Resting and K-evoked release of serotonin and norepine- phrine in vivo from the rat and cat spinal cord

Using a spinal superfushion system, the release of serotonin (5-HT) and norepinephrine (NE) from rat and cat spinal cord was measured using a high performance liquid chroatograph with an electrochemical detector. Resting levels of 5-HT and NE in the chloralose-urethanized rat were of the order of 0.8 and 0.4 ng/ml, respectively. Potassium (40 0r 80mM, in excess) produced a dose-dependent increase in the levels of both monoamines in the suprfusate. The substitution of cobalt blocked this evoked release. Depletion of spinal 5-HT of NE by the prior intrathecal administration of 5,6-dihydroxytryptamine (5,6-DHT) or 6-hydroxydopamine (6-OHDA) reduced the resting levels of 5-HT and NE, respectively, and prevented the increase produced by excess potassium. The experiments indicate the ability to reliably collect and measure monoamines which overflowfrom spinal terminals and which reflect the degree of activation of the spinal monoamine system.     

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.     

Serotonin 2A receptor mRNA levels in the neonatal dopamine-depleted rat striatum remain upregulated following suppression of serotonin hyperinnervation.

Sixty days after bilateral dopamine (DA) depletion (>98%) with 6-hydroxydopamine (6-OHDA) in neonatal rats, serotonin (5-HT) content doubled and 5-HT(2A) receptor mRNA expression rose 54% within the rostral striatum. To determine if striatal 5-HT(2A) receptor mRNA upregulation is dependent on increased 5-HT levels following DA depletion, neonatal rats received dual injections of 6-OHDA and 5,7-dihydroxytryptamine (5,7-DHT) which suppressed 5-HT content by approximately 90%. In these 6-OHDA/5,7-DHT-treated rats, striatal 5-HT(2A) receptor mRNA expression was still elevated (87% above vehicle controls). Comparative analysis of 5-HT(2C) receptor mRNA expression yielded no significant changes in any experimental group. These results demonstrate that upregulated 5-HT(2A) receptor biosynthesis in the DA-depleted rat is not dependent on subsequent 5-HT hyperinnervation.     

Evidence for a mutual interaction between noradrenergic and serotonergic agonists in stimulation of ACTH and corticosterone secretion in the rat

We investigated the mutual interactions between hypothalamic norepinephrine (NE) and serotonin (5-HT) in mediating the ACTH and corticosterone responses to direct stimulation of the paraventricular nucleus (PVN) with adrenergic and serotonergic agonists. The hormone responses to the intrahypothalamic injection of the alpha1-adrenergic agonist phenylephrine (20 nmol/2 microl) were significantly reduced by prior depletion of hypothalamic 5-HT with intra-PVN injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), but not after depletion of hypothalamic NE by intra-PVN injection of the noradrenergic neurotoxin 6-hydroxydopamine (6-OHDA). The ACTH and corticosterone responses to intrahypothalamic injection of the 5-HT(1A) receptor agonist 8-OH-DPAT (20 n mol/2 microl) were significantly reduced by depletion of hypothalamic NE with 6-OHDA, but not after depletion of hypothalamic 5-HT with 5,7-DHT. These mutual interactions between the NE and 5-HT neuronal systems, which innervate the PVN, may explain previous findings of equivalent reductions in the hypothalamic-pituitary-adrenal axis responses to neural stimulation after neurotoxic lesioning of either the NE or 5-HT systems.     

