Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain

Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.     

Regional changes in monoamine content and uptake of the rat brain during postnatal development.

Regional norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) contents in the developing rat brain were estimated. The rate of increase in NE content was the highest in diencephalon, followed by the lower brain stem, limbic-striatum, neocortex and cerebellum. With postnatal aging, DA concentration increased markedly in limbic-striatum, slightly in the neocortex and negligibly in other regions. In each region except cerebellum, 5-HT content increased gradually but the rate of increase in diencephalon was relatively high. Comparison of the kinetics of high affinity uptake of L-[3H]NE and [3H]5-HT between the neonatal and the adult brain indicated that Km values of L-[3H]NE and [3H]5-HT uptake were 2.9 X 10(-7) M and 1.7 X 10(-7) M respectively in neocortex, diencephalon and lower brain stem and 4.3 X 10(-7) M and 2.3 X 10(-7) M in limbic-striatum in the neonate as well as in the adult. Vmax values of both amines uptake differed regionally and the values in the neonate were lower than those in the adult in all regions. Limbic-striatum showed a higher Vmax value than other regions in uptake of both amines. These results suggested that innervation of monoaminergic neurons in the brain progressed with increasing age, that projections of both NE and 5-HT neurons were relatively high into hypothalamus and limbic-striatum and that DA neuron projections concentrated at striatum. Although the brain, except for limbic-striatum, showed neither regional nor developmental differences in affinity of L-[3H]NE and [3H]5-HT to synaptosomes, the density of nerve terminal of both monoaminergic neurons increased in all regions of the brain during postnatal development. In limbic-striatum, higher Km and Vmax values of both amines, uptake suggest the existence of both amines' uptake into DA terminal to some extent.     

Interleukin-1 induces changes in norepinephrine metabolism in the rat brain

Interleukin-1 (IL-1) is a hormone that, apart from playing a key role in immune and inflammatory processes, can also affect mechanisms under brain control. To gain a better understanding of the action of this cytokine on the CNS, its effects on the contents of norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their main metabolites and precursors, were evaluated in different regions of the forebrain, brain stem, and spinal cord. Following administration of human recombinant IL-1 (beta form) to rats, a modest decrease in the content of NE was observed in the hypothalamus as well as in the dorsal posterior brain stem. However, the most relevant finding was that 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the main NE metabolite, and the relation MHPG/NE were increased in all the regions studied, revealing a stimulatory effect of IL-1 on NE metabolism in the CNS. This effect seems to be specific for NE since no comparable changes in the brain content of DA, 5-HT, or its metabolite, 5-hydroxyindole acetic acid, were detected after administration of the cytokine. However, tryptophan was significantly increased in all brain regions and in the cervical spinal cord. The capacity of IL-1 to affect the metabolism of NE, a neurotransmitter involved in the control of a variety of brain functions, provides further proof for the relevance of this cytokine in brain-immune interactions.     

Comparative effects of the neurotoxins N-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) and 6-hydroxydopamine on hypothalamic noradrenergic, dopaminergic and 5-hydroxytryptaminergic neurons in the male rat

The intracerebroventricular (i.c.v.) administration of 6-hydroxydopamine (6-OHDA; 50 micrograms X 3) and the systemic administration of DSP4 (50 mg/kg X 2; i.p.), alone and in combination, were compared for their abilities to alter the concentrations of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) in selected hypothalamic and extra-hypothalamic (striatum, frontal cortex, hippocampus) regions of the male rat brain. DSP4 markedly lowered NE concentrations in extrahypothalamic regions, and within the hypothalamus produced a mild and variable reduction of NE without altering concentrations of DA, DOPAC or 5-HT. 6-OHDA markedly lowered NE concentrations in all brain regions, but was without effect on DA, DOPAC and 5-HT concentrations in any region analyzed. Combined treatment with DSP4 and 6-OHDA did not produce additional effects on levels of NE, DA and DOPAC over either drug alone, but did cause a mild reduction of 5-HT in several brain regions. These results indicate that systemic treatments with DSP4 per se are not as effective as i.c.v. 6-OHDA in depleting NE in the hypothalamus, and that when the two neurotoxins are administered there appears to be some destruction of 5-HT neurons.     

