Responding in a test of decision-making under risk is under moderate genetic control in the rat.

BACKGROUND: Risk-taking, measured with laboratory tasks such as the Balloon Analog Risk Task (BART), is associated with real-life manifestations of risky behaviors, which may be an important component of inherited liability to alcohol use disorders. To identify genomic factors that influence these traits, the current study (i) characterized performance of a rodent version of the BART in multiple inbred rat strains, (ii) tested the degree to which performance was under genetic control, (iii) explored sex differences in performance, and (iv) evaluated the risk-taking behavior of F1 progeny of high-risk- and low-risk-taking strains to examine modes of inheritance. METHODS: Male and female rats (N = 100) from 5 inbred strains (Wistar-Furth, Fischer-344, Lewis, Spontaneously Hypertensive, Brown Norway) and Wistar-Furth × Fischer-344 hybrids were tested in the rat-BART, as well as in tests of locomotor activity, sucrose preference, and general motivation. RESULTS: About 55% of the variance in risk-taking behavior was attributable to heritable factors. The Fischer-344 strain was the most risk-taking and the most variable in responding. The mating of low-risk-taking Wistar-Furth and Fischer-344 rats produced progeny that behaved most like the Fischer-344 strain. Consistent with prior research in this laboratory (Jentsch et al., 2010), all rats were sensitive to changes in both risk and reinforcement parameters in the rat-BART; rats decreased voluntary risk-taking in the face of increasing risk and increased lever pressing when reinforcement probabilities were reduced. CONCLUSIONS: Our results endorse a moderately heritable pattern of risk-taking behavior in rats. The behavior of the hybrid progeny suggests a polygenic model with most gene effects transmitted by mode of dominant inheritance. The identification of high-risk and low-risk strains allows for isolation of quantitative trait loci associated with task performance and for probing the relationships between risk-taking and dimensions of alcohol use disorders.

Impact of predatory threat on fear extinction in Lewis rats.

Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome. Lewis rats were subjected to classical auditory fear conditioning before or after exposure to a predatory threat that mimics a type of traumatic stress that leads to PTSD in humans. Exploratory behavior on the elevated plus maze 1 wk after predatory threat exposure was used to distinguish resilient vs. PTSD-like rats. Properties of extinction varied depending on whether fear conditioning and extinction occurred before or after predatory threat. When fear conditioning was carried out after predatory threat, PTSD-like rats showed a marked extinction deficit compared with resilient rats. In contrast, no differences were seen between resilient and PTSD-like rats when fear conditioning and extinction occurred prior to predatory threat. These findings in Lewis rats closely match the results seen in humans with PTSD, thereby suggesting that studies comparing neuronal interactions in resilient vs. at-risk Lewis rats might shed light on the causes and pathophysiology of human PTSD.

Lewis rats have greater response impulsivity than Fischer rats.

Impulsivity, a tendency toward immediate action without consideration of future consequences, is associated with a wide array of problematic behaviors. Response impulsivity, a type of behaviorally-assessed impulsivity characterized by behavioral disinhibition, is also associated with health risk behaviors. Response impulsivity is distinct from choice impulsivity, which is characterized by intolerance for delay. Lewis rats have higher levels of choice impulsivity than Fischer rats (Anderson & Woolverton, 2005; Madden et al., 2008; Stein et al., 2012). However, no studies have examined whether Lewis and Fischer rats have different levels of response impulsivity. The present research examined response impulsivity in the two rat strains. Subjects were 16 male Lewis and Fischer rats. Rats' response impulsivity was measured using the Five Choice Serial Reaction Time Task (5-CSRTT). In addition, their locomotor activity was measured in locomotor activity chambers. Lewis rats had more premature responses than Fischer rats during the 5-CSRTT assessment [F(1, 14)=5.34, p<0.05], indicating higher levels of response impulsivity. Locomotor activity did not differ between rat strain groups [F(1, 14)=3.05, p=.10], suggesting that overall movement did not account for group differences in response impulsivity on the 5-CSRTT. It can be concluded from this research that Lewis rats have higher levels of response impulsivity than Fischer rats, and therefore provide a valid rat model of individual differences in impulsivity.

Delay discounting in Lewis and Fischer 344 rats: steady-state and rapid-determination adjusting-amount procedures.

Lewis rats have been shown to make more impulsive choices than Fischer 344 rats in discrete-trial choice procedures that arrange fixed (i.e., nontitrating) reinforcement parameters. However, nontitrating procedures yield only gross estimates of preference, as choice measures in animal subjects are rarely graded at the level of the individual subject. The present study was designed to examine potential strain differences in delay discounting using an adjusting-amount procedure, in which distributed (rather than exclusive) choice is observed due to dynamic titration of reinforcer magnitude across trials. Using a steady-state version of the adjusting-amount procedure in which delay was manipulated between experimental conditions, steeper delay discounting was observed in Lewis rats compared to Fischer 344 rats; further, delay discounting in both strains was well described by the traditional hyperbolic discounting model. However, upon partial completion of the present study, a study published elsewhere (Wilhelm & Mitchell, 2009) demonstrated no difference in delay discounting between these strains with the use of a more rapid version of the adjusting-amount procedure (i.e., in which delay is manipulated daily). Thus, following completion of the steady-state assessment in the present study, all surviving Lewis and Fischer 344 rats completed an approximation of this rapid-determination procedure in which no strain difference in delay discounting was observed.

