Research reportModified single prolonged stress reduces cocaine self-administration during acquisition regardless of rearing environment
Introduction
Anxiety and mood disorders, induced by or precipitated by stress, are often co-morbid with addiction [1]. In fact, studies suggest that lifetime prevalence of addiction is double in people suffering from mood or anxiety disorders compared to the general population [1]. Specifically, post-traumatic stress disorder (PTSD), a disorder typically caused by exposure to a traumatic event and characterized by flashbacks of the event, generalized anxiety, fear extinction retention deficits, and anhedonia [2], [3], is 3–10% more common in substance abusers than in the general public [4]. In addition, one estimate suggests that PTSD is twice as common in individuals with a cocaine use disorder specifically [5].
The high rate of co-morbidity between PTSD and cocaine use disorder is not surprising since stress and addiction engage many of the same underlying brain systems, including the hypothalamic-pituitary-adrenal (HPA) axis [6]. Normal activation of this system, comprised of a series of structures in the central nervous system and periphery, results in release of glucocorticoids from the adrenal glands (primarily cortisol in humans and corticosterone (CORT) in rodents [7]). Glucocorticoids are released during stress and are thus considered “stress hormones”. These steroid hormones can cross the blood-brain-barrier and act as negative regulators of their own release by binding glucocorticoid receptors (GRs [8]). Long-lasting perturbations in HPA axis function can have negative health consequences, including impaired immune function [9] and altered glucose metabolism [10].
Patients with PTSD and cocaine use disorder display abnormal HPA axis function, albeit in different ways. PTSD produces lower circulating CORT levels [11] and enhanced negative feedback due to greater GR expression [12], [13]. Conversely, acute and repeated psychostimulant use causes enhanced release of cortisol in humans [14] and CORT in rats [15]. CORT is reinforcing by itself [16], [17], but also has been shown to alter psychostimulant self-administration. Release of CORT is linked to cocaine self-administration, as adrenalectomy drastically attenuates self-administration and flattens the dose-response curve [18], [19]. GRs partially mediate CORT’s effects on self-administration; GR antagonists [20], [21], [22] and GR knockout in dopamine D1 immunoreactive cells also decrease self-administration of psychostimulants [23].
Another reason PTSD and addiction often co-occur is that stress directly contributes to many stages of the addiction cycle, including escalation from casual use to problematic use and relapse [24]. Rodent models demonstrate that exposure to stress can increase overall levels of cocaine self-administration [25], escalation of intake [26], and drug-seeking [27]. However, not all stressors produce the same behavioral and biological effects. Important factors affecting outcome include number of lifetime stressors [28], [29], age of the individual at first stress exposure [30], and the specific stress protocol employed [31].
Early life stress, which occurs during childhood or adolescence, can predispose individuals to develop PTSD [32] and substance use disorder [33]. Likewise, preclinical experiments produce similar findings [34]. One common model of early life stress involves rearing rats during adolescence in social isolation (isolation condition, Iso). Decades of research have demonstrated that rats reared in Iso during adolescence display profound behavioral differences from rats raised in standard conditions (Std) or enriched conditions (Enr). Most studies indicate that Iso rats are more prone to addictive- and depressive-like behavior, while Enr rats are protected from these same outcomes [35], [36], [37]. In addition, several studies have suggested that levels of HPA markers such as CORT [21], [38], [39], [40] and GR in hippocampus [41], [42], [43] differ between rats raised in Iso and Enr, although the data are inconsistent.
In rodents, drug-taking or seeking after stress depends on the stress protocol employed [44], [45]. While the effects of restraint stress and unpredictable foot-shock on drug taking and seeking have been well studied, relatively few studies have employed a stress paradigm relevant to PTSD. One PTSD-like model utilizes a single prolonged stress (SPS), consisting of one episode of a series of 3 stressors: 2 h restraint stress, followed by 15 min swim stress, and finished with ether gas exposure until loss of consciousness [46]. This model possesses validity since animals exposed to SPS demonstrate fear extinction retention deficits and enhanced negative feedback of the HPA axis, both common in patients with PTSD [47], [48]. While initial studies employing the whole SPS model did not observe differences in cocaine self-administration after SPS exposure [49], a modified SPS protocol that substituted isoflurane for ether found stress-induced decreases in cocaine escalation [50]. However, no previous studies have determined if SPS-induced alterations in cocaine self-administration can be moderated by isolation rearing.
Given the literature on early life stress and the behavioral differences between Iso and Enr rats, it is likely that adolescent exposure to these environments could differentially affect cocaine self-administration and HPA response to SPS in adulthood. The current experiments administered 2 stressors: isolation rearing starting in adolescence followed by a modified SPS (modSPS) session in young adulthood. The modSPS session was used in lieu of SPS to avoid ceiling effects on stress responses; differences between rearing environments are most often observed at lower doses of drug in pharmacological studies [20], [37]. This modified protocol has demonstrated similar changes in the HPA axis, but does not reproduce fear extinction retention deficits [48]. To date, no experiments have examined cocaine self-administration after exposure to this modified procedure. Analysis of acquisition, maintenance, and the dose-response curve of cocaine self-administration were conducted and changes in CORT and GR expression were quantified. It was hypothesized that Iso rats would be most sensitive to the effects of modSPS; they were expected to acquire cocaine self-administration faster than other groups and were expected to show greater CORT release and a greater increase in GR expression in brain following modSPS. In testing this hypothesis, we chose to use a relatively high unit dose of cocaine (0.56 mg/kg/infusion) in order to minimize baseline (non-stressed) differences in Enr and Iso rats in rates of cocaine self-administration [37]. Thus, we expected to observe differences in cocaine intake among Enr, Std, and Iso rats, but only when exposed to modSPS.
Section snippets
Animals and housing
Male Sprague-Dawley rats purchased from envigo-Harlan (Indianapolis, IN) arrived in the colony PND 21–22 and were immediately assigned to either an Enr, a Std or an Iso environment where they remained for the entire experiment. Enr rats were housed 5–12 per cage in large, stainless steel cages (122 × 61 × 45.5 cm) with ample bedding. Fourteen objects were placed throughout the cage and were rearranged daily and replaced every other day. Std rats were pair housed in standard IVC cages (33 × 38 × 20 cm)
Cocaine self-administration
For acquisition (Fig. 1), linear mixed effects identified main effects of stress (F(1, 25) = 10.05, p < 0.05) and session (F(1, 25) = 11.11, p < 0.05) on active lever presses. These main effects indicated that stress produced an overall reduction in lever pressing and that lever pressing increased across sessions. Further analyses within each environment revealed that the slope of the acquisition line differed significantly between modSPS and control groups within the Iso environment only (F(1, 73) =
Discussion
One important finding from this study was that modSPS produced an overall decrease in cocaine self-administration during initial acquisition. However, contrary to our hypothesis, rearing environment largely did not influence cocaine self-administration or HPA markers after modSPS. One exception to this was the finding that the pattern of acquisition in modSPS Iso rats differed from modSPS Enr and Std rats which was represented by a steeper acquisition slope. While all modSPS groups displayed a
Conclusions
The current experiment identified unique alterations in the acquisition of cocaine self-administration using rearing environment and a rodent model of PTSD. The importance of stress history on PTSD outcomes is often overlooked. While rearing environment did not alter most effects of modSPS on cocaine self-administration, the effect of other stressors during the juvenile or adolescent period might impact these outcomes. Experiments using the SPS model in combination with other stressors are
Acknowledgement
This work was supported by National Institute of Health grants [DA012964, DA036291].
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