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PubMed1990

Inhibition of spontaneous and evoked unit activity in the rat medial prefrontal cortex by mesencephalic raphe nuclei.

The rat medial prefrontal cortex (PFC) receives a serotoninergic (5-HT) innervation which originates from the mesencephalic raphe nuclei. In the present study we determined the influence of the 5-HT ascending systems on the spontaneous and evoked activity of PFC neurons in anesthetized rats. Stimulation of the dorsal (DRN) and of the median raphe (MRN) nuclei inhibited the spontaneous activity of 35.0% and 52.8% of the PFC cells tested (mean duration of the inhibition: 75.5 and 82.2 ms, respectively). These inhibitory responses are likely mediated by the 5-HT-containing neurons since they were decreased markedly following selective destruction of ascending 5-HT pathways induced by local injections of 5,7-dihydroxytryptamine. Moreover, the inhibitory effect of MRN stimulation could be blocked by systemic administration of the 5-HT2 receptor antagonists: ketanserin and ritanserin. The effects of MRN stimulation on two types of evoked responses were studied. The excitatory responses of PFC neurons induced by the stimulation of the mediodorsal nucleus of the thalamus (MD) were inhibited by MRN stimulation applied before that of MD. Similarly, the activation of PFC cells induced by a noxious tail pinch was suppressed by a concomitant stimulation of the MRN. These results indicate that 5-HT neurons exert an inhibitory control on spontaneous or evoked activity in the rat PFC.

5,7-Dihydroxytryptamine↗

PubMed1990

alpha-Methyl-p-tyrosine pretreatment partially prevents methamphetamine-induced endogenous neurotoxin formation.

Depletion of brain dopamine (DA) by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMT) has been shown to prevent the long-term neurotoxic effects of methamphetamine (MA). In addition, it has recently been reported that the neurotoxins 6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT) are formed endogenously in neostriatum and hippocampus, respectively, following a single neurotoxic dose of MA. We, therefore, have examined the ability of AMT pretreatment to prevent the MA-induced formation of 6-OHDA and 5,6-DHT. We report that AMT pretreatment significantly decreases the frequency with which 6-OHDA and 5,6-DHT are detected following MA administration. Neurotoxin formation is compared with brain levels of DA and 5-hydroxytryptamine (5-HT) 2 weeks after MA administration. It is concluded that the ability of AMT to attenuate both 6-OHDA formation and long-term depletions of DA is due to a decrease in the MA-releasable pool of DA. The effect of AMT on MA-induced depletions of 5-HT is less clear and may involve additional factors.

5,6-Dihydroxytryptamine↗

PubMed1990

Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord.

Intrathecal (i.t.) coadministration of calcium (Ca2+), 50 micrograms potentiates the spinal antinociceptive action of morphine and noradrenaline (NA) but not cyclohexyladenosine, 5'-N-ethylcarboxamido adenosine or 5-hydroxytryptamine in the rat tail flick test. This dose of Ca2+ has no intrinsic effect in this test. Higher doses of Ca2+ (200-400 micrograms) produce antinociception in the tail flick and hot plate tests, which is completely blocked by pretreatment with the adenosine receptor antagonists theophylline, 50 micrograms and 8-phenyltheophylline, 3 micrograms. 8-Phenyltheophylline also eliminates potentiation of the antinociceptive action of NA by 50 micrograms Ca2+. The intrinsic antinociceptive effect of Ca2+ is blocked by i.t. pretreatment with the neurotoxins capsaicin, 50 micrograms and 6-hydroxydopamine, 50 micrograms but not 5,7-dihydroxytryptamine, 50 micrograms. Antinociception also is blocked by pretreatment with phentolamine but not by methysergide. These results suggest that the antinociceptive action of high doses of Ca2+ is due to release of adenosine (or a nucleotide which is metabolized to adenosine) from the spinal cord. At lower doses, the release of adenosine is insufficient to cause antinociception, but potentiates the action of NA. Adenosine appears to originate from capsaicin-sensitive small diameter primary afferent nerve terminals. A subsequent interaction of adenosine with spinal adrenergic receptors contributes to antinociception.

5,7-Dihydroxytryptamine↗

PubMed1990

Transplantation of serotonergic neurons into the 5,7-DHT-lesioned rat olfactory bulb restores the parameters of kindling.

