Noradrenaline In Frontal Cortex Research Articles

Binge-Like Eating Attenuates Nisoxetine Feeding Suppression, Stress Activation, and Brain Norepinephrine Activity

Stress is often associated with binge eating. A critical component of the control of stress is the central norepinephrine system. We investigated how dietary-induced binge eating alters central norepinephrine and related behaviors. Young male Sprague Dawley rats received calorie deprivation (24 h) and /or intermittent sweetened fat (vegetable shortening with sucrose; 30 min) twice a week for 10 weeks. The groups were Restrict Binge (calorie deprivation/sweetened fat), Binge (sweetened fat), Restrict (calorie deprivation), and Naive (no calorie deprivation/no sweetened fat). Dietary-induced binge eating was demonstrated by Restrict Binge and Binge, which showed an escalation in 30-min intake over time. Feeding suppression following nisoxetine (3 mg/kg; IP), a selective norepinephrine reuptake inhibitor, was not evident in Restrict Binge (Restrict Binge: 107±13, Binge: 52±9, Restrict: 80±8, Naive: 59±13% of saline injection at 1 h). In subsequent experiments with Restrict Binge and Naive, Restrict Binge had reduced corticosterone (Restrict Binge: 266±25; Naive: 494±36 ng/ml) and less feeding suppression (Restrict Binge: 81±12, Naive: 50±11% of non-restraint intake at 30 min) following restraint stress (1 h). Dietary-induced binge eating in Restrict Binge was not altered by a dorsal noradrenergic bundle lesion caused by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), but frontal cortex norepinephrine was positively correlated with the average 30-min intake post-lesion (0.69; p<0.01). In a separate set of animals, single-unit in vivo electrophysiological recording of locus coeruleus–norepinephrine neural activity demonstrated reduced sensory-evoked response as a consequence of the Restrict Binge schedule (Restrict Binge: 8.1±0.67, Naive: 11.9±1.09 Hz). These results, which suggest that a consequence of dietary-induced binge eating is to attenuate the responsiveness of the brain norepinephrine system, will further our understanding of how highly palatable foods dampen the stress neuraxis.

Agomelatine: A novel mechanism of antidepressant action involving the melatonergic and the serotonergic system

The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential. Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex). The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placebo–controlled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25 mg/day, with the possibility of increasing doses to 50 mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatine's efficacy over a longer treatment period.

Neuronal and astroglial responses to the serotonin and norepinephrine neurotoxin: 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine.

1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP) causes long-term loss of forebrain serotonin (5-HT) and norepinephrine (NE) and consequently, is unlike 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its other 2'-analogs that primarily deplete striatal dopamine (DA). In the present investigation into the acute effects of 2'-NH2-MPTP in mice, profound decreases in cortical and hippocampal 5-HT and NE to 10 to 40% of control were observed as early as 30 min post-treatment and lasted throughout the ensuing 21 days. Striatal DA was decreased to 60 to 80% of control during the first 48 h but returned to normal by 72 h. Reactive gliosis, which occurs in response to neurodegeneration was not evident by immunocytochemistry but was detected by enzyme-linked immunosorbent assay, where glial fibrillary acidic protein (GFAP) was increased to 130% of control in cortex, hippocampus, and brain stem 48 to 72 h post-treatment. To explore the possibility that 5-HT modulates the astrocytic response to injury, 2'-NH2-MPTP was used to damage 5-HT axons 2 weeks before administration of the potent DA neurotoxin 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP). Despite a 90% decrement in striatal DA in 2'-NH2-MPTP/2'-CH3-MPTP-treated mice, increases in GFAP were attenuated compared to mice treated with 2'-CH3-MPTP alone. Thus, 2'-NH2-MPTP causes severe and immediate decrements in 5-HT and NE in frontal cortex and hippocampus, yet induces a modest GFAP response compared with other MPTP analogs that have their primary effect on DA. These results demonstrate the importance of obtaining quantitative assessments of GFAP to detect astroglial responses associated with selective damage to neurotransmitter systems with low-density innervation and suggest that serotonin may facilitate the astrocytic response to striatal injury.

