Tepe, E. A. | Search bioRxiv

bioRxiv2024

Latrophilin-3 conditional knockout in tyrosine hydroxylase neurons (Lphn3-Th-Cre) compared with Lphn3 global KO rats: Role of Lphn3 in tyrosine hydroxylase neurons on cognitive and behavioral effects of this ADHD susceptibility gene

Latrophilin-3 (LPHN3) is a brain specific adhesion G-protein coupled receptor associated with elevated risk of attention deficit hyperactivity disorder (ADHD). We developed a global Lphn3 knock-out (gKO) rat using CRISPR/Cas9 to delete exon-3. Here we report the development of a floxed Lphn3 rat crossed with tyrosine hydroxylase (Th-Cre) rats to create a conditional Lphn3 KO rat specific for catecholaminergic- positive cells. The gKO rats are hyperactive and have egocentric and allocentric navigation deficits but showed sparing of conditioned contextual and novel object recognition memory. Here we compared gKO and cKO rats controlling for litter effects. Both gKO and cKO rats were hyperactive and were impaired in egocentric navigation in the Cincinnati water maze (CWM) with deficits greater in gKO rats. The gKO rats were impaired in allocentric navigation in the Morris water maze (MWM) whereas cKO rats were only slightly affected compared with WT, cre, and floxed rats. Striatal tyrosine hydroxylase and dopamine D1 receptors were not significantly different in either model, nor were NMDA-NR1 or NMDA-NR2 in the hippocampus. We previously showed, however, that dopamine is released more rapidly in the striatum of gKO rats by fast- scan cyclic voltammetry. The cKO model shows an important role of catecholamines in the phenotype of LPHN3 disruption and add evidence that this synaptic protein plays a role in neuroplasticity that are consistent with ADHD.

neuroscience↗

bioRxiv2023

Repeated footshock stress induces an escalation of cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1

Stress is a significant contributor to the development and progression of substance use disorders (SUDs) and is problematic as it is unavoidable in daily life. Therefore, it is important to understand the neurobiological mechanisms that underlie the influence of stress on drug use. We have previously developed a model to examine the contribution of stress to drug-related behavior by administering a stressor, electric footshock stress, daily at the time of cocaine self-administration in rats resulting in an escalation of cocaine intake. This stress-induced escalation of cocaine intake involves neurobiological mediators of stress and reward such as cannabinoid signaling. However, all of this work has been conducted in male rats. Here we test the hypothesis that repeated daily stress can produce an escalation of cocaine in both male and female rats. We further hypothesize that cannabinoid receptor 1 (CB1R) signaling is recruited by repeated stress to influence cocaine intake in both male and female rats. Male and female Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during a modified short-access paradigm wherein the 2-hr access was separated into 4-30 min self-administration blocks separated by 4-5 min drug free period. Footshock stress produced a significant escalation of cocaine intake similarly in both male and female rats. Female stress-escalated rats did display greater time-out non-reinforced responding and greater "front-loading" behavior. In males, systemic administration of a CB1R inverse agonist/antagonist Rimonabant only attenuated cocaine intake in rats with a history of combined repeated stress and cocaine self-administration. However, in females, Rimonabant attenuated cocaine intake in the no stress control group but only at the highest dose of Rimonabant (3 mg/kg, i.p.) suggesting that females show a greater sensitivity to CB1R antagonism. However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine intake in stress-escalated rats similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes.

neuroscience↗