Proposed animal model of attention deficit hyperactivity disorder

Dopamine (DA) neurons are implicated in the hyperlocomotion of neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Because serotonin (5-HT) neurons mediate some DA agonist effects, we investigated the possible role of 5-HT neurons on locomotor activity. Rats were treated at 3 days after birth with vehicle or 6-OHDA (134 μg ICV; desipramine pretreatment, 20 mg/kg IP, 1 h), and at 10 weeks with vehicle or 5,7-dihydroxytryptamine (5,7-DHT; 75 μg ICV; pretreatment with desipramine and pargyline, 75 mg/kg IP, 30 min), to destroy DA and/or 5-HT fibers. Intense spontaneous hyperlocomotor activity was produced in rats lesioned with both 6-OHDA and 5,7-DHT. Locomotor time in this group was 550 ± 17 s in a 600 s session, vs. 127 ± 13 s in the 6-OHDA group and <75 s in 5,7-DHT and intact control groups (p < 0.001). Oral activity dose-effect curves established that 5,7-DHT attenuated DA D₁ receptor supersensitivity and further sensitized 5-HT_2c receptors. Acute treatment with dextroamphetamine (0.25 mg/kg SC) reduced locomotor time in 6-OHDA+5,7-DHT-lesioned rats to 76 ± 37 s (p < 0.001). Striatal DA was reduced by 99% and 5-HT was reduced by 30% (vs. 6-OHDA group). Because combined 6-OHDA (to neonates) and 5,7-DHT (to adults) lesions produce intense hyperlocomotion that is attenuated by amphetamine, we propose this as a new animal model of ADHD. The findings suggest that hyperactivity in ADHD may be due to injury or impairment of both DA and 5-HT neurons.     

Effect of 6-hydroxydopamine and 5,7-dihydroxytryptamine on tissue uptake and cell nuclear retention of corticosterone in the rat hypothalamus

Previous studies have shown that norepinephrine and serotonin can modulate the glucocorticoid (GC) binding capacity in the hippocampus. The aim of the present study was to evaluate the role of these neurotransmitters in regulating GC receptors in the hypothalamus. Injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the ventral noradrenergic bundle (VNAB) and 5,7-dihydroxytryptamine (5,7-DHT) into the raphe nuclei caused a marked depletion in norepinephrine and serotonin, respectively, in the paraventricular nucleus (PVN) and mediobasal hypothalamus (MBH). The injection of these neurotoxins did not change the basal levels of ACTH and corticosterone. Injection of 6-OHDA into the VNAB caused a significant reduction in the cell nuclear binding of corticosterone in the PVN but not in the MBH. Conversely, injection of 5,7-DHT into the raphe nuclei caused a significant reduction in cell nuclear binding of corticosterone in the MBH but did not affect binding in the PVN. These results demonstrate that at least part of the nuclear corticosteroid receptors in the PVN and MBH are differentially regulated by the noradrenergic and serotonergic systems.     

Effects of intracisternal vs. intrahypothalamic 5,7-DHT on feeding elicited by hypothalamic infusion of NE.

A variety of evidence has led to suggestions that brain serotonin (5-HT) and norepinephrine (NE) interact within the medial hypothalamus to control food intake. To test the possibility that chronic decrements in 5-HT might enhance NE-induced feeding, adult male rats were prepared with permanently indwelling cannulae aimed at the paraventricular nucleus (PVN), then received either intracisternal (IC) or PVN injections of the 5-HT neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT) vs. its vehicle, 1% ascorbic acid. Over a 4-week period, IC-5,7-DHT rats showed no signs of enhanced daily feeding or drinking. However, in 40-min intake tests, feeding but not drinking was enhanced by injecting 20 nmol NE into the PVN commencing 2 weeks after neurotoxin treatment. Terminal monoamine assays confirmed that IC-5,7-DHT produced large (80-90%) depletions of brain regional 5-HT. A functional index of 5-HT terminal damage was also implied by the impaired short-term feeding responses IC-5,7-DHT rats showed to the systemic administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) when tested between 3 and 4 weeks after IC treatment. Over a comparable 4-week period, PVN-5,7-DHT rats also showed no tendencies to overeat or overdrink on a daily basis. However, in contrast to IC-5,7-DHT rats, they also showed no differences in their feeding or drinking responses to NE injections into the PVN. This was so despite reliable depletions of 5-HT in the hypothalamus (-28%) and hippocampus (-71%). These results support earlier work showing that neither widespread nor localized hypothalamic damage to brain 5-HT neurons produce chronic overeating. However, the data suggest that phasic enhancements of PVN NE activity may trigger enhanced feeding when there is widespread damage to brain 5-HT neurons, although the PVN does not appear to be the brain site mediating this effect.     