Dose preference and dose escalation in extended-access cocaine self-administration in Fischer and Lewis rats.

RATIONALE: Drug addiction is a disease with a genetic component that may be involved in different stages of its progression. Cocaine users escalate unit doses and frequency of self-administration events in naturalistic settings. Rats that self-administer drugs of abuse over extended sessions increase the number of infusions over days. OBJECTIVES: Comparison of two genetically different inbred rat strains, Fischer and Lewis, in a new self-administration paradigm whereby rats select between different unit doses of cocaine, thus potentially escalating the unit dose and the number of infusions. METHODS: Extended (18 h/day) self-administration sessions lasted for 14 days. Rats had access to two active levers associated with two different unit doses of cocaine. If a rat showed preference for the higher unit dose, then the available doses were escalated in the following session. Four cocaine unit doses were available (0.2, 0.5, 1.25, and 2.5 mg/kg/infusion). RESULTS: Lewis rats showed a clear preference for the two higher doses of cocaine (70% of rats), with a high percentage (35%) of the individuals escalating to the highest unit dose, and escalated the total amount of cocaine taken over days. Fischer rats, however, preferred the two lower doses (63%) and did not escalate the amount of cocaine taken over days. Fischer, but not Lewis, rats showed an activated hypothalamic-pituitary-adrenal axis in acute withdrawal (24 h). CONCLUSION: This work shows the power of a model of extended-access self-administration that allows for the subject-controlled dose-escalation of the unit dose of cocaine, and underlines the genetic differences that modulate cocaine intake.

Differences in home cage behavior and endocrine parametres in rats of four strains.

OBJECTIVE: The majority of studies that involve behavioral testing in different rat strains is based on measuring behavioral responses to stressful situations in a novel environment. Very little is known on the spontaneous behavior in rat strains. The aim of the present study was to compare home cage behavior and basal hormone levels in two outbred rat strains, Sprague-Dawley (SD) and Wistar as well as two inbred strains, Lewis and Spontaneously Hypertensive Rats (SHR). METHODS: Twenty-eight male rats from four strains of rats (n=7/strain) were used in this study. Behavior of each rat in his home cage was recorded by a video camera for 45 minutes during the dark phase of the day. The parameters considered included rearing, jumps, ambulation, grooming, feeding/drinking and no movements. Blood plasma was analyzed for aldosterone, plasma renin activity (PRA), adrenocorticotropin hormone (ACTH) and corticosterone by specific radioimmunoassays. RESULTS: One-way ANOVA revealed significant inter-strain differences in counts of jumps and rearing. In comparison with Sprague-Dawley and Wistar rats, Lewis rats displayed significantly more jumps and rearing. Statistical analysis showed significant inter-strain differences in the levels of aldosterone and of plasma renin activity. The highest levels of aldosterone were found in Lewis rats. Plasma renin activity was significantly lower in SHR than in Sprague-Dawley rats. Correlation analysis failed to reveal any relationships between behavioral and endocrine parameters. Significant strain differences were observed also in relative weights of the spleen, adrenals and thymus. CONCLUSION: Plasma renin activity and basal mineralocorticoid secretion did not show parallel pattern if compared among different rat strains. Locomotor activity in the home cage, which could represent general activity to be considered in evaluating emotional responses, was highest in the Lewis rats.

Effects of nimodipine on psychological-stress situation in aged rats.

Female aged rats treated with nimodipine, a calcium-blocker dihydropyridine derivative, were submitted to a psychological-stress situation. Nimodipine at the doses of 3 and 6 mg/Kg antagonized the stress-related body-weight decrease and lethality. These findings seem to validate the role of Ca-mediated mechanisms in the physiopathology of stress and the protective effects of the Ca-blockers in the stress-related illnesses.

Suppression of the development of adjuvant arthritis by a conditioned aversive stimulus.

The present study evaluated the effect of a conditioned aversive stimulus (CS) on the development of adjuvant-induced arthritis in Lewis rats. Experiment 1 showed that presentation of a CS, on days 12, 14, and 16 following injection with adjuvant containing mycobacterium tuberculosis, resulted in a pronounced suppression of the development of arthritis as measured by a clinical disease severity rating scale and spleen weight. In contrast, presentation of the CS on days 0, 2, and 4 following injection did not have any effect on the development of arthritis. Experiment 2 showed that the suppression of adjuvant arthritis by exposure to the CS was blocked by administration of propranolol, a nonselective beta-adrenergic receptor antagonist. These results demonstrate that a CS can alter the development of adjuvant-induced arthritis, but the effect is dependent upon the timing of the antigen exposure and the presentation of the CS. Moreover, the present findings suggest that blocking beta-adrenergic receptors during presentations of the CS prevents the suppressive effect of the CS.