Abstract:Our studies reveal distinct SERT contributions to cocaine action, reinforcing the possibility of targeting specific aspects of cocaine addiction by modulation of 5-HT signalling.
“…As expected, SERT Met172 mice, and DAT Val559 mice expressing the SERT Met172 mutation, failed to exhibit 5-HT elevations (Fig. 6a, b) [One-way ANOVA: F (3,19) = 11.89, P = 0.0001], consistent with the expected loss of cocaine affinity at SERT shown in our previous studies [25]. Fig.…”
Section: Resultssupporting
confidence: 89%
“…To confirm a role for SERT blockade in the anomalous loss of cocaine locomotor activation in the DAT Val559 mice, we capitalized on the ability of the SERT Met172 mutation to retain normal SERT function but significantly reduce cocaine affinity at SERT, findings documented in vitro [27] and in vivo using SERT Met172 knock-in mice [28]. Importantly, our prior work revealed that the SERT Met172 mutation fails to impact SERT protein expression, 5-HT transport or 5-HT levels in vivo [25]. Consistent with prior findings of reduced cocaine potency with SERT Met172 expressed on a pure C57BL/6 background [25], cocaine potency for SERT-dependent, striatal 5-HT uptake inhibition was reduced by 45-fold when the SERT Met172 mutation was placed on the hybrid 129S6-C57BL/6 background used in our DAT Val559 studies (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Importantly, our prior work revealed that the SERT Met172 mutation fails to impact SERT protein expression, 5-HT transport or 5-HT levels in vivo [25]. Consistent with prior findings of reduced cocaine potency with SERT Met172 expressed on a pure C57BL/6 background [25], cocaine potency for SERT-dependent, striatal 5-HT uptake inhibition was reduced by 45-fold when the SERT Met172 mutation was placed on the hybrid 129S6-C57BL/6 background used in our DAT Val559 studies (Fig. 5a).…”
Section: Resultsmentioning
confidence: 99%
“…Synaptosomes were prepared from the striata of wildtype, DAT Val559 and SERT Met172 mice and [ 3 H]DA and [ 3 H]5-HT uptake assays performed for 10 min at 37 °C as previously described [19, 25]. Synaptosomes were pre-incubated with drugs [cocaine, 10 −9 –10 −3 M; RTI-113, 10 −9 –10 −4 M] for 10 min at 37 °C prior to the addition of 50 nM [ 3 H]5-HT (specific activity 28 Ci/mmol; PerkinElmer, Waltham, MA) or 50 nM [ 3 H]DA (specific activity 46 Ci/mmol; PerkinElmer).…”
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT
2C
receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT
2C
signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
“…As expected, SERT Met172 mice, and DAT Val559 mice expressing the SERT Met172 mutation, failed to exhibit 5-HT elevations (Fig. 6a, b) [One-way ANOVA: F (3,19) = 11.89, P = 0.0001], consistent with the expected loss of cocaine affinity at SERT shown in our previous studies [25]. Fig.…”
Section: Resultssupporting
confidence: 89%
“…To confirm a role for SERT blockade in the anomalous loss of cocaine locomotor activation in the DAT Val559 mice, we capitalized on the ability of the SERT Met172 mutation to retain normal SERT function but significantly reduce cocaine affinity at SERT, findings documented in vitro [27] and in vivo using SERT Met172 knock-in mice [28]. Importantly, our prior work revealed that the SERT Met172 mutation fails to impact SERT protein expression, 5-HT transport or 5-HT levels in vivo [25]. Consistent with prior findings of reduced cocaine potency with SERT Met172 expressed on a pure C57BL/6 background [25], cocaine potency for SERT-dependent, striatal 5-HT uptake inhibition was reduced by 45-fold when the SERT Met172 mutation was placed on the hybrid 129S6-C57BL/6 background used in our DAT Val559 studies (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Importantly, our prior work revealed that the SERT Met172 mutation fails to impact SERT protein expression, 5-HT transport or 5-HT levels in vivo [25]. Consistent with prior findings of reduced cocaine potency with SERT Met172 expressed on a pure C57BL/6 background [25], cocaine potency for SERT-dependent, striatal 5-HT uptake inhibition was reduced by 45-fold when the SERT Met172 mutation was placed on the hybrid 129S6-C57BL/6 background used in our DAT Val559 studies (Fig. 5a).…”
Section: Resultsmentioning
confidence: 99%
“…Synaptosomes were prepared from the striata of wildtype, DAT Val559 and SERT Met172 mice and [ 3 H]DA and [ 3 H]5-HT uptake assays performed for 10 min at 37 °C as previously described [19, 25]. Synaptosomes were pre-incubated with drugs [cocaine, 10 −9 –10 −3 M; RTI-113, 10 −9 –10 −4 M] for 10 min at 37 °C prior to the addition of 50 nM [ 3 H]5-HT (specific activity 28 Ci/mmol; PerkinElmer, Waltham, MA) or 50 nM [ 3 H]DA (specific activity 46 Ci/mmol; PerkinElmer).…”
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT
2C
receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT
2C
signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.
“…Substances acting to increase DA levels via DAT inhibition and/or DA reverse transport might therefore cause dependence, possibly progressing to addiction. However, the 5-HT system can oppose dopaminergic effects (Daw et al 2002;Alex and Pehek 2007) and serotonergic properties can lower the abuse liability of psychostimulants (Simmler et al 2017;Suyama et al 2016;Liechti 2015;Bauer et al 2013;Rothman and Baumann 2006;Wee et al 2005). Accordingly, the relative action at DAT vs. SERT is crucial for assessing abuse liability of psychostimulants (Baumann et al 2012).…”
New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