Effects of adrenergic and serotonergic agonists in the amygdala on the hypothalamo-pituitary-adrenocortical axis

The effect of direct administration of adrenergic and serotonergic (5-HT) agonists into the central nucleus of the amygdala (AMG) on the hypothalamo-pituitary-adrenal (HPA) axis have been studied in intact male rats and in animals with 6-hydroxydopamine (6-OHDA) or 5, 7-dihydroxytryptamine (5,7-DHT) neurotoxic lesions in the paraventricular nucleus of the hypothalamus (PVN). In intact animals, the administration of phenylephrine, an alpha1 adrenergic agonist or 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) a 5-HT(1A) agonist caused depletion of median eminence corticotropin releasing hormone and a rise in serum adrenocorticotrophic hormone (ACTH) and corticosterone (CS) levels. Isoproterenol a beta agonist was more effective than phenylephrine and a 5-HT(1B) agonist CP-93, 129 was less effective than 8-OH-DPAT on the adrenocortical activity. The 6-OHDA or 5,7-DHT hypothalamic lesions prevented the stimulatory effects of phenylephrine and 8-OH-DPAT, respectively, which where injected into the AMG, on serum ACTH and CS levels. In view of our previous studies on the effects of the adrenergic and 5-HT antagonists in the AMG and the present data, it is suggested that norepinephrine and 5-HT play an important role in the stimulatory effect of the AMG on the HPA axis. These effects depend on the presence of these excitatory neurotransmitters in the PVN.     

The effect of intracerebral injections of 5,7-dihydroxytryptamine and 6-hydroxydopamine on the serotonin-immunoreactive cell bodies and fibers in the adult rat hypothalamus

The effect of intracerebral injections of 5,7-dihydroxytryptamine (5,7-DHT) and 6-hydroxydopamine (6-OHDA) on the serotonin (5-HT)-immunoreactive (IR) cell bodies ¹¹ and fibers in the adult rat hypothalamus was studied with 5-HT immunocytochemistry. In rats pretreated with pargyline and l-tryptophan, 5-HT-IR cells were seen in the ventromedial part of the dorsomedial nucleus (DMN) and 5-HT-IR fibers in all hypothalamic areas. In the ventrolateral part of the DMN the 5-HT-IR fibers were of a much finer type than those seen in other hypothalamic areas. Five days after unilateral injection of 5,7-DHT into the dorsolateral hypothalamus, the 5-HT-IR cells were absent from the DMN, and there was a decrease in the number of 5-HT-IR fibers throughout the hypothalamus ipsilateral to the injection. Contralateral to the injection there was evidence of selective 5-HT fiber degeneration but the 5-HT-IR cells and the group of fine fibers in the ventrolateral DMN remained. Unilateral injection of 6-OHDA into the dorsolateral hypothalamus had no effect on the 5-HT-IR fibers or cell bodies in the hypothalamus.Twelve days after unilateral injection of 5,7-DHT into the rostral midbrain, the majority of 5-HT-IR fibers in the ipsilateral hypothalamus had disappeared. The 5-HT-IR cell bodies in the DMN and the group of fine 5-HT-IR fibers in the ventrolateral DMN remained on both sides of the hypothalamus. These results support our previous finding of a group of 5-HT-IR cell bodies in the ventromedial DMN of the hypothalamus, and suggest that these cells innervate the ventrolateral part of the same nucleus. Evidence that these cells constitute a new 5-HT cell group, B-10, is discussed.     