Effects of neonatal rat Borna disease virus (BDV) infection on the postnatal development of the brain monoaminergic systems

Effects of neonatal Borna disease virus infection (BDV) on the postnatal development of brain monoaminergic systems in rats were studied. Tissue content of norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenol acetic acid (DOPAC), and serotonin (5-HT) and its metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed by means of HPLC-EC in frontal cortex, cerebellum, hippocampus, hypothalamus and striatum of neonatally BDV-infected and sham-inoculated male Lewis rats of 8, 14, 21, 60 and 90 days of age. Both NE and 5-HT concentrations were significantly affected by neonatal BDV infection. The cortical and cerebellar levels of NE and 5-HT were significantly greater in BDV-infected rats than control animals at postnatal days (PND) 60 and 90. Tissue content of NE in hippocampus was unaffected. In hippocampus, neonatally BDV-infected rats had lower 5-HT levels at PND 8 and significantly elevated levels at PND 21 and onwards. Neither striatal levels of 5-HT nor hypothalamic levels of 5-HT and NE were affected by neonatal BDV infection, suggesting that the monoamine systems in the prenatally maturing brain regions are less sensitive to effects of neonatal viral infection. 5-HIAA/5-HT ratio was not altered in BDV-infected rats indicating no changes in the 5-HT turnover in the brain regions damaged by the virus. Neither DA nor DOPAC/DA ratio was affected by neonatal BDV infection in any of the brain regions examined. The present data demonstrate significant and specific alterations in monoaminergic systems in neonatally BDV-infected rats. This pattern of changes is consistent with the previously reported behavioral abnormalities resulting from neonatal BDV infection.     

Yohimbine-induced alterations of monoamine metabolism in the spontaneously hypertensive rat of the Okamoto strain (SHR). II. The central nervous system (CNS)

Steady state levels of monoamine neurotransmitters were examined in SHR, a genetic model of hypertension and compared to its normotensive control (WKY). SHR and WKY were also challenged with alpha 2-adrenergic antagonists, (yohimbine, YOH, idazoxan) or an alpha 1-antagonist (prazosin) and alterations in CNS monoamine metabolism evaluated. SHR were found to have elevated levels of NE and 5-HT in a number of brain regions involved in cardiovascular control when compared to WKY. DA levels and metabolism were also altered in the SHR. Blockade of alpha 2-adrenoceptors and other direct and indirect actions of YOH exacerbated the abnormalities in central monoaminergic neurotransmission in SHR. Significant decreases in NE content were produced by YOH or idazoxan treatment in both SHR and WKY, presumably the result of the inhibition of alpha 2-adrenoceptor medicated presynaptic control of NE release. YOH treatment abolished the differences in steady state levels of NE between SHR and WKY, however, idazoxan did not. YOH administration resulted in significant increases in DA and 5-HT in a number of brain regions of both SHR and WKY. Idazoxan or prazosin produced few changes in DA and 5-HT metabolism except for increases in DA content in the spinal cord and brainstem of SHR given idazoxan. The YOH-induced increases in DA and 5-HT content of SHR were of a greater magnitude than the WKY in several brain regions. DOPAC levels were significantly elevated by YOH in both WKY and SHR, reflecting the antidopaminergic properties of YOH. 5-HIAA content was significantly reduced by YOH in a number of brain regions in both SHR and WKY, however, this effect was attenuated in several brain regions in SHR. The results of the present study demonstrate the multifarious nature of the alterations in CNS monoamine metabolism in SHR.     

Regional differences in catecholamine formation and metabolism in the rat spinal cord

Catecholamine metabolism was assessed from the content of norepinephrine (NE), dopamine (DA) and their metabolites in various regions of the rat spinal cord during steady-state conditions and following treatment with alpha-methyl-p-tyrosine. The content of NE was rather uniform along the cord while DA was higher in the rostral portion of the cord than in the caudal portion.For both NE and DA there was a rostrocaudal decrease of their turnover rates along the cord. In the cervical cord, DA was formed at a faster rate than NE. There was no correlation between the content of catecholamine metabolites and amine turnover rates. The non-uniformity of catecholamine turnover in the cord probably arises from the fact that different regions of brain project to different regions of cord, each having a specific physiological function. Furthermore, our study provides added support for the presence of an independent DA-containing neuronal system in the spinal cord.     

