Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins

Although morphine induces both analgesia and dependence through -opioid receptors (MORs), the respective contributions of the intracellular effectors engaged by MORs remain unknown. To examine the contribution of G-protein-gated inwardly rectifying K ϩ (GIRK, Kir3) channels to morphine dependence and analgesia, we quantified naloxone-precipitated withdrawal behavior and morphine analgesia using GIRK knock-out ( Ϫ/Ϫ ) mice. The morphine withdrawal syndrome was strongly attenuated, whereas morphine analgesia was mostly preserved in mice lacking both GIRK2 and GIRK3 (GIRK2/3 Ϫ/Ϫ mice). In acute slices containing the locus ceruleus (LC) from GIRK2/3 Ϫ/Ϫ mice, the increase in spontaneous firing typically associated with morphine withdrawal was absent. Moreover, although morphine elicited normal presynaptic inhibition in the LC, postsynaptic GIRK currents were completely abolished in GIRK2/3 Ϫ/Ϫ mice. Altogether, these data suggested that morphine-evoked postsynaptic inhibition of the LC was required for the induction of dependence. Consistent with this hypothesis, morphine withdrawal behavior was rescued in GIRK2/3 Ϫ/Ϫ mice by ablation of adrenergic fibers using the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Our data suggest that inhibition of adrenergic tone is required for the induction of dependence, and that channels containing GIRK2 and GIRK3 serve as an inhibitory gate.

Section: Discussionsupporting

confidence: 78%

Absence and Rescue of Morphine Withdrawal in GIRK/Kir3 Knock-out Mice

Cruz¹,

Berton²,

Sollini³

et al. 2008

“…We also combined PCPA and ␣MT injections. PCPA treatments in mouse pups have been found previously to cause a 80 -50% decrease of brain 5-HT levels (Rebsam et al, 2005;Dailly et al, 2006). Anti-serotonin immunoreactivity showed a reduction of serotonin-immunolabeled axons after PCPA injections (Fig.…”

Section: Neurotransmitter Phenotypementioning

confidence: 64%

“…Our data failed to show an increase in cell death in the cerebral cortex. However, these pharmacological treatments are not specific and may cause only partial monoamine depletion [80% reduction of 5-HT in the cortex (Dailly et al, 2006); 50% in the whole brain (Rebsam et al, 2005)]. To avoid any confounding effect of pharmacological treatment, we used mice lacking the transcription factor Pet-1.…”

Section: Inhibition Of Monoamine Synthesismentioning

confidence: 99%

Developmental Cell Death Is Enhanced in the Cerebral Cortex of Mice Lacking the Brain Vesicular Monoamine Transporter

Stankovski¹,

Alvarez²,

Ouimet

et al. 2007

Neurotransmitters have emerged as important players in the control of programmed cell death in the cerebral cortex. We report that genetic depletion of serotonin, dopamine, and norepinephrine in mice lacking the vesicular monoamine transporter (VMAT2 KO mice) causes an increase in cell death in the superficial layers of the cingulate and retrosplenial cortices during early postnatal life (postnatal days 0 -4). Electron microscopy and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling indicated that this represents a form of apoptosis. Caspase-3 and -9 are over activated in the VMAT2 KO cortex and Bcl-X L is downregulated, whereas the apoptosis-inducing factor caspase-8 and FasL/FasR pathway are not involved. Partial inhibition of serotonin or/and catecholamine synthesis by pharmacological treatments or genetic reduction of serotonin neuron number in mice lacking the transcription factor Pet-1 (pheochromocytoma 12 E26 transformation-specific) did not modify the cell death ratios in the cerebral cortex. However, when monoamine oxidase type A was invalidated in the VMAT2 KO background (VMAT2-MAOA DKO mice), increases in 5-HT levels coincided with a reduction of cell death and a normalization of Bcl-X L expression. trkB signaling is not implicated in the anti-apoptotic effects of MAOA inhibition because BDNF mRNA levels were unchanged in VMAT2-MAOA DKO mice and because the massive cell death in the cerebral cortex of trkB KO mice is also reverted by genetic invalidation of the MAOA gene. Finally the broad 5-HT 2 receptor agonist (Ϫ)-2,5-dimethoxy-4-iodoamphetamine hydrochloride prevented the increase in cell death of VMAT2 KO mice. Altogether, these results suggest that high levels of serotonin, acting through 5-HT 2 receptors, have neuroprotective action on cortical neurons by controlling Bcl-X L mRNA levels and that this action is independent of trkB signaling.

“…The reasons for these contradictory results are not clear, but there are several possible explanations. Whereas PCPA is very effective in depleting central 5-HT, it can also deplete peripheral 5-HT (Koe and Weissman, 1966) and other monoamines (Reader and Gauthier, 1984;Dailly et al, 2006), and does not affect neuropeptides colocalized in 5-HT neurons, such as thyrotropin-releasing hormone and substance P (Walker et al, 1990;Przegalinski et al, 1992). Possibly for these reasons, data obtained using PCPA have contributed previously to erroneous conclusions about the role of 5-HT in sleep (Jouvet, 1999).…”

Section: Role Of Central 5-ht Neurons In Respiratory Controlmentioning

confidence: 99%

Defects in Breathing and Thermoregulation in Mice with Near-Complete Absence of Central Serotonin Neurons

Hodges¹,

Tattersall²,

Harris³

et al. 2008

291

345

f/f/p mice was decreased by 50% compared with wild-type mice, whereas baseline ventilation and the hypoxic ventilatory response were normal. In addition, Lmx1b f/f/p mice rapidly became hypothermic when exposed to an ambient temperature of 4°C, decreasing core temperature to 30°C within 120 min. This failure of thermoregulation was caused by impaired shivering and nonshivering thermogenesis, whereas thermosensory perception and heat conservation were normal. Finally, intracerebroventricular infusion of 5-HT stimulated baseline ventilation, and rescued the blunted hypercapnic ventilatory response. These data identify a previously unrecognized role of 5-HT neurons in the CO 2 chemoreflex, whereby they enhance the response of the rest of the respiratory network to CO 2 . We conclude that the proper function of the 5-HT system is particularly important under conditions of environmental stress and contributes significantly to the hypercapnic ventilatory response and thermoregulatory cold defense.