Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady-state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within 30 min when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated with the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within 5 min of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggest a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals.

Anxiety vulnerability in women: a two-hit hypothesis.

Females are twice as likely to develop an anxiety disorder compared to males, and thus, are believed to possess an innate vulnerability that increases their susceptibility to develop an anxiety disorder. However, studies using aversive learning paradigms to model anxiety disorders in humans and animals have revealed contradictory results. While females exhibit the ability to rapidly acquire stimulus-response associations, which may result from a greater attentional bias towards threat, females are also capable to readily extinguish these associations. Thus, there is little evidence to suggest that the female sex represents a vulnerability factor of anxiety, per se. However, if females are to possess a second vulnerability factor that increases the inflexibility of stimulus-response associations, then an anxiety disorder may be more likely to develop. Behavioral inhibition (BI) is a vulnerability factor associated with the formation of inflexible stimulus-response associations. In this "two hit" model of anxiety vulnerability, females possessing a BI temperament will rapidly acquire stimulus-response associations that are resistant to extinction, resulting in the development of an anxiety disorder. In this review we explore evidence for a "two-hit" hypothesis underlying anxiety vulnerability in females. We explore the literature for evidence of a sex difference in attentional bias towards threat that may lead to the facilitated acquisition of stimulus-response associations in females. We also provide evidence that BI is associated with inflexible stimulus-response association formation. We conclude with data generated from our laboratory that highlights the additive effect of the female sex and behavioral inhibition vulnerabilities using a model behavior for anxiety disorder-susceptibility, active avoidance.

The role of the hippocampus in avoidance learning and anxiety vulnerability.

The hippocampus has been implicated in anxiety disorders and post-traumatic stress disorder (PTSD); human studies suggest that a dysfunctional hippocampus may be a vulnerability factor for the development of PTSD. In the current study, we examined the effect of hippocampal damage in avoidance learning, as avoidance is a core symptom of all anxiety disorders. First, the effect of hippocampal damage on avoidance learning was investigated in outbred Sprague Dawley (SD) rats. Second, the function of the hippocampus in Wistar-Kyoto (WKY) rats was compared to SD rats. The WKY rat is an animal model of behavioral inhibition, a risk factor for anxiety, and demonstrates abnormal avoidance learning, marked by facilitated avoidance acquisition and resistance to extinction. The results of the current study indicate that hippocampal damage in SD rats leads to impaired extinction of avoidance learning similar to WKY rats. Furthermore, WKY rats have reduced hippocampal volume and impaired hippocampal synaptic plasticity as compared to SD rats. These results suggest that hippocampal dysfunction enhances the development of persistent avoidance responding and, thus, may confer vulnerability to the development of anxiety disorders and PTSD.