In order to restore a normal pattern of kindling, kindled rats, previously lesioned in the olfactory nuclei with 5,7-dihydroxytryptamine, were grafted with serotonin (5-HT) neurons in the right olfactory bulb and then implanted for kindling procedure. It was observed that complete 5-HT lesions accelerated the kindling profile, and that the transplants containing 5-HT neurons restored, in lesioned rats, quite normal parameters.

5,7-Dihydroxytryptamine↗

PubMed1990

Paroxetine as an in vivo indicator of 3,4-methylenedioxymethamphetamine neurotoxicity: a presynaptic serotonergic positron emission tomography ligand?

The present study sought to determine whether [3H]paroxetine, a potent and selective inhibitor of serotonin uptake in vitro, could be used to label the serotonin transporter in the rat brain in vivo such that it might be employed to develop a presynaptic serotonergic positron emission tomography ligand. Tritium labeled paroxetine was administered intravenously to rats by means of tail vein injection. Four hours later, specific [3H]paroxetine binding was determined by subtracting non-specific binding in the cerebellum from total binding in other brain regions of interest. The distribution of specific [3H]paroxetine binding paralleled the distribution of serotonin uptake sites in all brain regions examined. Pretreatment with serotonin re-uptake inhibitors (citalopram or sertraline) reduced in vivo specific [3H]paroxetine binding by as much as 99%. Specific in vivo [3H]paroxetine binding was further characterized through the use of 5,7-dihydroxytryptamine (5,7-DHT), a known serotonergic neurotoxin. 5,7-DHT (200 micrograms, i.c.v.) caused a marked reduction in specific [3H]paroxetine binding, and induced a prolonged depletion of regional brain serotonin. In a final study, the feasibility of using in vivo [3H]paroxetine binding as an indicator of serotonergic damage induced by another neurotoxin (3,4-methylenedioxymethamphetamine, MDMA) was tested. MDMA-treated rats showed a profound reduction in in vivo [3H]paroxetine binding, along with a lasting depletion of regional brain serotonin. These results demonstrate that [3H]paroxetine can be used to label serotonin uptake sites in the rat brain in vivo, and that the damage induced by serotonergic neurotoxins can be detected using in vivo [3H]paroxetine binding as an indicator. Paroxetine (or one of its derivatives) therefore holds promise as a PET ligand for studying serotonergic neurons in the living human brain in health as well as after neurotoxic injury.

3,4-Methylenedioxyamphetamine↗

PubMed1990

Behavioural modification of bulbospinal serotonergic inhibition and morphine analgesia.

Habituation to the stress of sham nociceptive testing enhances a rat's sensitivity to noxious thermal stimuli and reduces the antinociceptive effect of a subsequent acute dose of morphine. Since serotonin (5-hydroxytryptamine, 5-HT) mediates stress responses, experiments were designed to elucidate the role of 5-HT in these phenomena. Intrathecal methysergide or 5,7-dihydroxytryptamine (5,7-DHT) reduced baseline tail-flick latencies of novice rats to those of habituated animals. Morphine dose-response relationships were fitted to a 4 parameter sigmoidal function. Baseline latencies of novice animals were increased by 5-hydroxytryptophan (5-HTP) and reduced by parachlorophenylalanine (PCPA) in both reflex tests and in the hot-plate test, but latencies of habituated animals were unchanged by either treatment. In both reflex tests, the maximum effect due to morphine was increased by 5-HTP and reduced by PCPA in novice but not in habituated animals. We conclude that the serotonergic component of morphine's bulbospinal action represents the stress of the testing environment rather than an essential part of morphine's action.

5,7-Dihydroxytryptamine↗

PubMed1991

Transplantation of fetal mesencephalic and medullary raphe tissues into the cerebellum of denervated adult rats--an immunohistochemical study.

Pieces of mesencephalic and medullary raphe tissues were transplanted into the cerebella of 5,6-dihydroxytryptamine-treated adult rats. The extent of axonal outgrowth of serotonergic and dopaminergic neurons in the grafts was immunohistochemically studied. At 3 months after transplantation, numerous dopaminergic neurons with many processes extending within the graft were detected in the mesencephalic raphe graft, but not in the medullary raphe graft. In contrast, both the mesencephalic and medullary raphe grafts contained numerous serotonergic neurons and a dense plexus of their fibers. The outgrowing serotonergic fibers from the mesencephalic raphe graft showed a hyperinnervation pattern in the cerebellar cortex adjacent to the graft. Furthermore, a glomerulus-like accumulation of serotonergic fibers was observed in the granular layer. In the cases of medullary raphe grafts, the relatively abundant outgrowing serotonergic fibers showed a laminar organization in the cerebellar cortex near the graft, which was similar to the normal distributional pattern. These results indicate that serotonergic and dopaminergic neurons located within the mesencephalic raphe graft clearly differed from each other in their ability to extend their processes into the host cerebellum, which provides further evidence for the existence of specific interactions between outgrowing serotonergic fibers and their terminal fields (targets).

