Extracellular Concentrations Of Norepinephrine Research Articles

Role of ionotropic glutamate receptors in the regulation of hippocampal norepinephrine output in vivo

In vitro evidence indicates that norepinephrine release in the mammalian hippocampus is modulated by glutamate receptors. With the use of microdialysis, we have now evaluated the role of ionotropic glutamate receptors in the regulation of hippocampal norepinephrine output in vivo. Stimulation of N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors by local administration of NMDA (1–100 μM) resulted in a concentration-dependent decrease in the extracellular concentration of norepinephrine in the hippocampus of freely moving rats, whereas the blockade of these receptors with MK801 (1–100 μM) induced a concentration-dependent increase in norepinephrine output. Activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptors with AMPA (1–100 μM) resulted in a biphasic effect on the extracellular norepinephrine concentration, with a decrease in this parameter apparent at 10 μM and an increase at 100 μM. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione had no effect on norepinephrine output. The GABA A receptor antagonist bicuculline (10 μM) prevented the decrease in hippocampal norepinephrine output induced by either NMDA or 10 μM AMPA. Our results thus implicate ionotropic glutamate receptors as key regulators of norepinephrine release in the hippocampus and may therefore provide a basis for the development of new drugs for stress-related disorders.

The effect of progesterone on spontaneous and agonist-evoked contractions of the rat aorta and portal vein.

The mechanisms underlying the suppression of vasocontractility caused by progesterone were investigated by studying changes in the contractile force of rat isolated aorta and portal vein, induced by altering extracellular concentrations of noradrenaline (NA) potassium ions (K+) and calcium ions (Ca2+). In the aorta, progesterone (10 microM) had a general suppressive effect on NA-, Ca2+- and K+-induced contractions. In contrast, in the portal vein a more selective suppression of contractions was observed. Both tonic and phasic components of contractions induced by cumulative addition of Ca2+ to tissues equilibrated in Ca2+-free saline were suppressed. The phasic but not tonic components of contractions induced by NA addition were suppressed. There was no significant effect on tonic contractions induced by elevated (40-120 mM) K+, but a concentration-dependent suppression of the phasic component of contractions was observed during depolarisation with smaller elevations of K+ concentrations (5-20 mM). These results suggest that on the portal vein the suppressive effect of progesterone is due to a potassium channel opening action, whilst on the aorta a different or additional mechanism of suppression exists.

Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective α2A-adrenoceptor antagonism

Biogenic amines such as norepinephrine, dopamine, and serotonin play a well-described role in the treatment of mood disorders and some types of pain. As alpha2A-adrenoceptors regulate the release of these neurotransmitters, we examined the therapeutic potential of BRL 44408, a potent (Ki=8.5 nM) and selective (>50-fold) alpha2A-adrenoceptor antagonist (K(B)=7.9 nM). In rats, BRL 44408 penetrated the central nervous system resulting in peak brain and plasma concentrations of 586 ng/g and 1124 ng/ml, respectively. In a pharmacodynamic assay, pretreatment with BRL 44408 to rats responding under a fixed-ratio 30 operant response paradigm resulted in a rightward shift of the clonidine dose-response curve, an effect indicative of alpha2-adrenoceptor antagonism in vivo. Consistent with presynaptic autoreceptor antagonism and tonic regulation of neurotransmitter release, acute administration of BRL 44408 elevated extracellular concentrations of norepinephrine and dopamine, but not serotonin, in the medial prefrontal cortex. Additionally, BRL 44408, probably by inhibiting alpha2A heteroceptors, produced a significant increase in cortical levels of acetylcholine. In the forced swim test and schedule-induced polydipsia assay, BRL 44408 produced an antidepressant-like response by dose-dependently decreasing immobility time and adjunctive water intake, respectively, while in a model of visceral pain, BRL 44408 exhibited analgesic activity by decreasing para-phenylquinone (PPQ)-induced abdominal stretching. Finally, BRL 44408 did not produce deficits in overall motor coordination nor alter general locomotor activity. This preclinical characterization of the neurochemical and behavioural profile of BRL 44408 suggests that selective antagonism of alpha2A-adrenoceptors may represent an effective treatment strategy for mood disorders and visceral pain.

The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex

Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia. Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP). In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat. The top of an activity chamber was modified to allow us to perform microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat. PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC). Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC. Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels. Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia. Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models. Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs.

