Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have synthesized several derivative of dl-threo-methylphenidate (Ritalin) bearing substituents on the phenyl ring. IC50 values for binding these compounds to rat brain monoamine transporters were assessed using [3H]WIN 35,428 (striatal membranes, dopamine transporters, DAT), [3H]nisoxetine (frontal cortex membranes, norepinephrine transporters, NET) and [3H]paroxetine (brain stem membranes, 5HT transporters, 5HTT). Affinities (1/Ki) decreased in the order: DAT > NET >> 5HTT. Substitution at the para position of dl-threo-methylphenidate generally led to retained or increased affinity for the dopamine transporter (bromo > iodo > methoxy > hydroxy). Substitution at the meta position also increased affinity for the DAT (m-bromo > methylphenidate; m-iodo-p-hydroxy > p-hydroxy). Substitution at the ortho position with bromine considerably decreased affinity. Similar IC50 values for binding of o-bromomethylphenidate to the dopamine transporter were measured at 0, 22 and 37 degrees. N-Methylation of the piperidine ring of methylphenidate also considerably reduced affinity. The dl-erythro isomer of o-bromomethylphenidate did not bind to the DAT (IC50 > 50,000 nM). Affinities at the dopamine and norepinephrine transporters for substituted methylphenidate derivatives were well correlated (r2=0.90). Abilities of several methylphenidate derivatives to inhibit [3H]dopamine uptake in striatal synaptosomes corresponded well with inhibition of [3H]WIN 35, 428 binding. None of the compounds examined exhibited significant affinity to dopamine D1 or D2 receptors (IC50 > 500 or 5,000 nM, respectively), as assessed by inhibition of binding of [3H]SCH 23390 or [123I]epidepride, respectively, to striatal membranes.
 ...
PMID:Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. 878 5

Single and multiple high-dose administrations of methamphetamine (METH) differentially decrease dopamine (DA) transporter (DAT) function, as assessed by measuring [(3)H]DA uptake into rat striatal synaptosomes prepared 1 h after treatment. Prevention of METH-induced hyperthermia attenuated the decrease in DAT activity induced by multiple injections of the stimulant. Likewise, this decrease was attenuated by previous depletion of striatal DA levels using alpha-methyl-p-tyrosine (alphaMT) or pretreatment with the D1 and D2 antagonists SCH-23390 and eticlopride, respectively. However, METH-induced hyperthermia was also blocked by alphaMT and eticlopride. Reinstatement of hyperthermia to alphaMT- or eticlopride-pretreated rats partially restored the METH-induced decrease in DAT activity. In contrast, neither prevention of METH-induced hyperthermia depletion of DA, nor DA antagonists altered the decrease in DAT function induced by a single administration of METH. Pretreatment with the antioxidant N-t-butyl-alpha-phenylnitrone prevented part of the decrease in DAT function associated with multiple, but not a single, METH injections. Although not tested directly, additional data presented here suggest that the reduction in DAT activity induced by a single METH administration constitutes a part of the total reduction observed immediately after multiple administrations. Taken together, the results indicate that DA, hyperthermia, and oxygen radicals contribute to a component of the rapid decrease in DAT function induced by multiple injections of METH but do not appear to be associated with the reduction induced by a single administration of the stimulant.
 ...
PMID:Methamphetamine-induced rapid decrease in dopamine transporter function: role of dopamine and hyperthermia. 1108 43

Despite a wealth of data indicating that morphine modulates immune status by acting at mu-opioid receptors in the brain, there is little known about how the opioid system interacts with other neurotransmitter systems to modulate specific immune parameters. The aim of the present study was to investigate whether dopaminergic projections to the nucleus accumbens are involved in morphine-induced suppression of splenic natural killer (NK) cell activity. The results indicate that administration of the dopamine D1 antagonist SCH-23390 into the nucleus accumbens shell, but not core, blocked morphine's suppressive effect on NK activity in male Lewis rats. In support of these findings, the effect of morphine was also prevented by intra-accumbens microinfusions of the dopaminergic immunotoxin anti-DAT-saporin. Additionally, administration of the D1 agonist SKF-38393 into the nucleus accumbens shell produced reductions in splenic NK activity comparable to morphine, suggesting a critical role for D1 receptors in the modulation of NK activity. Collectively, these findings demonstrate that dopaminergic inputs to the nucleus accumbens are critically involved in opioid-induced immunosuppression and suggest that opioid-induced increases in D1 receptor activation may have adverse consequences on immune status.
 ...
PMID:Suppression of natural killer cell activity by morphine is mediated by the nucleus accumbens shell. 1646 91