The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways.

Agomelatine (S20098) displayed pKi values of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors, respectively. It also interacted with h5-HT2B receptors (6.6), whereas it showed low affinity at native (rat)/cloned, human 5-HT2A (<5.0/5.3) and 5-HT1A (<5.0/5.2) receptors, and negligible (<5.0) affinity for other 5-HT receptors. In antibody capture/scintillation proximity assays, agomelatine concentration dependently and competitively abolished h5-HT2C receptor-mediated activation of Gq/11 and Gi3 (pA2 values of 6.0 and 6.1). As measured by [3H]phosphatidylinositol depletion, agomelatine abolished activation of phospholipase C by h5-HT2C (pKB value of 6.1) and h5-HT2B (pKB value of 6.6) receptors. In vivo, it dose dependently blocked induction of penile erections by the 5-HT2C agonists (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine (Ro60,0175) and 1-methyl-2-(5,8,8-trimethyl-8H-3-aza-cyclopenta[a]inden-3-yl) ethylamine (Ro60,0332). Furthermore, agomelatine dose dependently enhanced dialysis levels of dopamine in frontal cortex of freely moving rats, whereas they were unaffected in nucleus accumbens and striatum. Although the electrical activity of ventrotegmental dopaminergic neurons was unaffected agomelatine, it abolished their inhibition by Ro60,0175. Extracellular levels of noradrenaline in frontal cortex were also dose dependently enhanced by agomelatine in parallel with an acceleration in the firing rate of adrenergic cell bodies in the locus coeruleus. These increases in noradrenaline and dopamine levels were unaffected by the selective melatonin antagonist N-[2-(5-ethyl-benzo[b]thien-3-yl)ethyl] acetamide (S22153) and likely flect blockade of 5-HT2C receptors inhibitory to frontocortical dopaminergic and adrenergic pathways. Correspondingly, distinction to agomelatine, melatonin showed negligible activity 5-HT2C receptors and failed to modify the activity of adrenergic and dopaminergic pathways. In conclusion, in contrast to melatonin, agomelatine behaves as an antagonist at 5-HT2B and 5-HT2C receptors: blockade of the latter reinforces frontocortical adrenergic and dopaminergic transmission.

Neurotransmission of cognition, part 2. Selective NRIs are smart drugs: exploiting regionally selective actions on both dopamine and norepinephrine to enhance cognition.

Selective norepinephrine reuptake inhibitors such as atomoxetine increase both dopamine and norepinephrine in frontal cortex and may thereby enhance cognitive functioning in attention-deficit/hyperactivity disorder.

In vitro and in vivo approaches to the characterization of the alpha2-adrenoceptor.

1. In order to more fully understand the role of the alpha2-adrenoceptor in brain function, a combination of in vitro and in vivo techniques were utilized including radioligand binding, autoradiography, brain microdialysis and antisense oligonucleotides. 2. Binding studies showed the tritiated form of the selective alpha2-adrenoceptor antagonist, RX821002 (methoxy-idazoxan) labelled an apparent single population of sites in rat brain membranes with high affinity (1 nM), for which prazosin had low affinity (1107 nM). Similar studies in rabbit brain membranes found that prazosin and oxymetazoline were able to displace [3H]-RX821002 in a biphasic manner indicating the presence of subtypes of alpha2-adrenoceptors. 3. Receptor autoradiography revealed a distribution of [3H]-RX821002 binding in rat brain consistent with the labelling of all alpha2-adrenoceptor subtypes, namely alpha(2A/D-), alpha2B and alpha2C. 4. In rat, in vivo brain dialysis experiments demonstrated peripherally administered RX821002 elevated basal noradrenaline in frontal cortex and also, although to a lesser extent, in ventral hippocampus. RX821002 was also able to elevate extracellular dopamine in the striatum. 5. A 7-day i.c.v. infusion of an antisense oligonucleotide targeting the alpha(2A/D)-adrenoceptor, resulted in a significant reduction in the autoradiographic density of [3H]-RX821002 binding in specific brain areas, notably the lateral septal nuclei and anterior hypothalamic area. 6. Several years of research by our group has extended our knowledge of the pharmacology and function of the alpha2-adrenoceptor and has provided evidence of the roles of this receptor in the control of monoamine turnover. The successful use of antisense technology to knockdown expression of the alpha(2A/D) subtype provides future opportunities to explore the physiology of this receptor subtype.

