Role Of Dopaminergic Transmission Research Articles

The Role of a Dopaminergic Component in the Analgesic Effect of the Low-Affinity NMDA Receptor Antagonist Hemantane

The role of dopaminergic transmission in the mechanism of analgesic action of the low-affinity NMDAreceptor antagonist hemantane [N-(2-adamantyl)hexamethyleneimine hydrochloride] was demonstrated experimentally. A single i.p. injection of hemantane at a dose of 20 mg/kg has the ability to inhibit dopamine reuptake and exhibits an analgesic effect in the somatic thermal pain model (tail-flick test) and visceral pain model (acetic-acid-induced writhing test) in ICR mice. The dopamine D1 receptor antagonist R(+)-SCH-23390 at a dose of 0.005 mg/kg and dopamine D2 receptor antagonist sulpiride at a dose of 5 mg/kg administered by a single i.p. injection 30 min before hemantane injection prevented manifestation of the antinociceptive activity of the NMDA receptor antagonist in the used methods, which was more pronounced for the spinal reflex (tail-flick test).

Роль дофаминергического компонента в механизме анальгетического действия низкоаффинного блокатора NMDA рецептора гимантана

В проведённом экспериментальном исследовании выявлена роль дофаминергического компонента в механизме анальгетического действия низкоаффинного блокатора NMDA рецептора гимантана (N-(2-адамантил)гексаметиленимина гидрохлорида). Гимантан, обладающий способностью ингибировать обратный захват дофамина, при однократном внутрибрюшинном введении в дозе 20 мг/кг проявляет анальгетический эффект на моделях соматической термической (тест отдёргивания хвоста от теплового излучения) и висцеральной (тест «Уксусные корчи») боли у мышей ICR. Блокатор D1-дофаминергического рецептора R(+)-SCH-23390 в дозе 0,005 мг/кг и блокатор D2-дофаминергического рецептора сульпирид в дозе 5 мг/кг при однократном внутрибрюшинном введении за 30 мин до инъекции гимантана предотвращают проявление антиноцицептивной активности изучаемого блокатора NMDA рецептора в используемых методиках, что более ярко проявляется при оценке его влияния на спинальный флексорный рефлекс.

Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.

The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine’s role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th. After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated significantly. In sum, methytransferase G9a/Glp complex partially controls dopaminergic transmission by methylating Th in peripheral nerve injury-induced neuropathic pain.

Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.

Patients suffering from major depression often experience memory deficits even after the remission of mood symptoms, and many antidepressant drugs do not affect, or impair, memory in animals and humans. However, some antidepressant drugs, after a single dose, enhance cognition in humans (Harmer et al., 2009). To compare different classes of antidepressant drugs for their potential as memory enhancers, we used a version of the novel object recognition task in which rats spontaneously forget objects 24 hr after their presentation. Antidepressant drugs were injected systemically 30 min before or directly after the training phase (Session 1 [S1]). Post-S1 injections were used to test for specific memory-consolidation effects. The noradrenaline reuptake inhibitors reboxetine and atomoxetine, as well as the serotonin noradrenaline reuptake inhibitor duloxetine, injected prior to S1 significantly enhanced recognition memory. In contrast, the serotonin reuptake inhibitors citalopram and paroxetine and the cyclic antidepressant drugs desipramine and mianserin did not enhance recognition memory. Post-S1 injection of either reboxetine or citalopram significantly enhanced recognition memory, indicating an effect on memory consolidation. The fact that citalopram had an effect only when injected after S1 suggests that it may counteract its own consolidation-enhancing effect by interfering with memory acquisition. However, pretreatment with citalopram did not attenuate reboxetine's memory-enhancing effect. The D1/5-receptor antagonist SCH23390 blunted reboxetine's memory-enhancing effect, indicating a role of dopaminergic transmission in reboxetine-induced recognition memory enhancement. Our results suggest that antidepressant drugs specifically inhibiting noradrenaline reuptake enhance cognition and may be beneficial in the treatment of cognitive symptoms of depression.

