![]() 3, 13 This is because OCT3 acts in the brain as a high-capacity, low-specificity transporter to provide clearance of cations, including monoamine neurotransmitters, 22– 25 particularly when extracellular levels exceed the capacity of dedicated monoamine transporters such as SERT, such as during stress. 12 Such an increase in vHipp OCT3 function may result in greater clearance of extracellular serotonin levels during stress to promote heightened anxiety and stress sensitivity throughout withdrawal. In contrast to SERT, an increased organic cation transporter 3 (OCT3) expression and function is observed in the vHipp at 24 hours of withdrawal following chronic amphetamine treatment. 13 Therefore, we measured the expression of SERT in the CeA and vHipp following both acute and protracted withdrawal from chronic amphetamine. ![]() 21 While the reduction in extracellular serotonin observed in the vHipp during acute withdrawal from chronic amphetamine does not appear to be mediated by changes in SERT expression or function, 12 this does not rule out the possibility that SERT expression in the vHipp or CeA may be altered beyond the 24-hour period to explain the changes in stress-induced extracellular serotonin seen during protracted withdrawal. Alterations in SERT expression or function have been associated with anxiety, 16– 18 fear-associated learning, 19 psychostimulant administration, 20 and depression. 15 Given the importance of serotonergic transmission in these brain regions for regulating emotion, the underlying mechanisms for serotonin dysregulation in the limbic system following chronic amphetamine need to be fully elucidated.Įxtracellular serotonin levels are regulated, in part, by reuptake via the serotonin transporter (SERT). 3 Conversely, increased extracellular serotonin in CeA in drug-naïve rats is associated with increased fear behavior. For example, serotonergic lesions in the vHipp of drug-naïve rats increase anxiety-like behavior on the elevated plus maze, while increasing serotonin in the vHipp alleviates heightened anxiety in rats undergoing amphetamine withdrawal. 10, 13 These differential changes in vHipp and CeA serotonergic function may contribute to the increased anxiety and stress sensitivity exhibited during withdrawal. 13, 14 In contrast, amphetamine withdrawal at both time points is characterized by augmented extracellular serotonin in the central nucleus of the amygdala (CeA) in response to either restraint stress or corticotrophin-releasing factor (CRF) infusion into the dorsal raphe. 10– 13 Specifically, rats undergoing either acute (24 hours) or prolonged (two weeks) amphetamine withdrawal show markedly attenuated stress- or corticosterone-induced extracellular serotonin levels in the ventral hippocampus (vHipp). In experimental animals, acute and extended withdrawal from chronic amphetamine leads to dysregulation of stress-induced extracellular serotonin in the limbic system. 1– 5 These negative emotional states contribute to relapse after both acute and prolonged withdrawal periods. These regionally specific changes in limbic OCT3 and SERT expression may partially contribute to the serotonergic imbalance and negative affect during amphetamine withdrawal.Ĭhronic amphetamine and subsequent withdrawal induce greater anxiety and heightened sensitivity to stress in both humans and animal models. No changes were evident in any other regions sampled. In the vHipp, OCT3 expression increased only at 24 hours of withdrawal, with an equivalent pattern seen in the dorsomedial hypothalamus. OCT3 and SERT expression increased in the CeA at both withdrawal timepoints. Male rats received amphetamine or saline for two weeks followed by 24 hours or two weeks of withdrawal, with transporter expression measured using Western immunoblot. We also determined whether changes in transporter expression were confined to these regions. Here, we tested whether OCT3 and SERT expression in the CeA is also affected during acute withdrawal to explain opposing regional alterations in limbic serotonergic neurotransmission and if respective changes continued with two weeks of withdrawal. Extracellular serotonin levels are regulated by the serotonin transporter (SERT) and organic cation transporter 3 (OCT3), and vHipp OCT3 expression is enhanced during 24 hours of amphetamine withdrawal, while SERT expression is unaltered. Amphetamine withdrawal increases anxiety and stress sensitivity related to blunted ventral hippocampus (vHipp) and enhances the central nucleus of the amygdala (CeA) serotonin responses.
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