Duloxetine (LY 248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate

Duloxetine is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NE) uptake in vitro and in vivo and is 3- to 5-times more effective at inhibiting 5-HT uptake. Duloxetine is a weak inhibitor of dopamine (DA) uptake and the binding of radioligands to neurotransmitter receptors. Upon administration of duloxetine in vivo, the inhibitory effects on uptake of 5-HT and NE persist for up to 8 h. Desmethylduloxetine, a potential metabolite, is also an inhibitor of 5-HT and NE uptake. Consistent with the ability to inhibit the uptake of 5-HT, duloxetine blocks p-chloroamphetamine induced depletion of mouse and rat brain 5-HT. Duloxetine also blocks the 6-hydroxydopamine induced depletion of mouse heart NE and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced depletion of NE in frontal cortex but does not block the MPTP induced depletion of DA in rat striatum. Electrophysiological studies show that duloxetine decreases the activity of 5-HT neurones in dorsal raphe and at a 5-times higher dose also decreases the activity of NE neurones in the locus coeruleus. Microdialysis techniques have demonstrated that duloxetine effectively elevates extracellular 5-HT and NE levels in rat frontal cortex and hypothalamus. Antagonists at somatodendritic 5-HT1A autoreceptors or at presynaptic alpha2-adrenergic receptors could augment the duloxetine induced elevation of extracellular 5-HT, NE and DA levels. Duloxetine produces behavioural responses consistent with the enhancement of 5-HT and NE neurotransmission. Pharmacokinetic studies in healthy human volunteers show that duloxetine has a half-life of 10 - 15 h without the influence of food. In preliminary clinical trials, duloxetine has shown antidepressive effects in patients with major depression. Duloxetine offers an opportunity to utilise combined central 5-HT and NE neuronal pathways to improve the treatment of patients with major depression.

Overflow of noradrenaline and dopamine in frontal cortex after [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP-4) treatment: in vivo microdialysis study in anaesthetized rats.

The changes in the extracellular concentration of endogenous noradrenaline and dopamine in the frontal cortex following pretreatment with noradrenergic neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] were studied by in vivo microdialysis in rats anaesthetized with chloral hydrate. Noradrenaline and dopamine levels in frontal cortex were detected only when the uptake inhibitor, nomifensine (10 microM) was present in dialysis fluid. Under those conditions, the Na+ channel agonist veratridine and a depolarising concentration of potassium chloride (60 mM), applied locally through the microdialysis probe, increased the overflow of noradrenaline. Tetrodotoxin had an opposite effect. These results indicate that most of the noradrenaline probably arose from exocytotic release. Noradrenaline efflux in the frontal cortex of DSP-4 pretreated rats (52 +/- 6.1 fmol/sample) did not differ significantly from that of the control animals (69 +/- 4.9 fmol/sample). Dopamine efflux was not changed either (64 +/- 9.6 and 62 +/- 3.9 fmol/sample, respectively). The alpha 2-adrenoceptor antagonist, atipamezole (3 mg/kg i.p.), increased the overflow of noradrenaline in the frontal cortex of saline-treated rats by 100%, whereas in DSP-4 treated rats the increase was only around 30%. The overflow of dopamine was not changed under the conditions described. The effect of atipamezole in DSP-4 treated rats may be of smaller magnitude due to the diminished pool of releasable noradrenaline or due to a downregulation of presynaptic alpha 2-adrenoceptors in the frontal cortex. The perfusion of 60 mM KCl at the end of the experiment unexpectedly produced equivalent increases in noradrenaline and dopamine content in dialysates of both vehicle and DSP-4 treated rats. We conclude that the uptake inhibitor, nomifensine, and atipamezole, which had a stronger effect in vehicle-treated animals, reduced the effect of KCl-stimulation and masked the true difference in changes of noradrenaline efflux. Post-mortem tissue concentrations of noradrenaline 7 days after DSP-4 administration (50 mg/kg) were significantly reduced in the frontal cortex (54%), hippocampus (62.5%) and to lesser extent in the hypothalamus (27%) as compared to vehicle-treated rats. Dopamine and 3,4-dihydroxyphenylacetic acid concentrations were not changed confirming the efficacy and selectivity of the DSP-4 lesion. These results demonstrate that one week after DSP-4 treatment the extracellular levels of noradrenaline and dopamine as assessed by in vivo microdialysis are not changed in the frontal cortex, but atipamezole-stimulated release of noradrenaline is decreased in DSP-4 treated rats.