Monoaminergic denervation of the rat hippocampus: Microiontophoretic studies on pre- and postsynaptic supersensitivity to norepinephrine and serotonin

The responsiveness of hippocampal CA₃ pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE), γ-aminobutyric acid (GABA) and isoproterenol (ISO) was assessed in rats following 5,7-dihydroxy-tryptamine (5,7-DHT) and 6-hydroxydopamine (6-OHDA) pretreatments and bilateral locus coeruleus lesions. The intraventricular administration of 200 μg (free base) of 5,7-DHT and of 6-OHDA produced 89% and 93% decreases of 5-HT and NE respectively. None of these pretreatments modified the initial responsiveness to, or recovery from iontophoretic application of 5-HT. In 6-OHDA pretreated and locus-lesioned rats, the initial effectiveness of NE was not altered but its effect was markedly prolonged. However, there was no such prolongation of the effect of ISO which is not a substrate for the high affinity NE reuptake. The effect of GABA was not affected by these pretreatments. Acute pharmacological blockade of the NE reuptake with desipramine (5 mg/kg, i.p.) similarly induced a prolongation of the effect of iontophoretically applied NE, while fluoxetine (10 mg/kg, i.p.) a 5-HT reuptake blocker, failed to alter the recovery of pyramidal cells from iontophoretic application of 5-HT.

It is concluded that 5-HT denervation induces neither pre- nor postsynaptic types of supersensitivity in hippocampal pyramidal cells, contrasting with the previously shown supersensitivity of ventral lateral geniculate and amygdaloid neurons following 5-HT denervation. NE denervation fails to induce a postsynaptic type of supersensitivity but leads to a marked prolongation of the response to NE indicative of a presynaptic mechanism. These results underscore the necessity for regional studies of neurotransmitters and drug action.     

Depletion of hypothalamic norepinephrine and serotonin enhances the dexamethasone negative feedback effect on adrenocortical secretion.

The role of norepinephrine (NE) and serotonin (5-HT) in the negative feedback effect of dexamethasone (DEX) on the adrenocortical response to ether stress was investigated. Injection of the catecholamine neurotoxin, 6-hydroxydopamine, into the ventral noradrenergic bundle or the paraventricular nucleus of the hypothalamus (PVN) which produced a very significant depletion in hypothalamic NE content enhanced the negative feedback effect of DEX. Injection of the 5-HT neurotoxin, 5,7-dihydroxytryptamine, into the raphé nuclei or PVN, which caused a depletion of hypothalamic 5-HT, produced a similar effect on the adrenocortical response to DEX. The degree of negative feedback may be viewed as a balance of neural stimulatory and glucocorticoid influences of the hypothalamus. Thus the removal of the stimulatory effects of NE and 5-HT on adrenocortical secretion, by the neurotoxic lesions, enhanced the inhibitory influence of DEX.     

Serotonin may play a role in the anorexia induced by amphetamine injections into the lateral hypothalamus

Amphetamine (AMPH) injections into the lateral hypothalamus (LH) are known to inhibit feeding and this effect has been shown to be mediated by the release and the reuptake blockade of catecholamines. LH serotonin (5-HT) has been suggested to be involved in feeding inhibition and a recent study showed that LH amphetamine infusion increases extracellular dopamine (DA), norepinephrine (NE) and 5-HT, which suggests that 5-HT might also be involved in amphetamine anorexia. The present study investigated this possibility. A correlational study was performed between the anorectic effect of LH unilateral microinjections of each monoamine and the anorectic effect of AMPH. Six groups of male rats were used. The rats in each group were submitted to 2 series of 6 experimental sessions. Each session consisted of one microinjection in 24 h food-deprived rats, followed by the measurement of food intake 30 min later. The first series was similar for all groups and explored the AMPH effect (difference between the mean food intake after 3 AMPH injections (40 micrograms/0.5 microliter) and the mean food intake after 3 saline injections (0.5 microliter)). The second series explored the effects of DA (40 micrograms), NE (25 micrograms), EPI (25 micrograms), 5-HT (25 micrograms) or AMPH again, in a similar way as described for AMPH in the first series. Linear regression analysis on the first series AMPH effect and the amine effect of the 2nd series showed a positive correlation between both series of AMPH, AMPH and DA, and AMPH and 5-HT. This last correlation was replicated in a different group. No correlation was found between AMPH and NE or AMPH and epinephrine (EPI).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMP releases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA) (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP (attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD.     