Studies on neurotransmitter-stimulated phospholipid metabolism with cerebral tissue suspensions: A possible biochemical correlate of synaptogenesis in normal and undernourished rats

The phenomenon of neurotransmitter-stimulated incorporation of 32Pi into phosphatidic acid and inositol phosphatides (neurotransmitter effect) in developing brain was studied in vitro as a possible measure of synaptogenesis. While the neurotransmitter effect was not observed with brain homogenates, highly consistent and significant effects were noted with brain tissue suspensions obtained by passing the tissue through nylon bolting cloth. The magnitude of the effect decreased with the increase in mesh number. Maximum stimulations obtained with the 33 mesh adult brain cortex preparations (mean +/- S.E.M. of 6 experiments) were 203 +/- 8%, 316 +/- 17% and 150 +/- 8% with 10(-3) M acetylcholine (ACh) + 10(-3) M eserine; 10(-2) M norepinephrine (NE) and 10(-2) M serotonin (5-HT), respectively. Experiments with developing rat brain at 7, 14 and 21 days of age showed that the neurotransmitter effects due to ACh, NE and 5-HT increase progressively in different regions of the brain but that there are marked regional differences. It is suggested that the neurotransmitter effect is a valid biochemical correlate of synaptogenesis. In rats undernourished from birth to 21 days of age, by increasing the litter size, the neurotransmitter effect with ACh, NE or 5-HT was not altered in the cortex but was significantly reduced in the brain stem. In cerebellum the effects due to ACh and NE were significantly altered, while that with 5-HT was unaffected. It is concluded that cholinergic, adrenergic and serotonergic synapses are relatively unaffected in the cortex but are significantly affected in the brain stem by undernutrition. In the cerebellum of undernourished rats the adrenergic and cholinergic, but not serotonergic systems, are altered.     

The role of locus coeruleus in decapitation convulsions of rats

The role of the central norepinephrine (NE) system, especially the locus coeruleus (LC), in the occurrence of decapitation convulsions was investigated in rats. Intraspinal injection of 6-hydroxydopamine (6-OHDA) caused a significant inhibition of decapitation convulsions as shown by prolongation of the latency and shortening of the convulsion's duration, as well as decreasing the NE content of the spinal cord to 35% of the control value without affecting the NE content of the various regions in the brain. Chemical lesion of the descending bundle from the LC by treatment with 6-OHDA significantly inhibited decapitation convulsions in a similar manner. Moreover, there was a decrease in the NE content of the spinal cord and hypothalamus to 24% and 47% of the control value, respectively. Bilateral electrolytic lesion of the LC also significantly inhibited decapitation convulsions and decreased the NE content of the cortex and spinal cord to 15% and 74% of the control value, respectively. However, lesions of the dorsal and ventral NE bundle by treatment with 6-OHDA, which caused a marked decrease in the NE content of the cortex and hypothalamus, respectively, did not affect the decapitation convulsion. Intraspinal injection of 5,6-dihydroxytryptamine resulted in a decrease in the 5-hydroxytryptamine content of the spinal cord only; moreover, it did not change the decapitation convulsion. These results suggest that coeruleospinal NE neurons play an important role in the occurrence of decapitation convulsions.     

Alterations in sympathetic neuroeffector transmission to mesenteric arteries but not veins in DOCA-salt hypertension

We studied hypertension-associated changes in prejunctional α₂ adrenergic receptor (α₂-AR) function using amperometry to monitor in vitro norepinephrine (NE) measured as oxidation currents. Vasoconstriction was measured using video imaging. NE release was induced by electrical stimulation of sympathetic nerves associated with mesenteric arteries (MA) and veins (MV) of sham and DOCA-salt hypertensive rats. NE oxidation currents were larger in DOCA-salt compared to sham MA; there were no differences between currents in sham and DOCA-salt MV. Increases in NE oxidation currents followed a multi-exponential time course in sham MA. In DOCA-salt MA and sham and DOCA-salt MV, the time course was mono-exponential. Yohimbine (α₂-AR antagonist, 1 µM), caused a mono-exponential increase in NE oxidation currents in sham and DOCA-salt MA. Yohimbine increased NE oxidation currents and constrictions more in sham compared to DOCA-salt MA and compared to MV. UK 14,304 (α₂-AR agonist, 1.0 µM), reduced currents less in DOCA-salt MA and sham and DOCA-salt MV compared to sham MA. Prazosin (α₁-AR antagonist, 0.1 µM) did not alter NE oxidation currents. Prazosin inhibited constrictions more in DOCA-salt compared to sham MA and almost completely blocked constrictions in sham and DOCA-salt MV. Prazosin-resistant constrictions in MA were blocked by the P2 receptor antagonist, PPADS (10 µM). Prejunctional α₂-ARs modify NE concentrations near neuroeffector junctions in MA and MV. α₂-AR function is most prominent in MA and is impaired in DOCA-salt MA but not MV. Purinergic transmission predominates in sham MA. NE is the dominant vasoconstrictor in DOCA-salt MA and sham and DOCA-salt MV.     

