Spontaneously Hypertensive Rat substrains show differences in model traits for addiction risk and cocaine self-administration: Implications for a novel rat reduced complexity cross

Abstract

Forward genetic mapping of F2 crosses between closely related substrains of inbred rodents - referred to as a reduced complexity cross (RCC) - is a relatively new strategy for accelerating the pace of gene discovery for complex traits, such as drug addiction. RCCs to date were generated in mice, but rats are thought to be optimal for addiction genetic studies. Based on past literature, one inbred Spontaneously Hypertensive Rat substrain, SHR/NCrl, is predicted to exhibit a distinct behavioral profile as it relates to cocaine self-administration traits relative to another substrain, SHR/NHsd. Direct substrain comparisons are a necessary first step before implementing an RCC. We evaluated model traits for cocaine addiction risk and cocaine self-administration behaviors using a longitudinal within-subjects design. Impulsive-like and compulsive-like traits were greater in SHR/NCrl than SHR/NHsd, as were reactivity to sucrose reward, sensitivity to acute psychostimulant effects of cocaine, and cocaine use studied under fixed-ratio and tandem schedules of cocaine self-administration. Compulsive-like behavior correlated with the acute psychostimulant effects of cocaine, which in turn correlated with cocaine taking under the tandem schedule. Compulsive-like behavior also was the best predictor of cocaine seeking responses. Heritability estimates indicated that 22 %-40 % of the variances for the above phenotypes can be explained by additive genetic factors, providing sufficient genetic variance to conduct genetic mapping in F2 crosses of SHR/NCrl and SHR/NHsd. These results provide compelling support for using an RCC approach in SHR substrains to uncover candidate genes and variants that are of relevance to cocaine use disorders.

Keywords: Addiction vulnerability traits; Cocaine; SHR/NCrl substrain; SHR/NHsd substrain.

Figure 1.

Longitudinal experimental timeline for behavioral phenotyping in adult SHR/NCrl and SHR/NHsd male rats.

Figure 2.

Differential reinforcement of low-rate (DRL) performances in SHR/NCrl (n=10) and SHR/NHsd (n=10) male rats. Values are the mean ± s.e.m. and individual rat data points for the percentage of reinforced responses (response efficacy) and percentage of responses with IRTs < 2s (burst responding) averaged over the last 3 daily sessions at criteria for the DRL 5s wait time (panels a and b) and the DRL 30s wait time (panels c and d). *ps<0.05 comparing SHR/NCrl to SHR/NHsd.

Figure 3.

Schedule-induced polydipsia (SIP) in SHR/NCrl (n=10) and SHR/NHsd (n=10) male rats. Values are the mean ± s.e.m. ml/kg water intake for each of the 12 daily sessions (panel a) or the mean ± s.e.m. and individual rat data points for ml/kg water intake averaged over the terminal 3 daily sessions (panel b). * ps<0.05 comparing ml/kg water intake between SHR/NCrl and SHR/NHsd on sessions 4-8, 10-12, and the terminal 3 sessions combined. ^ ps<0.02 relative to session 1.

Figure 4.

Sucrose preference testing in SHR/NCrl (n=10) and SHR/NHsd (n=10) male rats. Values are the mean ± s.e.m. and individual rat data points for the water and sucrose preference ratios (panel a) and the total ml/kg fluid intake during the water and sucrose preference tests (panel b). * ps<0.004 comparing total intake in SHR/NCrl to SHR/NHsd during the sucrose preference test and comparing total intake during the sucrose preference test to the water preference test in SHR/NCrl.

Figure 5.

Psychostimulant effects of acute cocaine in SHR/NCrl (n=10) and SHR/NHsd (n=10) male rats. Values are the mean ± s.e.m. locomotor activity counts in 5 min bins over the 30-min habituation sessions and the 1-hr cocaine tests in SHR/NCrl (panel a) and SHR/NHsd (panel b). * ps<0.03 comparing habituation day 1 to days 2 and 3 for bins 2-5 in SHR/NCrl and for bins 2-4 and 6 in SHR/NHsd. & p<0.001 comparing habituation day 1 to day 2 for bin 5 in SHR/NHsd. # p<0.01 comparing 20 mg/kg to 0 mg/kg and 15 mg/kg cocaine in both substrains ^ ps<0.04 comparing bins 1 and 2 in SHR/NCrl to SHR/NHsd after 20 mg/kg cocaine.

Figure 6.

Cocaine self-administration in SHR/NCrl (n=6) and SHR/NHsd (n=10) male rats. Values are the mean ± s.e.m. and individual rat data points for the number of taking lever responses under the FR1 schedule (panel a) and for the number of seeking lever responses (panel b) and seek-take cycles completed (panel c) under the tandem FR1, RI 120s; FR1, 600s TO schedule of cocaine (0.25 mg/kg/infusion) delivery. * ps<0.05 comparing SHR/NCrl to SHR/NHsd.

Figure 7.

Model traits predictive of cocaine use risk in SHR/NCrl (white circles) and SHR/NHsd (black circles). Illustrated are behaviors that significantly correlated with compulsive-like behavior (panels a and b), with cocaine-induced locomotor activity (panel c), with cocaine seeking responses (panels d and e), and with impulsive-like behavior (panels f and g).