The novel nicotinic receptor antagonist, N, N′-dodecane-1,12-diyl- bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked [ 3H]norepinephrine overflow from rat hippocampal slices

Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N, N′-dodecane-1,12-diyl- bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC 50 = 2 nM) inhibits nicotine-evoked striatal [ 3H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [ 3H]NE release from rat hippocampal slices (EC 50 = 50 μM). bPiDDB inhibited (IC 50 = 430 nM; I max = 90%) [ 3H]NE release evoked by 30 μM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the α7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [ 3H]NE release (IC 50 = 31 and 275 nM, respectively; I max = 91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [ 3H]DA release from striatum than those mediating nicotine-evoked [ 3H]NE release from hippocampus.

Extracellular monoamines and their metabolites in the mediobasal hypothalamus--median eminence of anestrous and estrous ewes during CRF treatment.

In order to clarify the effect of exogenous corticotropin-releasing factor (CRF) on catecholaminergic and serotoninergic system activity in the mediobasal hypothalamus-median eminence (MBH-ME) of ewes the changes in extracellular levels of noradrenaline (NA) and serotonin (5HT), and main metabolites of monoamines, 4-hydroxy-3-methoxyphenylglycol (MHPG), 3,4-dihydroxy-phenylacetic acid (DOPAC), homovanilic acid (HVA), and 5-hydroxy-indolo-3-acetic acid (5-HIAA) were quantified in the perfusates collected from MBH-ME. NA, 5-HT and monoamine metabolites in the perfusates were analyzed using high performance liquid chromatography with electrochemical detection. CRF induced a rise in extracellular concentration of NA and 5-HT only in the estrous ewes prior to a preovulatory LH surge. CRF treatment caused a heterogenous effect on extra-cellular concentrations of 5-HT in ewes during the preovulatory LH surge. Except for DOPAC and HVA in some estrous ewes during the preovulatory LH surge, CRF caused an increase in monoamine metabolites levels in the MBH-ME in anestrous and estrous animals. These results indicate that CRF facilities NA release in the MBH-ME during the presurge LH period in ewes, and that CRF increases metabolic activities of the monoaminergic systems in this structure in the anestrous and estrous ewes, except dopaminergic system in the ewes during the preovulatory LH surge. It is suggested that: 1) the responses of monoaminergic systems activity in the MBH-ME to CRF in large degree is dependent upon physiological state of ewes and 2) in some endocrinological phases CRF may affect LHRH and other hypothalamic hormone secretion indirectly by altering monoaminergic system activity in the MBH-ME.

Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure

Manganese (Mn) is an essential trace element, but overexposure is characterized by Parkinson's like symptoms in extreme cases. Previous studies have shown that Mn accumulation is exacerbated by dietary iron deficiency (ID) and disturbances in norepinephrine (NE) have been reported. Because behaviors associated with Mn neurotoxicity are complex, the goal of this study was to examine the effects of Mn exposure and ID-associated Mn accumulation on NE uptake in synaptosomes, extracellular NE concentrations, and expression of NE transport and receptor proteins. Sprague–Dawley rats were assigned to four dietary groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn exposure (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn (IDMn). 3H-NE uptake decreased significantly ( R = − 0.753, p = 0.001) with increased Mn concentration in the locus coeruleus, while decreased Fe was associated with decreased uptake of 3H-NE in the caudate putamen ( R = 0.436, p = 0.033) and locus coeruleus ( R = 0.86; p < 0.001). Extracellular concentrations of NE in the caudate putamen were significantly decreased in response to Mn exposure and ID ( p < 0.001). A diverse response of Mn exposure and ID was observed on mRNA and protein expression of NE transporter (NET) and α 2 adrenergic receptor. For example, elevated brain Mn and decreased Fe caused an approximate 50% decrease in NET and α 2 adrenergic receptor protein expression in several brain regions, with reductions in mRNA expression also observed. These data suggest that Mn exposure results in a decrease in NE uptake and extracellular NE concentrations via altered expression of transport and receptor proteins.