Monoaminergic compensation in the neuropeptide Y deficient mouse brain

Neuropeptide Y (NPY) is an important central regulator of food consumption and energy expenditure via the hypothalamus. NPY containing neurons have a broad central distribution and are often colocalized with norepinephrine (NE). However, NPY deficient mice do not exhibit any substantial changes in food consumption, body weight or body composition when compared to wild type mice. Since NE and serotonin (5HT) are also important regulators of appetite and metabolism, we evaluated these systems in NPY deficient mice. Brain sections from NPY deficient and wild type mice were labeled with either (3)H-nisoxetine for the NE transporter (NET) or (3)H-citalopram for the 5HT transporter (SERT). Tyrosine hydroxylase expression was evaluated by radioimmunohistochemistry. Brain monoamines and metabolites were evaluated using HPLC. NPY deficient mice exhibited a substantial decrease in NET binding in most brain regions examined. NET binding was less than 50% of control binding in the cerebral cortex and subregions of the thalamus with the greatest decrease seen in the hypothalamus. In contrast, more modest and regionally variable changes were observed in the SERT binding with decreases in regions such as the accessory olfactory nucleus, glomerular layer of the olfactory bulb and the CA1 region of the hippocampus. Measurement of NE and 5HT content as well as the primary metabolites revealed increased NE turnover and decreased 5HT content in the hypothalamus. Therefore, developmental compensation by the NE and 5HT systems may contribute to the absence of a body weight phenotype in NPY deficient mice.     

Effect of chronic naltrexone administration and its withdrawal on the regional activity of neurons that contain norepinephrine, dopamine and serotonin

A method is described that permits the simultaneous quantitation of norepinephrine (NE), dopamine (DA) serotonin (5-HT) and their respective major metabolites, 3-methoxy-4-hydroxy phenylglycol (MHPG), 3-methoxytyramine (3-MT), dihydroxyphenyl acetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) in discrete brain regions. The ratio of MHPG/NE, DOPAC/DA and 5-HIAA/5-HT was used to assess the effects of the chronic administration of the narcotic antagonist, naltrexone, and its withdrawal on the regional activity of neurons that contain NE, DA and 5-HT respectively. Chronic administration of naltrexone (8 days) is associated with a significant increase in the ratio of 5-HIAA/5-HT and DOPAC/DA in the frontal cortex and dorsal hippocampus respectively. Under this condition the thalamic concentration of 3-MT in 4 of 8 animals is also significantly elevated. In contrast, the mesolimbic forebrain exhibited a decrease in the MHPG/NE ratio (4 out of 8 animals). One day following naltrexone pellet removal the above ratios, as well as the mean content of 3-MT in the thalamus, returned to control values. At this time the content of 3-MT in the thalamus (5 of 5 animals) and frontal cortex (3 of 9 rats) was appreciably elevated, while its content in the dorsal hippocampus was significantly reduced (6 of 9 rats). These data suggest that the activity of several central monoaminergic neuronal systems are regulated by an opioid input that is tonically active.     

Infusion of a monoamine oxidase inhibitor into the locus coeruleus can prevent stress-induced behavioral depression

Behavioral depression produced by exposing animals to a stressor that they cannot control (uncontrollable shock) was reversed by infusion of the monoamine oxidase (MAO) inhibitor pargyline into the locus coeruleus (LC) region of the brain stem. Following exposure to uncontrollable shock, rats were infused through bilateral cannulas implanted in the LC region with either pargyline or vehicle. At 110 min after infusion, animals were tested for behavioral activity in a swim tank. Immediately following the behavioral test, animals were sacrificed for determination of the monoamines [norepinephrine (NE), dopamine (DA), serotonin (5-HT)], as well as 5-hydroxy-indoleacetic acid (5-HIAA) in various brain regions. The results showed that animals exposed to uncontrollable shock and then infused with vehicle exhibited significantly less activity in the swim test than animals not exposed to shock and similarly infused with vehicle; thus, the usual behavioral depression following exposure to uncontrollable shock was observed. On the other hand, shocked animals infused with pargyline did not show reduced activity in the swim test. Unshocked animals infused with pargyline showed no more activity than did shocked animals infused with pargyline or unshocked animals infused with vehicle, which demonstrated that the infusion of pargyline into shocked animals did not eliminate the shock-induced depression of activity simply by generally stimulating motor activity. Measurement of the concentration of NE, DA, 5-HT, and 5-HIAA present in seven brain regions at the conclusion of the swim test showed that pargyline infusion into the LC eliminated the large depletion of NE in the LC that is normally observed after exposure to uncontrollable shock while having no effect on NE levels in the other brain regions examined. The level of 5-HT in the LC was also raised by infusion of pargyline into the LC, but again, there was no effect of pargyline infusion on 5-HT levels in any of the other brain regions. In conclusion, infusion of pargyline into the LC region of the brain eliminated both the large depletion of NE in the LC region and the behavioral depression that otherwise results from exposure of animals to uncontrollable shock.     

