Chronic Reboxetine Desensitizes Terminal but not Somatodendritic α2-Adrenoceptors Controlling Noradrenaline Release in the Rat Dorsal Hippocampus

Parini, Stefania; Renoldi, Giuliano; Battaglia, Agatino; Invernizzi, Roberto William

doi:10.1038/sj.npp.1300661

Cited by 34 publications

(17 citation statements)

References 44 publications

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“…The effects of chronic NET blockade on NE signaling may differ between forebrain and brainstem regions. In support of this hypothesis, the decrease in b 1 -adrenergic receptors observed after chronic DMI treatment was much more evident in the cortex compared to subcortical regions (Bergstrom and Kellar, 1979), and a 2 -adrenergic receptor desensitization after chronic reboxetine was observed in the hippocampus but not the LC (Parini et al, 2005). Our results suggest that the compensatory downregulation of NE signaling may preferentially occur in the forebrain.…”

Section: Chronic Net Inactivation Has Both Proconvulsant and Anticonvsupporting

confidence: 73%

The Effects of Chronic Norepinephrine Transporter Inactivation on Seizure Susceptibility in Mice

Ahern

Javors

Eagles

et al. 2005

Neuropsychopharmacol

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Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.

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Section: Chronic Net Inactivation Has Both Proconvulsant and Anticonvsupporting

confidence: 73%

The Effects of Chronic Norepinephrine Transporter Inactivation on Seizure Susceptibility in Mice

Ahern

Javors

Eagles

et al. 2005

Neuropsychopharmacol

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“…Although arrestins are present in both (64), the postsynaptic compartment contains another player, spinophilin (65,66), which has been shown to functionally antagonize arrestin actions at the ␣ 2A AR (49). Herein lies a potential explanation for previous evidence of differential regulation of terminal versus somatodendritic ␣ 2A AR expression by chronic antidepressant (28,63,67). As well, although heteroreceptors have certainly been implicated in the antidepressant response (18, 68), we have not been able to examine ␣ 2A autoreceptors specifically, which remains a goal of future studies.…”

Section: Discussionmentioning

confidence: 91%

“…A mechanistic explanation for this phenomenon has been lacking, although it has been postulated to result from the actions of elevated NE levels in the brain. Experimental evidence suggests that synaptic concentrations of NE are basally around 1 nM, and approach 10 nM following treatment with reuptake inhibitors (28,57,63). However, the ability of such a physiological concentration of NE to affect receptor expression has not been shown.…”

Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Is an Arrestin-biased Ligand at the α2A-Adrenergic Receptor Driving Receptor Down-regulation in Vitro and in Vivo

Cottingham

Chen

Jiao

et al. 2011

Journal of Biological Chemistry

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The neurobiological mechanisms of action underlying antidepressant drugs remain poorly understood. Desipramine (DMI) is an antidepressant classically characterized as an inhibitor of norepinephrine reuptake. Available evidence, however, suggests a mechanism more complex than simple reuptake inhibition. In the present study, we have characterized the direct interaction between DMI and the α2A-adrenergic receptor (α2AAR), a key regulator of noradrenergic neurotransmission with altered expression and function in depression. DMI alone was found to be sufficient to drive receptor internalization acutely and a robust down-regulation of α2AAR expression and signaling following prolonged stimulation in vitro. These effects are achieved through arrestin-biased regulation of the receptor, as DMI selectively induces recruitment of arrestin but not activation of heterotrimeric G proteins. Meanwhile, a physiologically relevant concentration of endogenous agonist (norepinephrine) was unable to sustain a down-regulation response. Prolonged in vivo administration of DMI resulted in significant down-regulation of synaptic α2AAR expression, a response that was lost in arrestin3-null animals. We contend that direct DMI-driven arrestin-mediated α2AAR down-regulation accounts for the therapeutically desirable but mechanistically unexplained adaptive alterations in receptor expression associated with this antidepressant. Our results provide novel insight into both the pharmacology of this antidepressant drug and the targeting of the α2AAR in depression.

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“…Even at the highest dose of DOV 102,677 tested, DA levels in the prefrontal cortex were 80% higher than those of 5-HT, while in the n. accumbens, the overall levels were lower and more equivalent. This suggests that DOV 102,677 may exert preferential effects on neurotransmitter levels in the prefrontal cortex, due in part to differences in transporter populations (low densities of DAT and a higher affinity of DA for the NET compared to NE), (Tanda et al, 1997;Moron et al, 2002), and possibly, interactions with presynaptic receptors to modulate neurotransmitter release (Garris et al, 2003;Parini et al, 2005). The regional differences in potency of DOV 102,677 in elevating neurotransmitter levels indicate that DOV 102,677 may also have different clinical indications, depending on dose.…”

Section: Discussionmentioning

confidence: 97%

Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677

et al. 2006

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1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.

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Chronic Reboxetine Desensitizes Terminal but not Somatodendritic α2-Adrenoceptors Controlling Noradrenaline Release in the Rat Dorsal Hippocampus

Cited by 34 publications

References 44 publications

The Effects of Chronic Norepinephrine Transporter Inactivation on Seizure Susceptibility in Mice

The Effects of Chronic Norepinephrine Transporter Inactivation on Seizure Susceptibility in Mice

The Antidepressant Desipramine Is an Arrestin-biased Ligand at the α2A-Adrenergic Receptor Driving Receptor Down-regulation in Vitro and in Vivo

Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677

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