Noradrenergic Regulation of GABAergic Inhibition of Main Olfactory Bulb Mitral Cells Varies as a Function of Concentration and Receptor Subtype

The main olfactory bulb (MOB) receives a rich noradrenergic innervation from the pontine nucleus locus coeruleus (LC). Previous studies indicate that norepinephrine (NE) modulates the strength of GABAergic inhibition in MOB. However, the nature of this modulation and the NE receptors involved remain controversial. The goal of this study was to investigate the role of NE receptor subtypes in modulating the GABAergic inhibition of mitral cells using patch-clamp electrophysiology in rat MOB slices. NE concentration dependently and bi-directionally modulated GABA(A) receptor-mediated spontaneous and miniature inhibitory postsynaptic currents (sIPSCs/mIPSCs) recorded in mitral cells. Low doses of NE suppressed sIPSCs and mIPSCs because of activation of alpha2 receptors. Intermediate concentrations of NE increased sIPSCs and mIPSCs primarily because of activation of alpha1 receptors. In contrast, activation of beta receptors increased sIPSCs but not mIPSCs. These results indicate that NE release regulates the strength of GABAergic inhibition of mitral cells depending on the NE receptor subtype activated. Functionally, the differing affinity of noradrenergic receptor subtypes seems to allow for dynamic modulation of GABAergic inhibition in MOB as function of the extracellular NE concentration, which in turn, is regulated by behavioral state.

β2‐adrenoceptors are critical for antidepressant treatment of neuropathic pain

Tricyclic antidepressants (TCAs) are one of the first-line pharmacological treatments against neuropathic pain. TCAs increase the extracellular concentrations of noradrenaline and serotonin by blocking the reuptake transporters of these amines. However, the precise downstream mechanism leading to the therapeutic action remains identified. In this work, we evaluated the role of adrenergic receptors (ARs) in the action of TCAs. We used pharmacological and genetic approaches in mice to study the role of ARs in the antiallodynic action of the TCA nortriptyline. Peripheral neuropathy was induced by the insertion of a polyethylene cuff around the main branch of the sciatic nerve. The specific role of beta(2)-AR was evaluated by studying beta(2)-AR(-/-) mice. We used von Frey filaments to assess mechanical allodynia. The antiallodynic action of nortriptyline was not affected by cotreatment with the alpha(2)-AR antagonist yohimbine, the beta(1)-AR antagonists atenolol or metoprolol, or the beta(3)-AR antagonist SR 59230A. On the contrary, the beta-AR antagonists propranolol or sotalol, the beta(1)/beta(2)-AR antagonists alprenolol or pindolol, or the specific beta(2)-AR antagonist ICI 118,551 blocked the action of nortriptyline. The effect of nortriptyline was also totally absent in beta(2)-AR-deficient mice. Stimulation of beta(2)-AR is necessary for nortriptyline to exert its antiallodynic action against neuropathic pain. These findings provide new insight into the mechanism by which antidepressants alleviate neuropathic pain. Our results also raise the question of a potential incompatibility between beta-blockers that affect beta(2)-AR and antidepressant drugs in patients treated for neuropathic pain.

Preclinical investigations into the antipsychotic potential of the novel histamine H3 receptor antagonist GSK207040

To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential. Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-fos immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations. GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-fos expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg. The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H(3) receptor antagonism versus positive symptoms is less likely, at least following acute administration.

Effect of co-administration of a serotonin–noradrenaline reuptake inhibitor and a dopamine agonist on extracellular monoamine concentrations in rats

Recent studies have shown that dopamine agonists are useful for the treatment of not only Parkinson's disease, but also major depressive disorders. However, while these dopamine agonists provide a new treatment strategy for major depressive disorders, such as treatment-resistant cases, the antidepressant effect of dopamine agonists has yet to be investigated. To examine the mechanism of the antidepressive effect of dopamine agonists, we investigated the acute effect of the dopamine receptor agonist, cabergoline, and the serotonin–noradrenaline reuptake inhibitor, milnacipran, on extracellular noradrenaline, dopamine and serotonin concentrations in the rat medial prefrontal cortex. There was a greater increase in extracellular noradrenaline concentrations when acute milnacipran (30 mg/kg intraperitoneally) was administered after acute high-dose cabergoline (1 and 2 mg/kg subcutaneously) than when acute milnacipran was administered following acute vehicle or low-dose cabergoline (0.25 mg/kg subcutaneously). There were no significant differences noted in the dopamine or serotonin concentrations. These results suggest that the addition of cabergoline has the potential to strengthen the antidepressant effects of milnacipran and that the mechanism of action of the antidepressive effect of dopamine agonists might be due to enhancement of induced increases of extracellular noradrenaline.