Variability among brain regions in the specificity of 6-hydroxydopamine (6-OHDA)-induced lesions

Summary 6-Hydroxydopamine (6-OHDA; 200 g, 150 g or 110 g) or vehicle was infused stereotaxically into the lateral ventricles of rats, usually following pretreatment with desmethylimipramine (DMI). Various brain regions were then assayed for dopamine (DA), serotonin (5-HT) and norepinephrine (NE). As expected, 6-OHDA depleted DA in all brain regions examined. Unexpectedly, however, the two highest doses of 6-OHDA significantly decreased 5-HT levels in the hippocampus and increased 5-HT levels in the striatum. In addition, despite pretreatment with doses of DMI commonly considered adequate to block 6-OHDA-induced depletion of NE, all doses of 6-OHDA tested significantly reduced NE levels in the hippocampus, hypothalamus and septum.We interpret our data as suggesting that some brain regions are susceptible to nonspecific toxic effects of 6-OHDA at doses commonly employed. Furthermore, these nonspecific effects may or may not occur, depending on seemingly minor variations in experimental technique.     

立体定向毁损大鼠杏仁核及隔核对脑内单胺类递质含量的影响

目的 :探讨杏仁核及隔核毁损后AMP模型大鼠脑内单胺类递质含量的变化。方法 :经腹腔注射苯丙胺 (amphetamine ,AMP)制作精神分裂症动物模型 ,用立体定向技术电极毁损大鼠杏仁核及隔核 ,采用荧光分光光度法和放射免疫法测定大鼠前额叶、间脑和脑干多巴胺 (DA)、5 羟色胺 ( 5 HT)和去甲肾上腺素 (NE)的含量。结果 :杏仁核及隔核毁损组前额叶DA低于模型组 (P <0 0 1) ,5 HT、NE均高于模型组 (P <0 0 1) ;杏仁核及隔核毁损组间脑DA、NE均低于模型组 (P <0 0 1) ,5 HT高于模型组 (P <0 0 1) ;脑干DA、NE均低于模型组 (P <0 0 1) ,5 HT高于模型组 (P <0 0 1)。结论 :AMP模型大鼠前额叶和脑干DA含量增高、5 HT和NE含量下降 ,间脑DA、NE含量增高、5 HT含量下降 ,立体定向毁损杏仁核及隔核能够改变脑内单胺类递质的水平。     

Alterations in monoamines level in discrete brain regions and other peripheral tissues in young and adult male rats during experimental hyperthyroidism

The present study was conducted to investigate the effect of experimentally-induced hyperthyroidism on dopamine (DA), norepinephrine (NE) and serotonin (5-HT) levels in different brain regions as well as in blood plasma, cardiac muscle and adrenal gland of young and adult male albino rats (60 rats of each age). Hyperthyroidism was induced by daily s.c. injection of L-thyroxine (L-T₄, 500 μg/kg body wt.) for 21 consecutive days. Induction of hyperthyroidism caused a significant elevation in DA and 5-HT levels in most of the tissues studied of both young and adult animals after 7, 14, and 21 days. NE content significantly decreased after 21 days in most of the brain regions examined and after 14 and 21 days in blood plasma of young rats following hyperthyroidism. In adult rats, NE content decreased after 14 and 21 days in cardiac muscle and after 21 days only in adrenal gland. It may be suggested that the changes in monoamines level induced by hyperthyroidism may be due to disturbance in the synthesis, turnover and release of these amines through the neurons impairment or may attributed to an alteration pattern of their synthesis and/or degradative enzymes or changes in the sensitivity of their receptors     

Norepinephrine and serotonin: Opposite effects on the activity of lateral geniculate neurons evoked by optic pathway stimulation