Amphetamine and mCPP Effects on Dopamine and Serotonin Striatalin vivo Microdialysates in an Animal Model of Hyperactivity

In the neonatally 6-hydroxydopamine (6-OHDA)-lesioned rat hyperlocomotor activity, first described in the 1970s, was subsequently found to be increased by an additional lesion with 5,7-dihydroxytryptamine (5,7-DHT) (i.c.v.) in adulthood. The latter animal model (i.e., 134 microg 6-OHDA at 3 d postbirth plus 71 microg 5,7-DHT at 10 weeks; desipramine pretreatments) was used in this study, in an attempt to attribute hyperlocomotor attenuation by D,L-amphetamine sulfate (AMPH) and m-chlorophenylpiperazine di HCl (mCPP), to specific changes in extraneuronal (i.e., in vivo microdialysate) levels of dopamine (DA) and/or serotonin (5-HT). Despite the 98-99% reduction in striatal tissue content of DA, the baseline striatal microdialysate level of DA was reduced by 50% or less at 14 weeks, versus the intact control group. When challenged with AMPH (0.5 mg/kg), the microdialysate level of DA went either unchanged or was slightly reduced over the next 180 min (i.e., 20 min sampling), while in the vehicle group and 5,7-DHT (alone) lesioned group, the microdialysate level was maximally elevated by approximately 225% and approximately 450%, respectively--and over a span of nearly 2 h. Acute challenge with mCPP (1 mg/kg salt form) had little effect on microdialysate levels of DA, DOPAC and 5-HT. Moreover, there was no consistent change in the microdialysate levels of DA, DOPAC, and 5-HT between intact, 5-HT-lesioned rats, and DA-lesioned rats which might reasonably account for an attenuation of hyperlocomotor activity. These findings indicate that there are other important neurochemical changes produced by AMPH- and mCPP-attenuated hyperlocomotor activity, or perhaps a different brain region or multiple brain regional effects are involved in AMPH and mCPP behavioral actions.     

Microdialysates of amines and metabolites from core nucleus accumbens of freely moving rats are altered by dizocilpine

In vivo microdialysis combined with high performance liquid chromatography (HPLC) with electrochemical detection, was used to study the effect of MK-801 (0.1 mg/kg i.p.) on extracellular concentrations of dopamine (DA) 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), norepinephrine (NE) and DOPAC/DA ratio in intact, 6-hydroxydopamine (6-OHDA)-lesioned, DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine hydrochloride)-lesioned and reserpine-treated rats. The results revealed high basal DA (0.735+/-0.05 fmol/microl), DOPAC (195.93+/-20.18 fmol/microl) and NE (0.585+/-0.01 fmol/microl), low 5-HT (0.334+/-0.032 fmol/microl) and high DOPAC/DA ratio (265.11+/-20.73) in intact cACC. 6-OHDA alone (8 microg/2 microl) depleted DA (-66%), DOPAC (-65%), and NE (-62%). On the other hand, in desipramine (DMI)-pretreated rats, 6-OHDA induced a large depletion of DA (-94%), DOPAC (-97%) and reduced DOPAC/DA ratio (-73%), but increased NE to 142% of intact and 369% of 6-OHDA-lesioned rats. DSP4 (50 mg/kg) decreased NE (-97%), DOPAC (-75%) and DOPAC/DA ratio (-69%). Reserpine (5 mg/kg s.c.) significantly decreased DOPAC (-84%), DOPAC/DA ratio (-81%), 5-HT (-69%) and NE (-86%), but nonsignificantly increased DA. In the intact rats, MK-801 did not change DA, but increased DOPAC and DOPAC/DA ratio. In 6-OHDA-lesioned rats, MK-801 increased DA, whereas in 6-OHDA+DMI rats MK-801 additionally increased DOPAC and DOPAC/DA ratio. DSP4 and reserpine reduced the ability of MK-801 to increase DOPAC and DOPAC/DA ratio. MK-801 did not change NE concentration in dialysates collected from intact rats, but increased that from 6-OHDA+DMI-lesioned rats. In DSP4-lesioned and reserpine-treated rats, MK-801 increased NE but to a level lower than that observed in the intact rats. These results suggest that systemic administration of a low dose of MK-801, which induces profound locomotor stimulation without stereotypy, increases DOPAC and DOPAC/DA ratio in the cACC of intact rats, whereas it additionally increases the depleted DA and NE concentrations especially in 6-OHDA-lesioned rats pretreated with DMI.     