Inhibition of uptake 2 (or extraneuronal monoamine transporter) by normetanephrine potentiates the neurochemical effects of venlafaxine

Two distinct norepinephrine (NE) transporter mechanisms (uptake 1 and uptake 2) regulate extracellular NE concentrations. An association has been observed between the gradual improvement in patients treated with antidepressants that inhibit the NE transporter (NET/uptake 1) and increases in urinary normetanephrine, the O-methylated NE metabolite and potent inhibitor of uptake 2. These observations led to the hypothesis that increased levels of normetanephrine, and consequently inhibition of uptake 2, may partly be responsible for the clinical efficacy of some antidepressants. To investigate this hypothesis, we employed microdialysis techniques in the rat frontal cortex to monitor extracellular changes in normetanephrine following chronic administration of the clinically effective antidepressant, venlafaxine (a serotonin (5-HT) and NE reuptake inhibitor). We evaluated the neurochemical effects of inhibiting uptake 2 alone, or in conjunction with venlafaxine, on extracellular levels of NE and 5-HT. Chronic venlafaxine administration (14 days, 10 mg/kg, s.c.) elicited significant increases in cortical NE and 5-HT while producing a non-significant trend to increase cortical levels of normetanephrine. Additional studies revealed that combining normetanephrine with venlafaxine (10 mg/kg, i.p.), at a dose of normetanephrine (10 mg/kg, i.p.) that did not produce changes in extracellular levels of NE on its own, potentiated antidepressant-induced increases in extracellular NE. We also report mouse behavioral data involving the tail suspension test that complement the neurochemical observations. These preclinical findings, taken together, suggest that inhibiting both uptake 1 and uptake 2 via venlafaxine and normetanephrine, respectively, elicits a greater increase in cortical levels of NE than inhibiting either transporter alone.

Theory of active antidepressants: A nonsynaptic approach to the treatment of depression

Although depression is one of the major neuropsychiatric disorders, the success rate of medication for any drug is about 60%, which means that approximately 40% of the patients does not respond to the initial treatment. The major aim of this review is to provide a possible explanation for the relative inefficacy of currently used antidepressants and to propose a novel mechanism of action, which might improve the success rate of clinical treatment. According to the monoamine theory the most important neurochemical process in depression is the impairment of monoaminergic neurotransmission and the concomitant decrease of extracellular concentration of noradrenaline and/or serotonin. Since the vast majority of monoaminergic varicosities makes no synaptic contact but is able to release transmitters directly into the extrasynaptic space, the monoaminergic neurotransmission is predominantly nonsynaptic in nature. Depression can be regarded, therefore, as a disease, which is developed (at least in part) on the basis of the impairment of nonsynaptic interactions and the effective treatment has to improve this non-conventional communication in the nervous system. The currently used antidepressants (reuptake inhibitors, negative feedback inhibitors, monoamino oxidase inhibitors) can increase the monoamine levels in the extracellular space only if the monoaminergic cells are electrically active and without an action potential-induced vesicular exocytosis these compounds are ineffective. It is proposed that a selective and moderate induction of the carrier-mediated release of NA and 5-HT might be a better therapeutic approach to the treatment of depression, since this new class of antidepressants, the so-called ‘active antidepressants’ have a mechanism of action, which is independent from the electrical activity of monoaminergic cells, therefore the extrasynaptic concentration of monoamines and thereby the nonsynaptic communication can be enhanced more efficiently.

Alterations in prefrontal glutamatergic and noradrenergic systems following MK-801 administration in rats prenatally exposed to methylazoxymethanol at gestational day 17