5,6-Dihydroxytryptamine↗

PubMed1991

Immunohistochemical study of short- and long-term effects of DL-fenfluramine on the serotonergic innervation of the rat hippocampal formation.

Owing to the long-lasting depletion in brain serotonin (5-HT) produced by high doses of the amphetamine derivative DL-fenfluramine, this drug has been suspected of neurotoxicity; the serotonergic innervation of the hippocampal formation being one of its most vulnerable targets. A first series of experiments has been carried out to determine, through a 5-HT immunohistochemical study in the rat, the validity of this claim, as well as the rate and the degree of 5-HT recovery. Five to 12 days after a high intraperitoneal dose of DL-fenfluramine (26.8 mg/kg) there is a profound, increasing reduction in the density of serotonin-immunoreactive (5-HT-IR) axons in all portions of the hippocampal formation. The fine-caliber fibers being more affected than the thicker axons. In parallel with this decrease, numerous 5-HT-IR fibers in the cingulum bundle, fornix-fimbria and the hippocampal parenchyma exhibit structural changes, similar to those produced by 5,7-dihydroxytryptamine, a specific neurotoxin of the 5-HT system. By 20 days after the treatment, abnormal axons have disappeared and the density of 5-HT-IR normal axons is markedly increased. By 40 days, the pattern of 5-HT hippocampal innervation is restored but its density is still lower than in controls. These findings, which corroborate the neurotoxic action of fenfluramine, provide anatomical evidence that the chemical ablation is followed by a slow process of axonal regeneration, started between 12 and 20 days and still uncompleted at 40 days. A second series of experiments, with chronic oral administration of DL-fenfluramine, has been conducted to determine presumptive potentiation through a cumulative effect of the drug, and to analyze the recovery process. One day after the end of the treatment with high dose regimens (210 mg/kg, distributed into 5 mg/kg twice daily for 21 days), together with a marked decrease in the density of 5-HT-IR fibers there are some rare forms of axonal pathology. 15 days later, altered axonal forms have disappeared and the density of 5-HT-IR axons has considerably increased, reaching normal levels by 30 days (56 days after the first exposure to the drug). Hence, despite the ability of the fenfluramine to exert its action on 5-HT axons all over the duration of the treatment, it does not exert a noxious cumulative effect as revealed by the low level of axonal pathology noticeable 22 days after the initiation of the treatment, and the relatively fast and complete recovery.(ABSTRACT TRUNCATED AT 400 WORDS)

5,7-Dihydroxytryptamine↗

PubMed1991

Contribution of serotonin neurons to the functional recovery after spinal cord injury in rats.

The contribution of serotonin neurons to the functional recovery after spinal cord injury was studied pharmacologically in rats with moderately severe neurologic impairment (complete paraplegia but responsive to tail pinching) 24 h after thoracic spinal cord (T11) compression-induced injury. Fourteen days after cord injury the levels of endogenous norepinephrine (NE, -33%), dopamine (DA, -50%) and serotonin (5-HT, -55%) in the lumbar cord in the injury control rats were decreased and there were significant correlations between the neurologic score and the NE level (rs = 0.562, P less than 0.01) and the 5-HT level (rs = 0.745, P less than 0.001) but not the DA level. Bilateral i.c.v. injection of 5,7-dihydroxytryptamine (200 micrograms/rat) 24 h after cord injury significantly retarded the neurologic recovery during the 14 days after injury, accompanied by a further reduction in the 5-HT level (-86%) but not in the NE or DA level. On the other hand, neither p-chlorophenylalanine (PCPA) (300 mg/kg, i.p., once daily starting 24 h after injury for 13 consecutive days) nor reserpine (1 mg/kg, i.p., 4 times, once 24 h after injury and then every fourth day) had any influence on the time course of the neurologic recovery during the 14 days after injury, although PCPA treatment further reduced the levels of NE (-50%) and 5-HT (-91%), and reserpine treatment further reduced the levels of NE (-95%), DA (-73%) and 5-HT (-85%).(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗

PubMed1991

Depletion of brain serotonin by 5,7-DHT modifies hamster circadian rhythm response to light.

