Morphine history sensitizes postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats

Abstract

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Previous work has shown that the dorsal raphe nucleus (DR)-5-HT system is inhibited by swim stress via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor (CRF). Additionally, the DR 5-HT system is regulated by opioids. The present study tests the hypothesis that the DR 5-HT system regulates stress-induced opioid relapse. In the first experiment, electrophysiological recordings of GABA synaptic activity in 5-HT DR neurons were conducted in brain slices from Sprague-Dawley rats that were exposed to swim stress-induced reinstatement of previously extinguished morphine conditioned place preference (CPP). Behavioral data indicate that swim stress triggers reinstatement of morphine CPP. Electrophysiology data indicate that 5-HT neurons in the morphine-conditioned group exposed to stress had increased amplitude of inhibitory postsynaptic currents (IPSCs), which would indicate greater postsynaptic GABA receptor density and/or sensitivity, compared to saline-controls exposed to stress. In the second experiment, rats were exposed to either morphine or saline CPP and extinction, and then 5-HT DR neurons from both groups were examined for sensitivity to CRF in vitro. CRF induced a greater inward current in 5-HT neurons from morphine-conditioned subjects compared to saline-conditioned subjects. These data indicate that morphine history sensitizes 5-HT DR neurons to the GABAergic inhibitory effects of stress as well as to some of the effects of CRF. These mechanisms may sensitize subjects with a morphine history to the dysphoric effects of stressors and ultimately confer an enhanced vulnerability to stress-induced opioid relapse.

Effects of cocaine history on postsynaptic GABA receptors on dorsal raphe serotonin neurons in a stress-induced relapse model in rats

“…One thing to note is that the frequencies of IPSCs for both DRN-5-HT and -non-5-HT neurons in our current study were low compared with our previous studies (Kirby et al, 2008; Staub et al, 2012). This is possibly the result of using older animals (~11–14 week old) in the current study, necessitated by the lengthy behavioral training, compared to our previous studies with CPP-trained (11–12 weeks; Staub et al, 2012) and naïve rats (~4–5 week old; Kirby et al, 2008).…”

“…This is possibly the result of using older animals (~11–14 week old) in the current study, necessitated by the lengthy behavioral training, compared to our previous studies with CPP-trained (11–12 weeks; Staub et al, 2012) and naïve rats (~4–5 week old; Kirby et al, 2008). For example, using vehicle treated or naïve Sprague-Dawley rats in our laboratory under the same electrophysiological conditions, we have recorded the following mIPSC frequencies in 5-HT DRN neurons: 4–5-week-old: mean=6.21 ± 0.59, range=0.80–14.82 ( N =39); 11–12-week-old: mean=3.98 ± 0.54, range=1.09–6.55 ( N =12); 11–14-week-old: mean=1.16 ± 0.15, range=0.67–1.71 ( N =7).…”

“…For example, infusion of GABA agonists into the DRN reduces cocaine-induced anxiety (Ettenberg et al, 2011) and escalates alcohol-heightened aggression (Takahashi et al, 2010). Using a swim stress-induced reinstatement of conditioned place preference (CPP) model, data from our laboratory indicate that morphine history sensitizes DRN-5-HT neurons to the GABAergic inhibitory effects of swim stress (Staub et al, 2012). Moreover, we provided direct evidence that stimulation of GABA signaling in the DRN is both necessary and sufficient for swim stress-induced reinstatement of morphine CPP (Li et al., 2013).…”

Stress and opioids: Role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference

“…Earlier, Staub and collaborators described that exposure to morphine sensitizes the 5-HT system in the dorsal horn neurons to GABAergic inhibitory effects of stress and CRH (Staub et al, 2012). A recent study examined the role of GABA B receptors in morphine-induced CPP, extinction and stressinduced relapse in chronicstress subjected mice.…”

ERK1/2 Phosphorylation in the Rat Supraoptic Nucleus, Dorsal Raphe Nucleus, and Locus Coeruleus Neurons Following Noxious Stimulation to the Hind Paw

“…The DRN contains 5-hydroxytryptamine (5-HT) neurons projecting to the forebrain and is a target for the stress hormone corticotropin releasing factor and opioids. Stress and opioids converge on the DRN to regulate 5-HT neurotransmission [26]. It has been demonstrated that the DRN neurons express the major opioid receptors; mu-opioid receptors inhibit GABAergic synaptic input and thus disinhibit 5-HT neurons in the DRN [27].…”