Prenatal methylazoxymethanol (MAM) administration at gestational day 17 has been shown to induce in adult rats schizophrenia-like behaviours as well as morphological and/or functional abnormalities in structures such as the hippocampus, medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), consistent with human data. The aim of the present study was to further characterize the neurochemical alterations associated with this neurodevelopmental animal model of schizophrenia. We performed simultaneous measurements of locomotor activity and extracellular concentrations of glutamate, dopamine and noradrenaline in the mPFC and the NAcc of adult rats prenatally exposed to MAM or saline after acute systemic injection of a noncompetitive NMDA antagonist, MK-801 (0.1 mg/kg s.c.). A significant attenuation of the MK-801-induced increase in glutamate levels associated with a potentiation of the increase in noradrenaline concentrations was found in the mPFC of MAM-exposed rats, whereas no significant change was observed in the NAcc. MAM-exposed rats also exhibited an exaggerated locomotor hyperactivity, in line with the exacerbation of symptoms reported in schizophrenic patients after administration of noncompetitive NMDA antagonists. Given the importance of the mPFC in regulating the hyperlocomotor effect of NMDA antagonists, our results suggest that the prefrontal neurochemical alterations induced by MK-801 may sustain the exaggerated locomotor response in MAM-exposed rats.

Difference in magnitude of psychostimulant-induced extracellular norepinephrine in the ventral tegmental area contributes to discrepant prefrontal dopamine outflow

The dopamine (DA) efflux in the medial prefrontal cortex (mPFC) can be modulated by the interaction between afferent norepinephrine (NE) and somatodendritic DA in the ventral tegmental area (VTA). However, it is unclear how locally administered amphetamine (AMPH) or cocaine in the VTA results in discrepant response of DA efflux in the mPFC. In this study, intra-VTA infusion of AMPH (1000 microM) or cocaine (200 microM) in anesthetized rats was employed to study the concurrent profile of extracellular DA level in the VTA and mPFC. In addition, the extracellular NE levels during the intra-VTA infusion of these two psychostimulants were analyzed to compare their effects on prefrontal DA efflux. During the intra-VTA infusion of AMPH, both extracellular DA and NE increased significantly in the VTA (270 +/- 12% and 819 +/- 40%, respectively). Meanwhile, the DA efflux in the mPFC elevated significantly. During the intra-VTA infusion of cocaine, the extracellular DA and NE in the VTA also increased (271 +/- 21% and 150 +/- 15%, respectively). However, the DA efflux decreased significantly in the mPFC. Noteworthy, the increase of extracellular NE in the VTA was much more robust via AMPH infusion, as compared with cocaine. It is suggested that AMPH and cocaine enhance the extracellular NE concentrations in the VTA in different magnitudes, which in turn contribute to discrepant profiles of distal DA efflux in the mPFC.

Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat

The vagus nerve is an important source of afferent information about visceral states and it provides input to the locus coeruleus (LC), the major source of norepinephrine (NE) in the brain. It has been suggested that the effects of electrical stimulation of the vagus nerve on learning and memory, mood, seizure suppression, and recovery of function following brain damage are mediated, in part, by the release of brain NE. The hypothesis that left vagus nerve stimulation (VNS) at the cervical level results in increased extracellular NE concentrations in the cortex and hippocampus was tested at four stimulus intensities: 0.0, 0.25, 0.5, and 1.0 mA. Stimulation at 0.0 and 0.25 mA had no effect on NE concentrations, while the 0.5 mA stimulation increased NE concentrations significantly in the hippocampus (23%), but not the cortex. However, 1.0 mA stimulation significantly increased NE concentrations in both the cortex (39%) and hippocampus (28%) bilaterally. The increases in NE were transient and confined to the stimulation periods. VNS did not alter NE concentrations in either structure during the inter-stimulation baseline periods. No differences were observed between NE levels in the initial baseline and the post-stimulation baselines. These findings support the hypothesis that VNS increases extracellular NE concentrations in both the hippocampus and cortex.

