Chronic mild stress induces differential depression-like symptoms and c-Fos and 5HT1A protein levels in high-anxiety female Long Evans rats.

Depression and anxiety disorders overlap in clinical populations, suggesting common mechanisms that may be further investigated in reliable animal models. We used filial 8 female Long-Evans rats bred for high (HAn; n = 19) and low anxiety (LAn)-like behavior (n = 21) to assess forced swim test mobility strategies and chronic mild stress (CMS)-induced depression-like symptoms. We measured (1) weight, (2) fur piloerection, (3) sweet food consumption, (4) grooming behavior, and (5) circulating estradiol (E2). One month after CMS terminated and following a terminal forced swim test, brains were processed for immunohistochemistry targeting c-Fos and serotonin 1 A receptor (5-HT1AR) protein in the paraventricular nucleus (PVN) of the hypothalamus. HAn female rats showed increased anxiety-like behavior (i.e., lower open to closed arm ratios, increased closed arm entries), more swimming (i.e., mobility), and less floating (i.e., immobility) behavior in the forced swim test. Overall, HAn females weighed less than their LAn counterparts. After chronic mild stress, HAn lines displayed even greater mobility and consumed fewer Froot Loops™. Fur and grooming analyses indicated no significant differences in mean counts across experimental groups. One month after CMS, cycling E2 concentrations (pg/ml) did not differ between HAn and LAn animals. Elevated c-Fos and 5-HT1AR expression were observed in the PVN, where HAn CMS rats expressed the most c-Fos and 5-HT1AR immunoreactivity. In summary, outbred HAn rats show robust anxiety-like behavior, exhibit more mobility in the forced swim test, and are more sensitive to chronic mild stress-induced grooming and decline in palatable food ingestion.

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats.

Adolescent psychostimulant abuse has been on the rise over the past decade. This trend has demonstrable ramifications on adolescent behavior and brain morphology, increasing risk for development of addiction during adolescence and in later adulthood. Neuroimmune substrates are implicated in the etiology of substance use disorders. To add to this body of work, the current study was developed to explore the role of a chemokine receptor, CXC Chemokine Receptor 4 (CXCR4), in the development of amphetamine (AMPH) sensitization. We targeted CXCR4 as it is implicated in developmental processes, dopaminergic transmission, neuroimmune responses, and the potentiation of psychostimulant abuse pathology. To evaluate the role of CXCR4 activity on the development of AMPH sensitization, a CXCR4 antagonist (Plerixafor; AMD3100) was administered to rats as a pretreatment variable. Specifically, adolescent Long Evans male rats (N = 37) were divided into four groups: (1) AMD3100 (IP, 4.0 mg/kg) + AMPH (IP, 4.0 mg/kg), (2) saline (SAL; 0.9% NaCl) + AMPH, (3) AMD3100 + SAL, and (4) SAL + SAL. Animals were first habituated to locomotor activity (LMA) chambers, then injected with a pretreatment drug (AMD3100 or SAL) followed by AMPH or SAL every other for four days. After a one-week withdrawal period, all animals were administered a low challenge dose of AMPH (IP, 1.0 mg/kg). AMPH-injected rats displayed significantly more locomotor activity compared to controls across all testing days. CXCR4 antagonism significantly attenuated AMPH-induced locomotor activity. On challenge day, AMD3100 pre-treated animals exhibited diminutive AMPH-induced locomotor activity compared to SAL pre-treated animals. Postmortem analyses of brain tissue revealed elevated CXCR4 protein levels in the striatum of all experimental groups. Our results implicate CXCR4 signaling in the development of AMPH sensitization and may represent an important therapeutic target for future research in psychostimulant abuse.

5-HT1A and α2 adrenergic receptor levels are associated with high anxiety-like patterns and impulsivity in selectively bred Long Evans rats.

Impulsivity and anxiety are psychological traits involved in many aspects of the drug addiction cycle. However, few preclinical models exist for examining both impulsive and anxiety patterns. In the current study, we investigated whether 6th generation rats selectively bred for high anxiety (HAn)-like behavior would display amphetamine (AMPH) hyperactivity. In the same generational line, we also determined if HAn animals would display impulsivity in an operant task. Filial 5 male Long Evans rats phenotyped as HAn and low anxiety (LAn) were tested on the elevated plus maze (EPM) and in locomotor chambers following a low dose of AMPH (0.5 mg/kg, IP). Next, a separate group of F5 animals was exposed to a differential reinforcement of low rate of responding (DRL: 30 s) operant schedule to assess impulsivity. Postmortem, 5-HT1A and α2 adrenergic receptor protein levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) core and shell, and α2 adrenergic counts were assessed in the locus coeruleus (LC), and the paraventricular nucleus (PVN) of the hypothalamus. F5 outbred HAn rats had decreased percent open arm time and entries on the EPM and elevated AMPH-induced locomotion. In the DRL, HAn rats displayed an impulsive profile, they attained fewer total rewards, had more inter-response times, and showed greater burst ratios. We found that HAn rats had a higher number of 5-HT1A receptor immunostained cells in the mPFC but were not different than LAn in NAc core or shell. By contrast, levels of the α2 adrenergic receptor protein were no different in the mPFC while HAn rats had greater levels in the LC and lower levels in the PVN. Overall, these data further validate our outbred trait anxiety rats: HAn males show anxiety-like behavior, AMPH hypersensitivity, greater impulsivity, and varying levels of limbic and midbrain 5-HT1A and α2 adrenergic receptor proteins.