We previously reported that brief (1 h), but not extended (6 h), daily access to cocaine results in a sensitized locomotor response to cocaine and in elevated c-Fos immunoreactivity and DAT binding in the nucleus accumbens (N.Acc) core. In order to better our understanding of the neural adaptations mediating the transition from controlled drug use to addiction, the current experiments were set to further explore the neural adaptations resulting from these two access conditions. Rats received either brief daily access to saline or cocaine, or brief daily access followed by extended daily access to cocaine. Subjects were then sacrificed either 20 min, or 14 or 60 days, after the last self-administration session. Samples of the ventral tegmental area (VTA), N.Acc core and shell, dorsal striatum, and medial prefrontal cortex (mPFC) were taken for analysis of D1 ([3H]SCH-23390), D2 ([3H]Spiperone), and NMDA ([3H]MK-801) receptor binding (using the method of receptor autoradiography). At 20 min into withdrawal, D2 receptors were elevated and NMDA receptors were reduced in the mPFC of the brief access animals while D1 receptors were elevated in the N.Acc shell of the extended access animals, compared to saline controls. D2 receptors were reduced in the N.Acc shell of the brief access animals compared to saline controls after 14 days, and compared to extended access animals after 60 days of withdrawal. In summary, extended access to cocaine resulted in only transient changes in D1 receptors binding. These results suggest that the development of compulsive drug use is largely unrelated to changes in total binding of D2 or NMDA receptors.
 ...
PMID:Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine. 1716 92

The genetic factors involved in the regulation of physical activity are not well understood. The dopamine system has been implicated in the control of voluntary locomotion and wheel running (WR) in mice and is thus a likely candidate as a genetic/biological system important to the regulation of physical activity. This study evaluated the effects of four different dopaminergic acting drugs on WR in differentially active inbred strains of mice. High active C57L/J (n=7, 3 controls, 4 experimental) and low active C3H/HeJ (n=8, 3 controls, 5 experimental) were analyzed for baseline wheel-running indices of distance (km/day), duration (mins/day), and speed (m/min) for 21 days. Experimental mice received increasing doses over four days of each of the following drugs: SKF 81297 (D1 agonist), SCH 23390 (D1 antagonist), GBR 12783 (DAT inhibitor), and AMPT (tyrosine hydroxylase inhibitor). Each drug dose response treatment was separated by three days of recovery (no drug injections). WR indices were monitored during drug treatments and during drug wash-out phases. SKF 81297 significantly reduced (p=0.0004) WR in the C57L/J mice, but did not affect WR in the C3H/HeJ mice. GBR 12783 significantly increased (p=0.0005) WR in C3H/HeJ mice, but did not affect WR in C57L/J mice. Only duration (not overall WR) was significantly reduced in C57L/J mice in response to SCH 23390 (p=0.003) and AMPT (p=0.043). SCH 23390 (p=0.44) and AMPT (p=0.98) did not significantly affect WR in C3H/HeJ mice. These results suggest that genetic differences in dopamine signaling may play a role in the WR response to dopaminergic-acting drugs in inbred strains of mice. The high activity in the C57L/J strain appears most responsive to D1-like receptor acting drugs, while in the C3H/HeJ strain, dopamine re-uptake appears to have an influence on activity level.
 ...
PMID:Pharmacological manipulation of the dopaminergic system affects wheel-running activity in differentially active mice. 2247 3

Methylone (2-methylamino-1-[3,4-methylenedioxy-phenyl]propan-1-one), an amphetamine analog, has emerged as a popular drug of abuse worldwide. Methylone induces hyperthermia, which is thought to contribute toward the lethal consequences of methylone overdose. Methylone has been assumed to induce hyperthermic effects through inhibition of serotonin and/or dopamine transporters (SERT and DAT, respectively). To examine the roles of each of these proteins in methylone-induced toxic effects, we used SERT and DAT knockout (KO) mice and assessed the hyperthermic and lethal effects caused by a single administration of methylone. Methylone produced higher rates of lethal toxicity compared with other amphetamine analogs in wild-type mice. Compared with wild-type mice, lethality was significantly lower in DAT KO mice, but not in SERT KO mice. By contrast, only a slight diminution in the hyperthermic effects of methylone was observed in DAT KO mice, whereas a slight enhancement of these effects was observed in SERT KO mice. Administration of the selective D1 receptor antagonist SCH 23390 and the D2 receptor antagonist raclopride reduced methylone-induced hyperthermia, but these drugs also had hypothermic effects in saline-treated mice, albeit to a smaller extent than the effects observed in methylone-treated mice. In contradistinction to 3,4-methylenedioxymethamphetamine, which induces its toxicity through SERT and DAT, these data indicate that DAT, but not SERT, is strongly associated with the lethal toxicity produced by methylone, which did not seem to be dependent on the hyperthermic effects of methylone. DAT is therefore a strong candidate molecule for interventions aimed at preventing acute neurotoxic and lethal effects of methylone.
...
PMID:Methylone-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. 2579 33