Increased levels of extracellular noradrenaline in the frontal cortex of rats exposed to naturalistic environmental stimuli: modulation by acute systemic administration of diazepam or buspirone.

In vivo microdialysis was used to investigate the effects of an IP injection of diazepam or buspirone (each at 3 mg/kg) on spontaneous efflux of noradrenaline in rat frontal cortex, and on changes in efflux induced by naturalistic stress. After drug administration, rats either remained in their home cages or were transferred individually to a novel cage, 1 h later. The novel cage was brightly lit (1500 lux) and contained another, unfamiliar rat. After transfer to the novel cage, noradrenaline efflux was lower in diazepam-injected rats than in their vehicle-injected counterparts. However, in both cases, stress caused a significant increase in efflux and the net increase was not affected by diazepam. Similarly, buspirone, which increased spontaneous efflux of noradrenaline, did not affect the net increase in efflux during stress. Neither compound modified locomotor activity in the novel cage. This suggests that any changes in noradrenaline efflux are unrelated to drug effects on non-specific arousal. It is concluded that generically unrelated anxiolytic agents can have different effects on spontaneous efflux of noradrenaline but do not modify the noradrenergic response to naturalistic stimuli.

Contrasting effects of the imidazol(in)e alpha 2-adrenoceptor agonists, medetomidine, clonidine and UK 14,304 on extraneuronal levels of noradrenaline in the rat frontal cortex: evaluation using in vivo microdialysis and synaptosomal uptake studies.

1. In vivo microdialysis in halothane-anaesthetized rats and synaptosomal [3H]-noradrenaline uptake studies in vitro were used to evaluate the effects of imidazole (medetomidine) and imidazoline (clonidine and UK 14,304) alpha 2-adrenoceptor agonists on extraneuronal levels of noradrenaline in the frontal cortex. 2. Levels of noradrenaline in the dialysate were increased by a depolarizing concentration of K+ (60 mM for 20 min) and substantially attenuated by reducing Ca2+ supply in the perfusate. These results suggest that spontaneous efflux of noradrenaline in the cortex is regulated predominantly by cation-dependent exocytotic mechanisms. 3. At a low perfusion concentration (0.5 microM), medetomidine, clonidine and UK 14,304 all reduced the level of noradrenaline in cortical dialysates. Continuous perfusion of the selective alpha 2-adrenoceptor antagonist, atipamezole (0.5 microM) caused a sustained increase in noradrenaline efflux and reversed the inhibitory effects of medetomidine. All these changes are consistent with drug actions at presynaptic alpha 2-adrenoceptors. 4. Higher concentrations of medetomidine (5-50 microM), but not clonidine or UK 14,304, evoked a non-desensitizing increase in noradrenaline efflux. This effect was not antagonized by 0.5 microM atipamezole. 5. The tricyclic noradrenaline reuptake inhibitor, desmethylimipramine (0.5-50 microM), increased noradrenaline efflux in a concentration-dependent manner. 6. The specific uptake of [3H]-noradrenaline into cortical synaptosomes was inhibited by medetomidine and desmethylimipramine with IC50 values of approximately 7 microM and 8 microM respectively. Neither clonidine nor UK 14,304 inhibited [3H]-noradrenaline uptake. 7. These results indicate that micromolar concentrations of the selective alpha2-adrenoceptor agonist,medetomidine, can augment extraneuronal levels of noradrenaline in the rat frontal cortex; this effect seems to involve an inhibition of noradrenaline reuptake rather than an action at alpha2-adrenoceptors.