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.     

Changes in cortical and subcortical levels of monoamines and their metabolites following unilateral ventrolateral cortical lesions in the rat

Suction lesions were made in the anterior, posterior or both halves of the right ventrolateral cortex in rats. Six days later, levels of the monoamine neurotransmitters, norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), were measured in cortical and subcortical regions of lesioned rats and compared to values in sham-operated animals. NE and 5-HT were decreased in sections of ipsilateral (right) cortex including, and posterior to lesions, while 5-HIAA was increased throughout the ipsilateral cortex. Decreases in monoamines and increases in metabolites and metabolite:monoamine ratios (especially 5-HIAA:5-HT) were found in ipsilateral subcortical structures, including striatum, nucleus accumbens, hippocampus, hypothalamus, midbrain and brainstem, depending on the type of lesion. Subacutely, focal ventrolateral cortical lesions may profoundly alter the levels and utilization rates of monoamine neurotransmitters in widespread regions of the ipsilateral hemisphere.     

Role of descending monoaminergic neurons in the control o sexual behavior: Effects of intrathecal infusions of 6-hydroxydopamine and 5,7-dihydroxytryptamine

The present study concerns the possible participation of descending monoamine pathways in the control of sexual behavior. Male and female rats received micro-injections of the neurotoxins, 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), in the spinal subarachnoid space, which were found to deplete spinal synaptosomal uptake of radiolabeled noradrenaline and serotonin to 46.7% and 34.5%, respectively. Whereas intrathecal 5,7-DHT did not affect sexual behavior appreciably, female 6-OHDA-treated rats showed less sexual receptivity and proceptivity when exposed to constant estradiol; similarly treated males had prolonged post-ejaculatory refractory periods and were more sensitive than controls to androgen deprivation.     

Effects of blinding and pinealectomy on regional brain monoamine concentrations

The effects of blinding with or without pineal ablation on brain monoamine levels were studied in male rats. Brain dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) were measured by radioenzymatic assays. Four weeks following pinealectomy, E levels were significantly enhanced in the frontal cortex. Chronic blinding decreased striatal DA levels and increased striatal 5-HT levels in both sham-operated and pinealectomized (Px) animals. In a second experiment Px animals were sacrificed 1 or 7 d after pinealectomy in order to examine the short-term effects of pinealectomy. There were no differences between controls and Px animals in their cortical levels of DA, NE, and E and their hippocampal and hypothalamic 5-HT levels. However, the E concentrations measured 1 d after surgery were significantly greater than after 7 d. The implications of these findings with regard to the reported role of the pineal and melatonin in brain homeostasis and endocrine regulation are discussed.     

Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression

Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague-Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 microg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine (PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60-66% across three subregions of the A-STR and 52-59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50-62%) and P-STR (55-82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.