The midbrain raphe complex innervates the circadian rhythm regulating system by direct projections to the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL). The present experiments examined the changes in circadian rhythm regulation consequent to the depletion of brain serotonin by central 5,7-dihydroxytryptamine (DHT) application. Adult male hamsters with access to running wheels were entrained to a light-dark cycle 14:10 (LD) of photoperiod, pre-treated with desmethylimipramine and given bilateral lateral ventricle infusions of 75 micrograms DHT/2.5 microliters 0.5% ascorbic acid in saline or vehicle only. Two separate experiments were performed. Four weeks after surgery, animals were transferred to either constant light (LL; Experiment 1) or constant dark (DD; Experiment 2). Animals remained in LL for 85 days, then were transferred to DD for 50 days, followed by a return to LD 14:10 for 14 days. Animals in Expt. 2 remained in DD for 55 days, were given 3 days food deprivation, then, beginning 35 days later, were periodically exposed to 30 min light pulses as a phase response curve (PRC) to light was generated. DHT treatment induced rapid appearance of advanced activity onset, delayed offset and longer duration of the nocturnal activity phase. DHT animals in LL had circadian locomotor rhythms much longer than control animals (24.43 +/- 0.04 vs 24.19 +/- 0.05 h) and normal circadian rhythmicity was rapidly lost by DHT animals in LL. There was no effect of DHT on circadian period in DD, but the DHT treated animals in DD had a larger phase delay region of the PRC than did controls and this was associated with an overall change in the temporal properties of the PRC. Serotonin immunohistochemistry showed an approximate 90% loss of cells from the dorsal raphe nucleus and decreased density of the serotonergic terminal field in the SCN and IGL. The results support the view that the serotonergic system modulates the phasic actions of light on the hamster circadian rhythm system. The data also indicate that hamsters can have a Type 0 PRC.

5,7-Dihydroxytryptamine↗

PubMed1991

Serotonergic modulation of the hamster wheelrunning rhythm: response to lighting conditions and food deprivation.

Depletion of brain serotonin by 5,7-dihydroxytryptamine (DHT) produces large changes in photic regulation of the hamster circadian running rhythm. This study documents the changes in daily wheelrunning caused by DHT lesions and their relationship to changes in photic conditions or food availability. Hamsters were given bilateral infusions of the selective neurotoxin during entrainment to a light-dark cycle (LD) of 14:10 h. At a later time, animals were transferred to constant light (LL) or dark (DD) for a prolonged period. Animals in DD were also subject to 3 days of food deprivation. Destruction of the serotonergic system does not change the amount of daily running in LD 14:10, but does alter the rate of running. Control animals respond to LL by greatly decreasing running compared to those with lesions. Food deprivation, a condition that greatly elevates running in control animals, is not nearly as effective in lesioned animals. The results suggest that serotonin-depleted hamsters have diminished responsiveness to environmental stimuli.

5,6-Dihydroxytryptamine↗

PubMed1992

Cerebrovascular nerve fibers immunoreactive for tryptophan-5-hydroxylase in the rat: distribution, putative origin and comparison with sympathetic noradrenergic nerves.

The distribution of serotonergic nerves in major basal and isolated small pial arteries (diameter > or = 50 microns) was investigated immunohistochemically using an antibody directed against tryptophan-5-hydroxylase (TPOH), the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT or serotonin), and compared to that of the noradrenergic system labeled for the selective noradrenaline (NA) synthesizing enzyme, dopamine-beta-hydroxylase (DBH). In addition, the possible peripheral and/or central origins of the cerebrovascular serotonergic (TPOH-positive) nerve fibers were examined. Strongly labeled TPOH-immunoreactive (TPOH-I) fiber bundles were observed in major basal arteries and gave rise to small varicose fibers organized in a meshwork pattern. The highest density of TPOH-I fibers was found in the middle cerebral artery followed by the anterior cerebral and the anterior communicating arteries, with a moderate to low density in the internal carotid and the vertebro-basilar trunk. Of the isolated pial arteries, only the larger ones (diameter > 75 microns) were significantly endowed with TPOH-I varicose fibers. However, free floating TPOH-I nerves were observed coursing through the pia-arachnoid membranes and reaching small pial vessels. In contrast, DBH-I nerve fibers were fine and were visualized primarily as numerous varicosities distributed in a circumferential manner around the vessel wall. A very high density of DBH-I varicosities was seen in the rostral part of the circle of Willis, with the internal carotid being the most richly supplied followed by the anterior cerebral and the anterior communicating arteries; comparatively, the middle cerebral artery was moderately innervated. The differences in distribution pattern and density between TPOH-I and DBH-I cerebrovascular fibers clearly suggest that these two innervation systems are not exactly superimposable. Superior cervical ganglionectomy caused an almost complete disappearance of TPOH-I nerves in all vascular segments, with some residual fibers in selected vessels. Lesion of the central serotonergic component with the neurotoxin 5,7-dihydroxytryptamine had virtually no effect on the TPOH-I fibers in the major basal and isolated pial arteries. These results strongly suggest that the serotonergic innervation of major cerebral as well as pial arteries has a prominent peripheral origin closely related to the sympathetic system. Processing of superior cervical ganglion slices for TPOH immunocytochemistry, however, failed to unequivocally detect TPOH-I neurons.