Somatostatin content increases following norepinephrine depletion in frontal cortex of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on somatostatin (SS)-containing neurons were examined by measuring dopamine, norepinephrine (NE), SS, and SS mRNA in striatum and frontal cortex of C57/B16 mice at various times following treatment with MPTP-HCl (96 mg/kg i.p.). MPTP caused a 70% depletion of dopamine in striatum by 1 day and a 40% depletion of NE in frontal cortex within 3 days. SS content was increased in frontal cortex 4 days later, but not in striatum; there were no changes in SS mRNA. Maprotiline, a specific NE-uptake blocker, prevented both the depletion of NE and the increase of SS in frontal cortex due to MPTP administration. These results support the possibility that NE can regulate SS in frontal cortex and are discussed in terms of the decrease of SS seen in parkinsonian patients with dementia.

Fetal neocortical transplants into the medial forebrain bundle attract ingrowth of catecholaminergic fibers in adult rat brain

The hypothesis that fetal tissue grafts may exert a trophic influence on damaged catecholaminergic fibers was examined. Ascending dopamine and norepinephrine axons normally innervate frontal cortex targets in the intact rat brain. These and other ascending catecholaminergic fibers were disrupted with stereotaxic injections of 6-hydroxydopamine into the medial forebrain bundle (mfb), followed after 1 or 14 days by grafts of fetal neocortical tissue placed into the injection site, or by sham grafts. Glyoxylic acid histofluorescence techniques were then used to examine catecholaminergic fiber distribution. When such lesions were made without subsequent grafting, virtually no growth of catecholaminergic fibers occurred beyond the injection site and frontal cortex norepinephrine levels were depleted to 15% of control levels. However, when grafts of fetal neocortical tissue were made into the lesion site and animals examined 3 months later, catecholaminergic fibers grew through the lesion site to ramify within the graft tissue. Catecholaminergic fibers were seen in all portions of most grafts, though they were most dense on the caudal and ventral edges of the graft, close to the path of the mfb. Similar densities of graft innervation were seen 3 months after animals received grafts placed into the same site without prior lesioning of catecholaminergic fibers. Fetal neocortical grafts thus induce collateral sprouting from intact host catecholaminergic axons and may also promote regenerative sprouting when such fibers are otherwise irreparably damaged.

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain.

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.

Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57 BL/6 mice. Comparison with three other strains of mice

The effect of the parkinson-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57 BL/6 mice has been studied employing neuro- and histochemical techniques. The number of dopamine (DA) cell bodies in substantia nigra pars compacta (SNC) was reduced by 70% in MPTP-treated C57 BL/6 mice, as demonstrated both by tyrosine hydroxylase (TH) immunohistochemistry and conventional histology (Cresyl violet staining) and an almost complete loss of DA fibers in striatum was also found. A detailed analysis of the effects of MPTP on endogenous catecholamine levels in various brain regions revealed that MPTP caused a severe reduction of endogenous DA in substantia nigra and striatum (35 and 5% of control) which was accompanied by an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio. There was also a decrease of DA in nucleus accumbens and the olfactory tubercle to 41 and 44% of control, respectively, without any significant change in the DOPAC/DA ratio and density of TH-positive fibers. Small but significant decreases of the noradrenaline (NA) levels in septum, entorhinal cortex and frontal cortex were seen, although the uptake of [ 3H]NA in frontal cortex was not significantly changed. Minor MPTP-induced decreases of the serotonin levels in frontal cortex, occipital cortex and spinal cord were also seen. The MPTP treatment also induced a 55% increase of adrenaline levels in hypothalamus, while no changes were seen in pons-medulla and spinal cord. Comparing this with 3 other strains of mice, the MPTP-induced reduction of endogenous DA in striatum was most pronounced in C57 BL/6, less in N.M.R.I. and CBA/Ca mice, and least in Swiss-Webster. Concerning the effect of MPTP on cortical NA levels, the same relation was at hand except for C57 BL/6, where, as mentioned, the effect was merely detectable. No reduction of DA perikarya in SNC was seen in Swiss-Webster mice. These findings show that in mice major differences exist in sensitivity of catecholamine neurons to MPTP between different strains. The data show that MPTP can produce an almost complete, permanent and relatively selective degeneration of the nigrostriatal DA neurons in C57 BL/6 mice similar to that seen in primates. This strain may therefore serve as a useful model for studies on various aspects of MPTP-induced parkinsonism.

