Regulation Of Dopamine Transmission Research Articles

Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine.

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level–dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders.

Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury

Dopamine (DA) systems are implicated in cognitive deficits following traumatic brain injury (TBI). Rodent studies have demonstrated that both environmental enrichment (EE) and sex hormones can influence DA systems. The dopamine transporter (DAT) plays a crucial role in regulating DA transmission, and previous work shows that DAT is decreased after TBI in males. Therefore, the purpose of this study was to examine the effects of gender and EE on frontal cortex and striatal DAT expression after TBI. Sprague–Dawley male ( n = 24) and cycling female rats ( n = 24) were placed into EE or standard housing after controlled cortical impact (2.7 mm, 4.0 m/s) injury or sham surgery (eight groups, n = 6/group). Four weeks post-surgery, bilateral frontal cortex and striatal DAT expression was examined via Western blot. Results demonstrated that there was a significant effect of injury, EE, and region on DAT expression ( P < 0.05 all comparisons) on female groups. There were no significant DAT decreases in any region as a result of injury, however, EE did promote significant post-injury DAT decreases in the striatum and ipsilateral frontal cortex ( P < 0.05 all comparisons) compared to female shams housed in the standard environment. For males, there was a significant effect of injury, EE, and region for male groups ( P < 0.05 all comparisons). There were decreases in DAT expression in three regions studied for injured males housed in the standard environment compared to sham males in the standard environment ( P < 0.05 all comparisons), however, EE did not add significantly to post-injury DAT decreases in these regions. These results suggest that CCI causes larger relative decreases in DAT expression for males compared to females and that treatment with EE has larger effects on post-injury DAT expression for females than males. These findings may have some relevance to treatment paradigms using dopaminergic neurostimulants after TBI.

Sigma 1 receptor subtype is involved in the facilitation of cortical dopaminergic transmission in the rat brain.

Our previous studies have shown that three sigma (sigma) receptor ligands, (+)-N-allylnormetazocine ((+)-SKF-10,047), (+/-)-pentazocine and 1,3-di(2-tolyl)guanidine (DTG) differently regulated the dopamine (DA) transmission in the rat brain. In the present study, we attempted to clarify the role of sigma 1 receptor subtype in the regulation of DA transmission using a novel and selective sigma 1 receptor agonist, 1-(3,4-dimethoxyphenethyl)-4(3-phenylpropyl)piperazine dihydrochloride (SA4503) in the rat brain. Acute administration of SA4503 (1.0 mg/kg, p.o.) significantly increased DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the rat frontal cortex, but not in the other six regions, hippocampus, striatum, midbrain, cerebellum, medulla/pons and hypothalamus. The increase of cortical DA level elicited by SA4503 was fully reversed by N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) (0.25 mg/kg, p.o.), a putative sigma 1 receptor antagonist. In addition, SA4503 (1.0 mg/kg, p.o.) showed an increase of cortical L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation under the inhibition of dopa decarboxylase activity with m-hydrobenzylhydrazine (NSD-1015), suggesting that SA4503 has activated the cortical DA synthesis rate. These results suggest that the sigma 1 receptor subtype plays an important role in the facilitation of cortical DA transmission. In addition, this phenomenon is partially involved in the augmentation of DA synthesis rate.

Effects of BMY 33462, a selective and potent serotonin type‐3 receptor antagonist, on mesolimbic dopamine‐mediated behavior

AbstractThe compound BMY 33462 (4‐amino‐N‐(1‐azabicyclo‐[2,2,2]oct‐3‐yl)‐2‐(butan‐2‐one‐3‐yl)oxy‐5‐chlorobenzamine 1.25 fumerate hydrate) has been shown to be a selective and potent serotonin type‐3 (5‐HT3) receptor antagonist. Its receptor binding profile includes subnanomolar affinity for the 5‐HT3 receptor (Ki, 0.22 ± 0.06 nM) and no affinity for other serotonergic, dopaminergic, and adrenergic receptors (Ki &gt; 1,000 nM). BMY 33462 was also shown to be a potent inhibitor of the Bezold‐Jarisch reflex in the anesthetized rat (ED50, 0.09 μg/kg, iv), a functional correlate of 5‐HT3 receptor antagonism in vivo. It has been reported that ondansetron and other 5‐HT3 antagonists have the ability to block hyperactivity in rats induced by DiMe‐C7 ([pGlu5, Me‐Phe8, Sar9]SP5–11), a metabolically stable analogue of substance P [Hagan et al. (1990): Br J Pharmacol 99:227–232]. DiMe‐C7‐induced hyperactivity is thought to occur through activation of mesolimbic dopamine (DA) neurons which project to the nucleus accumbens [West and Michael (1991): Brain Res Bull 26:229–233]. BMY 33462 was examined for its ability to block DiMe‐C7‐induced hyperactivity as was haloperiodol and ondansetron. The dopamine‐2 (D2) antagonist haloperidol produced the greatest inhibition of DiMe‐C7‐induced hyperactivity at a dose of 0.025 mg/kg (53.7%). Ondansetron significantly inhibited the DiMe‐C7‐induced increase in locomotor activity at doses of 0.10 mg/kg and 0.50 mg/kg (42% and 30%, respectively). BMY 33462, at doses of 0.025 mg/kg and 0.05 mg/kg, significantly decreased DiMe‐C7‐induced hyperactivity by 41% and 37%, respectively. Haloperidol proved to be highly efficacious and potent in blocking increases in DiMe‐C7‐induced locomotor activity, a phenomenon which may correlate with its clinical effectiveness as a neuroleptic agent. BMY 33462 and ondansetron were equally efficacious, however, BMY 33462 was more potent. The ability of 5‐HT3 antagonists to alter a mesolimbic DA‐mediated behavior indicates a complex interaction between these two neurotransmitter systems and perhaps a role for central 5‐HT3 receptors and 5‐HT in the regulation of DA transmission. In addition, BMY 33462 and ondansetron were unable to inhibit stereotypy induced by apomorphine (inactive at 100 mg/kg, orally) suggesting a lack of interaction with the nigrostriatal DA pathway. These results support the notion that 5‐HT3 antagonists may be potential therapeutic agents for the treatment of hyperdopaminergic disease states, such as schizophrenia, without the side effect liability generally associated with classical neuroleptics. © 1993 Wiley‐Liss, Inc.