Effect of Inhibition of the Central Nucleus of the Amygdala and Drug Experience on the Regions Underlying Footshock-Induced Reinstatement of Morphine Seeking
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This study assessed the effect of inhibition of the central nucleus of the amygdala (CeA) and drug experience on brain regions underlying footshock-induced reinstatement of morphine-seeking behaviour in rats. The difference in time spent in two chambers of a place-preference apparatus was used to measure morphine-conditioned place preference. Fos was measured as a marker of neuronal activation in the ventral bed nucleus of the stria terminalis (BNSTv) and ventral tegmental area (VTA). Footshock was found to enhance Fos expression in the BNSTv regardless of drug experience. In the VTA, morphine and footshock had an interactive effect on the increase in Fos expression. Inhibition of the CeA decreased Fos expression in the BNSTv regardless of drug experience, whereas in the VTA this effect only occurred in morphine-treated rats. These results suggest that drug experience has no differential effect on the BNSTv however morphine produces footshock sensitization in the VTA. CeA inhibition modulates the footshock-induced activity of these regions of the brain and attenuates reinstatement of drug seeking behaviour.Keywords:
Conditioned place preference
Extended amygdala
Differential effects
Extended amygdala
c-Fos
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Extended amygdala
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Anxiogenic
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The bed nucleus of the stria terminalis (BNST) is in a key position to influence the integration of motivational and visceral functions, receiving inputs from limbic regions, including the amygdala, and sending projections to areas central to reward processing, including the ventral tegmental area and nucleus accumbens. The BNST also possesses a high density of noradrenergic fibers. The purpose of the present studies was to characterize the effects of cocaine self-administration on the regulation of norepinephrine transporter (NET) distribution and functional activity in the BNST of rhesus monkeys in the initial (5 d) or chronic (100 d) phases of cocaine self-administration. NET binding site densities in the BNST were assessed with quantitative in vitro receptor autoradiography using [(3)H]nisoxetine, and rates of local cerebral glucose utilization in the BNST were measured in the same monkeys using the 2-[(14)C]deoxyglucose method. Chronic exposure to cocaine self-administration resulted in significantly higher NET binding site densities (up to 52% relative to controls) throughout the BNST. Furthermore, cerebral metabolism was depressed significantly in a time-dependent manner with larger decreases after 100 d of cocaine self-administration. These data represent the first report of significant changes in the regulation of the NET resulting from cocaine exposure in primates. Furthermore, given the role of the BNST in cocaine withdrawal and stress-related reinstatement of self-administration, the changes reported here may provide a substrate for these phenomena.
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ABSTRACT: Although there is a close correspondence between fear and anxiety, and the study of fear in animals has been extremely valuable for under‐standing the neural basis of anxiety, it is also clear that a richer animal model of human anxiety disorders would include measures of both stimulus‐specific fear and something less stimulus specific, more akin to anxiety. Patients with posttraumatic stress syndrome seem to show normal fear reactions but abnormal anxiety measured with the acoustic startle reflex. Studies in rats, also using the startle reflex, indicate that highly processed explicit cue information (lights, tones) activates the central nucleus of the amygdala, which projects to and modulates the acoustic startle pathway in the brain stem. Less explicit information, such as that produced by exposure to a threating environment or by intraventricular administration of corticotropin‐releasing hormone, may activate another part of the extended amygdala, the bed nucleus of the stria terminalis, which also projects to the startle pathway. Because this information may be less specific and of long duration, activation of the bed nucleus of the stria terminalis may mediate anxiety, whereas activation of the central nucleus of the amygdala may mediate stimulus‐specific fear.
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It is well established that the central nucleus of the amygdala (CEA) is involved in responses to stress, fear and anxiety. Many studies have used c-fos expression to map the brain's response to processive stress, but curiously the CEA generally is not highly activated. We have previously shown that exposure to a novel vs. home environment reduces amphetamine-induced activation of the lateral CEA (CEAl) and the oval nucleus of the bed nucleus of the stria terminalis (BSTov). This is consistent with the idea that processive stress inhibits neurons in these nuclei. We have tested this hypothesis by exposing rats to noise, at a range of intensities from non-stressful to stressful, or to restraint conditions, immediately after a remote injection of amphetamine, 2 mg/kg i.p., or interleukin-1beta (IL-1beta) 0.5 microg/kg i.p. (used to obtain a level of c-fos mRNA against which to measure inhibition). In keeping with our hypothesis, amphetamine- or IL-1beta-induced c-fos and zif-268 mRNA were significantly decreased in the CEAl and BSTov under conditions of loud noise or restraint stress compared with control conditions. This inhibition does not require a stress-induced rise in corticosterone because data were similar in animals that had been adrenalectomized with a low-dose corticosterone replacement. As both the CEAl and BSTov are highly gamma-aminobutyric acid (GABA) -ergic and project to the medial CEA (CEAm), their inhibition potentially causes an increased input to the CEAm. As the CEAm is a major output nucleus of the amygdala, this could have important consequences within the neural circuitry controlling responses to processive stress.
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AbstractThere is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites, including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking.Key words: Bed nucleus of the stria terminalisCocaineCentral nucleus of the amygdalaDrug abuseHeroinStress
Extended amygdala
Septal nuclei
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