The effect of diet and chronic obesity on brain catecholamine turnover in the rat

Male Sprague-Dawley rats were fed a high calorie, high fat diet for 3 months to produce chronic diet-induced obesity (DIO) in which they gained 70% more weight than chow-fed controls. Thirty-six percent of the rats fed the DIO diet resisted the development of obesity (DR), gaining no more weight than chow-fed controls but serving as a comparison for the effects of the diet alone on the metabolism of brain catecholamines. The major influence of dietary composition was upon norepinephrine (NE) metabolism. Both DIO and DR rats had increased turnover of NE (107–217%) and/or shorter NE half-lives (42–67%) than controls in the hypothalamic paraventricular (PVN) and dorsomedial (DMN) nuclei and the median eminence (ME); dopamine (DA) turnover was similarly accelerated in the PVN. The DR rats alone exhibited decreased NE levels with increased disappearance of NE in frontal cortex and increased disappearance of DA in the ventromedial hypothalamic nucleus (VMH). The major effect of chronic obesity alone was a 31–33% decrease in DMN DA turnover and an 80% decrement in ME DA turnover associated with a 61% decrease in DA levels as compared to chow-fed controls. Therefore, the major effect of a high calorie, high fat diet was a diffuse acceleration of brain NE and DA turnover while chronic obesity led to decreased DA turnover in the DMN and ME.

Neurochemical and Histochemical Characterization of Neurotoxic Effects of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine on Brain Catecholamine Neurones in the Mouse

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a rapid and long-lasting reduction of both 3,4-dihydroxyphenylalanine (dopamine, DA) and noradrenaline (NA) in mouse brain, as observed histo- and neurochemically. The depleting effects were more pronounced after repeated MPTP administration and the most marked reductions were observed after 2 X 50 mg MPTP/kg s.c., when DA in striatum and NA in frontal cortex were reduced by greater than 90% 1 week after MPTP. Mice with such catecholamine depletions were markedly sedated and almost completely immobilized. The behavioural syndrome after MPTP resembled that seen after reserpine, a monoamine-depleting drug. MPTP also caused a long-lasting reduction of catecholamine uptake in striatal DA and cortical NA nerve terminals and reduced tyrosine hydroxylase activity in these regions. There was no evidence that MPTP caused any marked DA and NA cell body death. MPTP given acutely transiently elevated serotonin levels. The results are compatible with a neurotoxic action of MPTP on both DA and NA nerve terminals. The nigro-striatal DA and the locus coeruleus NA neurone systems appeared to be most susceptible. Synthesis and utilization of residual striatal DA and cortical NA were increased, as often observed in partially denervated monoamine-innervated brain regions. Both DA and NA showed a gradual recovery, which took months to become complete and may have been related to a regrowth of catecholamine nerve terminals.