The role of dopaminergic transmission through D1-like and D2-like receptors in amphetamine-induced rat ultrasonic vocalizations

Systemic amphetamine (AMPH) administration increases the rate of 50-kHz ultrasonic vocalizations (USVs) in adult rats and preferentially enhances the 'trill' subtype; these effects of AMPH critically depend on noradrenergic transmission, but the possible contributions of dopamine are unclear. To assess the role of dopamine in 50-kHz USVs emitted drug-free and following systemic AMPH administration. Adult male Long-Evans rats pre-selected for high AMPH-induced calling rates were tested with AMPH (1 mg/kg, intraperitoneal (IP)) and saline following pretreatment with the following dopamine receptor antagonists: SCH 23390 (0.005-0.02 mg/kg, subcutaneous (SC)), SCH 39166 (0.03-0.3 mg/kg, SC), haloperidol (0.1, 0.2 mg/kg, IP), sulpiride (20-80 mg/kg, SC), raclopride (0.1-0.5 mg/kg, SC), clozapine (4 mg/kg, SC), risperidone (0.5 mg/kg, SC), and pimozide (1 mg/kg, IP). The dopamine and noradrenaline reuptake inhibitors (GBR 12909 and nisoxetine, respectively) were also tested, alone and in combination. SCH 23390, SCH 39166, haloperidol, and raclopride dose-dependently inhibited vocalizations under AMPH and suppressed the proportion of trill calls. Sulpiride, however, had no discernable effect on call rate or profile, even at a high dose that reduced locomotor activity. Single doses of clozapine, risperidone, and pimozide all markedly decreased calling under saline and AMPH. Finally, GBR 12909 and nisoxetine failed to promote 50-kHz USVs detectably or alter the subtype profile, when tested alone or in combination. The rate of 50-kHz USVs and the call subtype profile following systemic AMPH administration depends on dopaminergic neurotransmission through D1-like and D2-like receptors. However, inhibiting dopamine and/or noradrenaline reuptake appears insufficient to induce calling.

The Successful Treatment of Mania Due to Acquired Immunodeficiency Syndrome Using Ziprasidone: A Case Series

The Successful Treatment of Mania Due to Acquired Immunodeficiency Syndrome Using Ziprasidone: A Case Series

The Effects of Acute Injections of Selective Dopamine Receptor Agonists and Antagonists on Three Models of Impulsivity in the Rat

A role for dopaminergic transmission in the expression of impulsivity in animal models has been demonstrated. The role of individual dopamine receptors in these actions is not entirely clear, however. Sprague Dawley rats were trained to respond on one of three purported models of impulsivity: the delay discounting task, a paced fixed consecutive number schedule, or an uncertain visual discrimination task. Agonists and antagonists selective for individual dopamine receptor subtypes or compounds acting at the dopamine transporter were administered and changes in behavior were recorded. Results indicate that dopaminergic transmission is important for each of the impulsivity models examined. Furthermore, the effects of specific compounds across models are sometimes in concordance and sometimes in discordance, indicating these models are not measuring the same aspect of behavior. This research was supported by USPHS/NIDA grants R01 DA020669 and T32 DA007267.

The κ-opioid receptor agonist U-69593 prevents cocaine-induced phosphorylation of DARPP-32 at Thr 34 in the rat brain

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) is a potent endogenous inhibitor of protein phosphatase-1, which plays an important role in dopaminergic transmission. A large body of evidence supports the key role of DARPP-32-dependent signalling in mediating the actions of multiple drugs of abuse, including cocaine, which, when acutely administered, increases the Thr 34 phosphorylation of DARPP-32 in the striatal and cortical areas. In this study, we have examined the contribution of the kappa opioid system to the regulation of DARPP-32 phosphorylation at Thr 34, following acute cocaine administration, in selected rat brain areas. Results showed that a single injection of cocaine induces a significant increase in DARPP-32 phosphorylation at Thr 34 in the hippocampus, caudate putamen and prefrontal cortex. In addition, pretreatment with the kappa opioid receptor agonist U-69593 prevented cocaine effects in all the investigated areas. These data could be considered consistent with the ability of kappa opioid agonists to attenuate many behavioural and neurochemical effects of cocaine.

