Zebrafish (Danio rerio) have been used as a model organism to explore the genetic basis for responsiveness to addictive drugs like cocaine. However, very little is known about how the physiological response to cocaine is mediated in zebrafish. In the present study electrocardiograms (ECG) were recorded from adult zebrafish treated with cocaine. Treatment with cocaine resulted in a bell-shaped dose response curve with a maximal change in heart rate seen using 5mg/L cocaine. Higher doses resulted in a higher percentage of fish showing bradycardia. The cocaine-induced tachycardia was blocked by co-treatment with propranolol, a ß-adrenergic antagonist, but potentiated by co-treatment with phentolamine, a α-adrenergic antagonist. Co-treatment with atropine, a classic cholinergic antagonist, had no effect on cocaine-induced tachycardia. Cocaine treatment of adult fish changed the ECG of treated fish, inducing a dose-dependent increase in QT interval after adjusting for heart rate (QTc), while not affecting the PR or QRS intervals. The acute effects of cocaine on heart rate were examined in 5-day old embryos to see if zebrafish might serve as a suitable model organism to study possible links of embryonic physiological response to subsequent adult behavioral response to the drug. Cocaine treatment of 5-day old zebrafish embryos also resulted in a bell-shaped dose response curve, with maximal tachycardia achieved with 10mg/L. The response in embryonic fish was thus comparable to that in adults and raises the possibility that the effects of embryonic exposure to cocaine on the developing cardiovascular system can be effectively modeled in zebrafish.

Cadmium (Cd) is a naturally occurring trace metal that is widely considered to be highly toxic to aquatic organisms and a significant health hazard to humans (Amzal et al 2009; Bernhoft 2013; Burger 2008; Satarug et al 2009). The zebrafish (Danio rerio) has been used as a model organism for toxicological studies with Cd (Banni et al 2011; Blechinger et al 2007; Chow et al 2009; Chow et al 2008; Favorito et al 2011; Kusch et al 2007; Matz et al 2007; Wang & Gallagher 2013). We asked what the lasting longitudinal effects would be from short early developmental Cd exposure (between 24-96 hours post-fertilization) in a range that larvae might experience living atop typical Cd-containing surface sediments (0, 0.01, 0.1, 1.0 and 10 μM CdCl2: 1.124, 11.24, 112.4 and 1124 μg Cd/L). The goal of this exposure window was to specifically target secondary neurogenesis, monoaminergic differentiation and cardiovascular development, without affecting earlier patterning processes. Developmental abnormalities in body size and CNS morphology increased with concentration, but were statistically significant only at the highest concentration used (10 μM). Heart rate for Cd-treated larvae increased with concentration, and was significant even at the lowest concentration used (0.01 μM). Longitudinal survival was significantly lower for fish developmentally exposed to the highest concentration. Except for brain weight, overall morphology was not affected by developmental Cd exposure. However, developmental exposure to lower concentrations of Cd (0.01, 0.1, and 1.0 μM) progressively lowered cocaine-induced conditioned place preference (CPP), used to measure function of the reward pathways in the brain. Baseline heart rate was significantly lower in longitudinal fish developmentally exposed to 1.0 μM Cd. Cardiovascular response to isoproterenol, a potent β-adrenergic agonist, in longitudinal adults was also significantly affected by developmental exposure to Cd at low doses (0.01, 0.1 and 1.0 μM). Surviving longitudinal adult fish exposed to the highest concentration of Cd showed normal CPP and cardiovascular physiology. The data imply that even lower exposure concentrations can potentially result in fitness-affecting parameters without affecting survival in a laboratory setting.

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.

The role of alpha1‐adrenergic receptors (alpha1‐ARs) in cognition and mood is controversial, likely due to past use of non‐selective agents. Activation of the alpha1A‐AR subtype was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of chronic alpha1A‐AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM). Previously, we found that CAM‐alpha1A‐AR mice demonstrated enhancements in several behavioral models of learning and memory. We now report that CAM‐alpha1A‐AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests when compared to normal wild‐type littermate control mice. Furthermore, the reduction in anxiety‐ and depressive‐like behaviors was present in both sexes and across all ages (young to old). Our results suggest that chronic alpha1A‐AR stimulation improves cognitive function and mood. These results suggest that long‐term alpha1A‐AR stimulation may afford a potential therapeutic target for treating anxiety and depression. This strategy may also be effective in counteracting the decline in cognitive function and mood associated with aging and neurological disorders. This study was supported in part by NSF CAREER Award 0347259, NSF REU Site Grant 0851869, UNDSMHS REFUNDU program, NIH NCRR INBRE Grant P20RR016471, and NIH Grant RO1HL61438.