5,7-Dihydroxytryptamine↗

PubMed1992

Effect of serotonergic agents on regional concentrations of somatostatin- and neuropeptide Y-like immunoreactivities in rat brain.

A possible role for neuropeptides in affective disorders is suggested by many investigators. Somatostatin-like immunoreactivity (SS-LI) and neuropeptide Y-like immunoreactivity (NPY-LI) concentrations are demonstrated to be reduced in cerebrospinal fluid from depressed patients. We have shown that long-term treatment with serotonin uptake inhibitors, clomipramine and zimelidine, reduce brain SS-LI concentrations in the rat. We have studied the effect of serotonergic agents on regional brain SS-LI and NPY-LI concentrations in rats. Long-term treatment with 5-hydroxytryptamine (5-HTP), a serotonin precursor, caused reductions in SS- and NPY-LI levels in the hypothalamus. SS- and NPY-LI concentrations in the brain were markedly elevated by treatment with p-chlorophenylalanine, a serotonin synthesis inhibitor. Intracerebroventricular administration of 5,7-dihydroxytryptamine, a serotonin neurotoxin, resulted in elevations of both peptides in the brain. These results suggest a inhibitory role for the serotonergic system in the brain in the regulation of SS and NPY.

5,7-Dihydroxytryptamine↗

PubMed1992

Serotonergic reinnervation of the hamster suprachiasmatic nucleus and intergeniculate leaflet without functional circadian rhythm recovery.

Intraventricular injections of the neurotoxin, 5,7-dihydroxytryptamine (DHT), were used to lesion hamster forebrain serotonin systems. The entrained circadian wheelrunning rhythm was studied for up to 20 weeks post-lesion as was the extent of reinnervation of nuclei regulating circadian rhythmicity. Reinnervation of the suprachiasmatic nucleus and intergeniculate leaflet by serotonergic fibers begins by 8 weeks and progresses to substantial, but not complete, levels by week 20. Four measures of the nocturnal activity phase of the circadian rhythm were rapidly modified by the lesions, but in contrast to the morphology, persisted unchanged during the entire 20 week test period. The circadian rhythm system of hamsters may be fundamentally different from other behavioral or neuroendocrine systems studied in rats with respect to its inability to recover from damage to its serotonergic innervation. Alternatively, the failure to demonstrate functional recovery may reflect a species difference or insufficient recovery time.

5,6-Dihydroxytryptamine↗

PubMed1992

Acetylcholine release in the hippocampus: regulation by monoaminergic afferents as assessed by in vivo microdialysis.

The role of monoamines in the functional regulation of the septo-hippocampal cholinergic system was studied using in vivo microdialysis of acetylcholine (ACh) release in the hippocampus of awake unrestrained rats. Systemic administration of the dopamine receptor agonist apomorphine (2.0 mg/kg) resulted in a 170% increase in hippocampal ACh overflow. Similarly the catecholamine-releasing agent amphetamine (2.5 mg/kg) produced a 400% increase in ACh overflow. The effect induced by amphetamine, but not that of apomorphine, was blocked in animals pretreated with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). The effect of amphetamine on ACh release was reduced by 75% after a 6-hydroxydopamine (6-OHDA) lesion of the ventral tegmental area (VTA) but was not affected by 6-OHDA lesions of the noradrenergic dorsal and ventral bundles. However, baseline ACh overflow was increased by 130% by the dorsal and ventral bundle lesions. The serotonin-releasing agent p-chloroamphetamine (2.5 mg/kg) produced a 160% increase in hippocampal ACh release, and this effect was enhanced after a 5,7-dihydroxytryptamine (5,7-DHT) lesion of the serotonin projection system. The results show that surgical or pharmacological manipulations of the ascending brainstem monoaminergic systems, which innervate wide areas of the forebrain, including the septum and the hippocampal formation, have pronounced effects on septo-hippocampal cholinergic activity. Thus, the present data provide support for the view that information regarding behavioral state and arousal is conveyed to the septo-hippocampal system via ascending monoaminergic systems.