Dopamine denervation of frontal cortex or nucleus accumbens does not affect acth-induced grooming behaviour

Studies with dopamine (DA) receptor antagonists have implicated brain DA systems in the increased grooming behaviour elicited by intracerebroventricular (i.c.v.) administration of ACTH or exposure to a novel environment. To evaluate the potential contributions of DA terminals innervating frontal cortex and nucleus accumbens, stereotaxically guided injections of 6-hydroxydopamine (6-OHDA) were made into these regions of rat brain following peripheral administration of desmethylimipramine and pargyline. Despite an 88% mean reduction of DA, and 68% mean reduction of noradrenaline in frontal cortex, the amount of grooming behaviour observed either in a novel cage, or after i.c.v. injection of ACTH 1–24 was not detectably altered. The lesions also did not affect locomotor activity measured during the scoring of grooming, in an open field, in photocell cages, or in a running wheel, even in the animals most severely depleted of DA. Following nucleus accumbens 6-OHDA infusions, depletions of DA as great as 99% were obtained. Animals with accumbens depletions greater than 90% showed the expected attenuation of amphetamine-stimulated locomotor activity. Nevertheless, they exhibited normal grooming scores in a novel cage, and in response to i.c.v. ACTH 1–24. It is concluded that dopaminergic terminals in nucleus accumbens and probably those in frontal cortex are not necessary for the expression of novelty- or ACTH-induced grooming.

Dissociable effects of 6-OHDA-induced lesions of neostriatum on anorexia, locomotor activity and stereotypy: the role of behavioural competition.

The effect of 6-OHDA-induced lesions of neostriatum on locomotor activity, stereotypy and anorexia induced by amphetamine (0.5 mg/kg, 1.5 mg/kg and 5.0 mg/kg IP) was examined. Lesioned rats demonstrated attenuated stereotypy and anorexia but enhanced locomotor activity to amphetamine. Biochemical analysis of dopamine and noradrenaline in specific forebrain areas demonstrated significant dopamine depletion in neostriatum. Dopamine levels in mesolimbic, frontal cortex and hypothalamic areas, and noradrenaline in frontal cortex and hypothalamic areas, were not significantly reduced. The data were interpreted in terms of a response incompatibility hypothesis. It is proposed that stereotyped responses mediated by nigrostriatal dopamine neurones are incompatible with eating. In addition, it is suggested that a second form of competition, at the neuro-anatomical level, occurs between mesolimbic and nigrostriatal systems for motor output pathways and the ultimate expression of behaviour. The role of noradrenaline in amphetamine anorexia is also discussed.

Selective brain noradrenaline depletion induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP 4) does not prevent the memory facilitation induced by a muscarinic agonist in mice.

These experiments investigated the effects of central noradrenaline (NA) depletion and its interaction with cholinergic and dopaminergic mechanisms upon retention of a passive-avoidance response in mice. The NA selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP 4) (50 mg/kg IP, 7 days) was injected into mice to produce depletion of NA in frontal cortex, hypothalamus, cerebellum, midbrain and brain stem without any significant change in dopamine (DA) levels in frontal cortex, striatum, hypothalamus and midbrain. Depletion of brain NA produced by DSP 4 was significantly but not completely prevented by the NA uptake inhibitor desmethylimipramine (DMI) (10 mg/kg IP, 30 min before DSP 4 injection). Despite the marked NA depletion, DSP 4 neither impaired the retention of a passive-avoidance response in mice nor prevented the enhancement of retention of this response induced by the central muscarinic agonist oxotremorine (OTM) (0.05 mg/kg IP, immediately after training. This lack of effect of DSP 4 on retention was prevented neither by DMI nor by the serotonin uptake inhibitor fluoxetine (5 mg/kg IP, 30 min before DSP 4 injection). The enhancement of retention induced by OTM in the groups of mice injected with either water or DSP 4 was prevented by atropine (0.5 mg/kg IP, 20 min before training) but not by methylatropine in the same experimental conditions. This suggests that both in controls and DSP 4-pretreated mice, the primary effect of OTM is due to an interaction with muscarinic brain receptors.(ABSTRACT TRUNCATED AT 250 WORDS)