Opposite modulation of regulators of G protein signalling-2 (RGS2) and RGS4 expression by dopamine receptors in the rat striatum

The role of dopaminergic transmission on striatal mRNA levels of regulators of G protein signalling proteins (RGS 2–12) was evaluated by quantitative in situ hybridisation. A single injection of l-dopa (50 mg/kg i.p.) significantly increased the RGS2 mRNA level (by 25%), an effect that was specifically abolished by the D1 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390), but not changed by S(−)-eticlopride. Interestingly, the administration of this D2 dopamine receptor antagonist alone markedly enhanced the expression of RGS2 (by 71%), which suggests a constitutive inhibition of RGS2 expression by D2 dopamine receptors. Opposite results were obtained concerning the regulation of RGS4 since l-dopa alone was without effect whereas co-administration of l-dopa and R(+)-SCH23390 significantly enhanced the RGS4 mRNA levels (by 38%). In conclusion, D1 and D2 dopamine receptors appear to mediate opposite regulatory effects on RGS2 and RGS4 expression in the striatum.

Dopamine antagonism attenuates the unconditioned incentive value of estrous female cues

The role of dopaminergic transmission in the incentive–motivational processes involved in the generation of male sexual behavior was examined. Three groups of sexually naı̈ve Long–Evans male rats traversed a straight alley for one of three goalbox targets: an empty goalbox, a nonestrous female, or an estrous female. A Plexiglas partition within the goalbox allowed for the perception of visual, auditory, and olfactory cues, but prevented physical contact. Baseline run times revealed that subjects returned to the goalbox significantly faster for an estrous female than for a nonestrous female, replicating our earlier work on the inherent incentive value of primary female cues. When subjects were then pretreated with the dopamine receptor antagonist, haloperidol (0.0, 0.075, or 0.15 mg/kg), they expressed decreased sexual motivation as reflected by increased run times for estrous female targets. Subjects' run times for the empty goalbox condition were unaffected by haloperidol, suggesting that the drug did not reliably impair motoric capacity. Results support the contention that central dopaminergic systems are involved in the regulation of the positive, unconditioned incentive value of estrous female cues.

Regulation of the phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors.

Dopamine D(1), dopamine D(2), and adenosine A(2A) receptors are highly expressed in striatal medium-sized spiny neurons. We have examined, in vivo, the influence of these receptors on the state of phosphorylation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). DARPP-32 is a potent endogenous inhibitor of protein phosphatase-1, which plays an obligatory role in dopaminergic transmission. A dose-dependent increase in the state of phosphorylation of DARPP-32 occurred in mouse striatum after systemic administration of the D(2) receptor antagonist eticlopride (0.1-2.0 mg/kg). This effect was abolished in mice in which the gene coding for the adenosine A(2A) receptor was disrupted by homologous recombination. A reduction was also observed in mice that had been pretreated with the selective A(2A) receptor antagonist SCH 58261 (10 mg/kg). The eticlopride-induced increase in DARPP-32 phosphorylation was also decreased by pretreatment with the D(1) receptor antagonist SCH 23390 (0.125 and 0.25 mg/kg) and completely reversed by combined pretreatment with SCH 23390 (0.25 mg/kg) plus SCH 58261 (10 mg/kg). SCH 23390, but not SCH 58261, abolished the increase in DARPP-32 caused by cocaine (15 mg/kg). The results indicate that, in vivo, the state of phosphorylation of DARPP-32 and, by implication, the activity of protein phosphatase-1 are regulated by tonic activation of D(1), D(2), and A(2A) receptors. The results also underscore the fact that the adenosine system plays a role in the generation of responses to dopamine D(2) antagonists in vivo.