5,7-Dihydroxytryptamine↗

PubMed1992

Ventral pontine catecholaminergic pathway mediates the vasopressin response to splanchnic osmostimulation in conscious rats.

This study examines the role of catecholamines, cell bodies and fibers of passage within the subcoeruleus area (subLC) in the arginine vasopressin (AVP) response to splanchnic osmotic stimulation and hemorrhage. Bilateral chemical lesions were induced into the subLC, approximately 1 mm ventral to the locus coeruleus (LC), using 6-hydroxydopamine (6-OHDA) and ibotenic acid to selectively destroy catecholaminergic components and cell bodies, respectively. Vehicle and 5,7-dihydroxytryptamine (5,7-DHT) injections into the subLC area, 6-OHDA injections into the LC, as well as systemic desipramine pretreatment, were performed as controls for the possible non-specific effects of the lesions. Seven and 8 days later, plasma AVP level, plasma osmolality, mean arterial pressure and heart rate were measured following either gastric infusion of hypertonic (598 mOsm/kg; 2 ml/4 min) or isotonic (290 mOsm/kg) saline or a mild hemorrhage (2.5 ml/300 g) in conscious rats with indwelling tail artery catheters and naso-gastric tubes. 6-OHDA injections into subLC reduced the AVP response to the osmotic stimulation by 62.3% (P less than 0.01), as compared to vehicle-injected controls. These same rats demonstrated a normal AVP response to hemorrhage implying a specificity of the disrupted pathway. All controls confirmed that the effects of the 6-OHDA were due to specific action on noradrenergic components within the subLC area. Ibotenic acid lesions in the subLC did not significantly decrease the AVP response, demonstrating that mainly fibers and not cell bodies in this region are part of the pathway. 6-OHDA injections just anterior to the LC, where the dorsal noradrenergic bundle (DNAB) forms, reduced the AVP secretion due to hemorrhage by 77.0% (P less than 0.05), but had minor effects on the response to osmotic stimulation. These results indicate that catecholaminergic fibers travelling primarily within the subLC, in the ventral noradrenergic bundle (VNAB), carry splanchnic osmotic input to the hypothalamus, whereas the DNAB may mediate the AVP response to hemorrhage.

5,7-Dihydroxytryptamine↗

PubMed1992

Characterization of opioid receptor-mediated regulation of incertohypothalamic dopamine neurons: lack of evidence for a role of 5-hydroxytryptaminergic neurons in mediating the stimulatory effects of morphine.

The purpose of the present study was to characterize opioid receptor-mediated regulation of incertohypothalamic dopaminergic (DA) neurons in the rat brain by examining the acute effects of selective mu or kappa opioid receptor agonists and antagonists on concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial zona incerta (MZI) and the dorsomedial hypothalamic nucleus (DMN) which contain cell bodies and terminals, respectively, of these neurons. Morphine caused a dose- and time-related increase in concentrations of DOPAC in MZI and DMN; this stimulatory effect was blocked by the mu opioid receptor antagonist naltrexone. In contrast, activation or blockade of kappa opioid receptors following administration of U-50,488 or nor-binaltorphimine, respectively, had no effect on DOPAC concentrations in either the MZI or DMN. The basal activity of incertohypothalamic DA neurons and their response to morphine was similar in male and female rats. Morphine also increased the concentrations of 5-hydroxyindoleacetic acid in MZI and DMN, indicating that morphine increases the activity of 5-hydroxytryptamine (5HT) neurons projecting to these regions. This might suggest that morphine-induced activation of incertohypothalamic DA neurons is mediated by 5HT neurons; but 5,7-dihydroxytryptamine-induced lesions of 5HT neurons did not alter the ability of morphine to increase DOPAC concentrations in MZI and DMN. These results indicate that the stimulatory effects of mu opioid receptor activation on incertohypothalamic DA neurons is not dependent upon the presence of 5HT neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

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.

5,7-Dihydroxytryptamine↗