Evidence that Cortical Dopamine is a Co-Transmitter in Noradrenergic Neurons

Dopamine and noradrenaline in the prefrontal cortex modulate superior cognitive functions and are implicated in the aetiology of depressive and psychotic symptoms. Experimental evidence reveals parallel variations in extracellular concentration of both catecholamines in the cerebral cortex. In this review, data are presented suggesting that extracellular dopamine in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for noradrenaline and as co-transmitter. Since the release of noradrenaline is controlled by alpha2-autoreceptors, it follows that release and extracellular concentration of both dopamine and noradrenaline in the cerebral cortex are controlled by alpha2-autoreceptors and noradrenaline transporter, whereas dopamine receptors and dopamine transporter do not seem to be involved in these processes. Atypical antipsychotics such as clozapine, and antidepressants such as mirtazapine, increase noradrenaline and dopamine release throughout the cerebral cortex, but not, or to a lesser extent, in subcortical areas. On the other hand, D2 selective drugs such as haloperidol, are potent in increasing dopamine levels in subcortical dopaminergic areas but are ineffective on dopamine and noradrenaline levels in the prefrontal cortex. Local stimulation or inhibition of locus coeruleus neurons by means of drug perfusion or electrical stimulation gives rise to parallel variations of noradrenaline and dopamine levels in the cerebral cortex, but not in prevalently dopaminergic subcortical areas. Extracellular dopamine of noradrenergic origin might represent the major portion of total extracellular dopamine not only in cortices with scarce dopaminergic innervation, such as the parietal and occipital cortex, but also in the densely innervated medial prefrontal cortex. In conclusion, drugs acting on the co-release mechanism of noradrenaline and dopamine may represent a tool with which to increase the selective output of dopamine in the cerebral cortex.

Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat

Atomoxetine is a selective inhibitor of norepinephrine transporters and is currently being used in the pharmacotherapy of attention deficit/hyperactivity disorder (ADHD). We have previously shown that atomoxetine increased extracellular (EX) concentrations of norepinephrine and dopamine in prefrontal cortex, but unlike the psychostimulant methylphenidate, did not alter dopamine EX in nucleus accumbens or striatum. Using the in vivo microdialysis technique in rat, we investigated the effects of atomoxetine on norepinephrine EX and dopamine EX concentrations in several other brain regions and also evaluated the role of inhibitory autoreceptors on atomoxetine-induced increases of norepinephrine EX concentrations. Atomoxetine (3 mg/kg i.p.) increased norepinephrine EX robustly in prefrontal cortex, occipital cortex, lateral hypothalamus, dorsal hippocampus and cerebellum, suggesting that norepinephrine EX is increased throughout the brain by atomoxetine. In lateral hypothalamus and occipital cortex where dopamine EX was quantifiable, atomoxetine did not increase dopamine EX concentrations, in contrast to parallel increases of norepinephrine EX and dopamine EX in prefrontal cortex, indicating a unique effect in prefrontal cortex. Administration of the α 2-adrenergic antagonist idazoxan 1 h after atomoxetine resulted in increases in prefrontal cortical norepinephrine efflux greater than either compound alone, indicating an attenuating effect of the adrenergic autoreceptors on norepinephrine efflux.

Subchronic milnacipran treatment increases basal extracellular noradrenaline concentrations in the medial prefrontal cortex of rats

In this study, we investigated the acute effects of milnacipran, a serotonin–noradrenaline reuptake inhibitor, following subchronic treatment with milnacipran (30 mg/kg periorally for 7 days) on extracellular noradrenaline, dopamine and serotonin concentrations in the medial prefrontal cortex. Subchronic administration of milnacipran produced significantly higher basal levels of extracellular noradrenaline. Acute milnacipran administration following subchronic milnacipran treatment for 7 days produced a greater increase in extracellular noradrenaline than a single dose of milnacipran alone. The present results suggest that subchronic milnacipran treatment enhances noradrenergic neural transmission beyond that achieved with acute administration of milnacipran alone, but has no effect on serotonergic or dopaminergic neural transmission.

Effect of milnacipran on extracellular monoamine concentrations in the medial prefrontal cortex of rats pre-treated with lithium

Antidepressants are effective in most patients with depression, but sometimes have sub-optimal effects. Thus, there is a need to use more powerful antidepressants when dealing with treatment-resistant cases. Lithium carbonate is widely used for this purpose. We investigated the acute effects of milnacipran, a serotonin-noradrenaline reuptake inhibitor, on extracellular serotonin, dopamine and noradrenaline concentrations, in the rat medial prefrontal cortex. The effects of milnacipran were examined in rats following 7 days of treatment with lithium, and in untreated controls. The lithium group had significantly greater basal levels of extracellular serotonin than the control group. Milnacipran (3 mg/kg) combined with lithium treatment caused a greater increase in extracellular noradrenaline and dopamine levels than milnacipran alone. Milnacipran (3 and 30 mg/kg) combined with lithium treatment also caused a greater increase in extracellular serotonin levels than milnacipran alone. Thus, lithium might augment the antidepressant effects of serotonin-noradrenaline reuptake inhibitors by augmenting serotonin release.