MRI) of the wrist in predicting functional outcome in rheumatoid arthritis. METHODS: MRI scans of the dominant wrist were scored for synovitis, tendon inflammation, bone oedema, and erosion at first presentation (n = 42), at 1 year (n = 42), and at 6 years (n = 31). At 8 years, clinical reassessment (n = 28) was undertaken. Tendon function was graded 0-3 for movement, tendon sheath swelling, and pain on resistance at nine flexor and extensor tendons of the hand. Hand function was also assessed using the Sollerman grip test. The requirement for joint or tendon surgery by 8 years was determined by telephone survey in 39 of the original 42 patients. RESULTS: At 8 years, tendon function was highly correlated with hand function (Sollerman score, R = -0.51, p = 0.005) and global function (health assessment questionnaire score, R = 0.53, p = 0.004). Using a model incorporating baseline and 1 year MRI scores, the MRI bone oedema score was strongly predictive of tendon function at 8 years (chi(2)(2) = 15.3, p = 0.0005), as was the MRI bone erosion score (chi(2)(2) = 9.23, p = 0.01). Hand function was also predicted by the baseline MRI erosion score (p = 0.02). MRI variables did not predict the requirement for surgery, but patients who had surgery were more likely to show progression of MRI bone erosion scores between baseline and 1 year (p = 0.008). CONCLUSIONS: Extensive MRI bone oedema and erosions at the wrist in early rheumatoid arthritis predict tendon dysfunction and impaired hand function in the medium term but not the requirement for joint or tendon surgery.

Scheduled access to ethanol results in motor impairment and tolerance in female C57BL/6J mice.

We recently reported a method where water-restricted mice were given scheduled access to ethanol followed by access to water. C57BL/6J mice would repeatedly self-administer ethanol in amounts that produced high and stable blood ethanol concentrations (BEC) [Finn DA, Belknap JK, Cronise K, Yoneyama N, Murillo A, Crabbe JC. A procedure to produce high alcohol intake in mice. Psychopharmacol 2005;178:471-480]. The studies reported here demonstrate that behavioral signs of motor impairment result from these high alcohol intakes, and that there was some evidence of tolerance development across repeated sessions. Female C57BL/6J mice were allowed 30 min access to ethanol (5% v/v) followed by 2.5 h access to water either: every 3rd day for 12 days; every 2nd day for 28 days; or every 2nd day for 9 days. On intervening days, mice had 3 h access to water. A control group had daily access to water only. Mice consumed 2-2.5 g/kg ethanol in 30 min, resulting in BECs of 1.4-1.5 mg/ml. Motor impairment was assessed using the accelerating or fixed speed rotarod, balance beam or screen test. In all studies, mice were tested for motor impairment immediately after 30 min access to ethanol or water. In Experiment 1, ethanol-exposed mice had shorter latencies to fall from the fixed speed rotarod and more foot slips on the balance beam than the control group, indicating motor impairment. After drinking ethanol, mice also fell from a screen more quickly than during sober pretraining. In Experiment 2, mice tested (without prior training) for motor impairment and tolerance on the fixed speed rotarod at 6.5 and 10 RPM showed repeated motor impairment in the ethanol group, but did not develop tolerance. In Experiment 3, mice were first given rotarod training at 10 RPM. Following each fluid access period, performance was impaired in mice self-administering ethanol at 10, but not 15 RPM, when compared to control mice. There was no evidence of tolerance across days. However, on the last day, all mice were tested at both RPM following an i.p. injection of 2 g/kg ethanol. Ethanol-experienced mice were less impaired at both RPM than the ethanol-naïve mice, indicating tolerance development according to this between-groups index. These results suggest that C57BL/6J mice will repeatedly consume alcohol in amounts that produce motor impairment under these scheduled fluid access conditions, and that a modest degree of tolerance can be detected using appropriate tests.

Characterization of the parallel rod floor apparatus to test motor incoordination in mice.

Impairment of motor coordination, or ataxia, is a prominent effect of alcohol ingestion in humans. To date, many models have been created to examine this phenomenon in animals. Evidence suggests that the tasks thought to measure this behavior in mice actually measure different components of this complex trait. We have characterized the parallel rod floor apparatus to quantify ethanol-induced motor incoordination. Using genetically heterogeneous mice, we evaluated the influence of rod diameter and inter-rod distance on dose-related ethanol-induced motor incoordination to select parameters that optimized testing procedures. We then used the DBA/2J and C57BL/6J inbred strains of mice to examine the effect of 2 g/kg of ethanol, by serially testing mice on two floor types, separated by 1 week. Finally, we tested eight inbred strains of mice on four floor types to examine patterns of strain sensitivity to 2 g/kg of intraperitoneal ethanol and determined the test parameters that maximized strain effect size. Motor incoordination varied depending on the floor type and strain. When data from strain 129S1/SvlmJ were removed from the analyses because of their extreme behavior, the greatest strain effect size was observed on one floor type during the first 10 min of testing after 2 g/kg of intraperitoneal ethanol. These findings suggest that the parallel rod floor apparatus provides a useful means for examining ethanol-induced motor incoordination in mice but that specific testing procedures are important for optimizing detection of motor incoordination and genetic influences.