This study compares the responses of single units in the rat dorsal lateral geniculate nucleus (LGNd) to microiontophoretically applied norepinephrine (NE) and serotonin (5-HT). Most of the cells were identified physiologically as P-type (geniculocortical relay) neurons. At low iontophoretic currents (1 to 20 nA), NE caused a delayed increase in the spontaneous firing rate of these units, whereas 5-HT invariably slowed the discharge frequency. To compare the effects of the two monoamines on evoked activity, P-cells were driven by electrical stimulation of the afferent visual pathway at the level of the optic chiasm. NE caused a marked facilitation of both the short-latency (2 to 4 ms) and the delayed (70 to 230 ms) responses to such stimulation. The α-adrenoceptor antagonist phentolamine (10 nA), which by itself had no consistent effect on evoked activity, strongly diminished the response to NE. In contrast to NE, 5-HT was a powerful depressant of electrically evoked activity; neither phentolamine nor the 5-HT antagonist methysergide antagonized this response. Firing of LGNd units evoked by flashes of light was also facilitated by NE and depressed by 5-HT. We conclude that LGNd relay neurons exhibit the following unique features in their responsiveness to monoamines: (i) microiontophoretically applied NE facilitates, but 5-HT depresses, the spontaneous or synaptically evoked activity of virtually every cell; (ii) there is no dissociation between the actions of NE on spontaneous and evoked activity, as is the case in other brain regions.     

Brain catecholamine content during the estrous cycle and in steroid-primed rats

Norepinephrine (NE) and dopamine (DA) levels were measured in several estrogen concentrating brain regions over the estrous cycle and in steroid-primed ovariectomized rats under experimental conditions used to study sexual receptivity. Norepinephrine content in the ventromedial hypothalamus (VMH), lateral septum (LS) and medial preoptic area (POA) varied during the estrous cycle. The highest NE levels were found during metestrus in these brain regions. In the ovariectomized rat, NE levels were increased in the POA and LS 12 hours (hr) after the injection of 3 micrograms of estradiol benzoate (65% and 33%, respectively). Norepinephrine content in the POA and LS remained elevated 24 hr and 48 hr (0.5 mg progesterone at 42 hr) after treatment but were not different from control levels at 96 hr. Dopamine concentrations were not significantly altered over the estrous cycle or by the administration of estradiol benzoate in any of the brain regions studied. These results suggest that estrogen may selectively alter noradrenergic activity in brain regions that are implicated in the control of sexual receptivity and/or ovulation.     

Unchanged regional norepinephrine glycol metabolite levels in rat brain two months after amygdala kindling

Concentrations of the norepinephrine (NE) glycol metabolites MHPG (3-methoxy-4-hydroxyphenylethyleneglycol) and DHPG (3,4-dihydroxyphenylethyleneglycol) were examined in 13 brain regions of amygdala-kindled and yoked control rats. The subjects were killed 2 months after the kindled rats had exhibited their sixth 'stage 4-5' generalized seizure. In experiment 1, small but statistically significant decreases in total MHPG levels were found in the right hippocampus (91.6% of control) and hypothalamus (90.7% of control). When the study was repeated with 2 additional control groups, non-kindled, electrically stimulated controls and maximal electroshock convulsion controls, however, these small changes were not seen. The data suggest that since amygdala kindling does not produce any consistent, long-lasting alterations in brain regional NE glycol metabolite levels, there are no consistent, long-term changes in central NE neuronal activity.     

Regional changes in brain norepinephrine content in relation to mouse-killing behavior by rats

Three separate series of experiments were conducted as follows: isolation housing, bilateral olfactory bulbectomy, and Δ⁹-tetrahydrocannabinol (THC) administration. All three experimental manipulations produced an increase in the incidence of mouse-killing behavior. In order to elucidate the possible neural mechanisms mediating the killing response, norepinephrine (NE) content was measured in 6 discrete areas of the brain (the cortex, striatum, amygdala, midbrain, hypothalamus, and pons plus medulla oblongata). Following isolation housing, no significant difference in NE levels of any of the brain areas was demonstrated between the aggregated and isolated rats, nor between the killer and nonkiller rats. The rats with olfactory bulbectomy exhibited high NE content in the hypothalamus as compared with the intact or sham-operated rats, but there was no significant difference between the killer and nonkiller rats. After injection of THC, NE content in both the hypothalamus and pons plus medulla oblongata was decreased independent of the manifestation of killing response. The evidence indicates no regional change in brain NE levels specific to the killing response and suggests that brain NE may not participate in the mediation of mouse-killing behavior.