Possible relationship of the locus coeruleus--hippocampal noradrenergic neurons to depression and mode of action of antidepressant drugs

Recent studies performed in our laboratory suggest involvement of locus coeruleus (LC) and hippocampal noradrenergic (NE) neurons in the mechanism of depression and mode of action of antidepressants. Both electrolytic and 6-OHDA lesions to the LC abolished desipramine action in forced swim test in rats. The action of desipramine was also reduced in rats pretreated with alpha 1 adrenolytic drugs -- phenoxybenzamine and prazosin. Electrical stimulation of the LC produced, like desipramine, activating effect in forced swim test, the phenomenon never observed in phenoxybenzamine-pretreated animals. Chronic (but not acute) administration of desipramine potentiated activatory effects of intrahippocampal injections of NE and phenylephrine but not isoprenaline in both open field and forced swim test. Depressant effect of intrahippocampal clonidine was reversed by chronic desipramine (in the open field test). The effect of desipramine was partially shared by citalopram.     

The role of brain serotonin in the electroconvulsive shock-induced changes in behavioural effects of intra-hippocampally injected clonidine

The influence of central serotonin depletion upon behavioural effects of intra-hippocampally injected clonidine in the electroconvulsive shock-treated rats (ECS), was studied. Repeated ECS significantly attenuated the depressive influence of clonidine upon the locomotor activity of the rats in the open field test. Chemical lesions to the median raphe nucleus (MR) did not significantly affect ECS-induced changes in clonidine activity in this test. In the forced swimming the MR lesions revealed the stimulatory potency of clonidine microinjections upon rat active behaviour. In animals pretreated with repeated ECS, clonidine also significantly potentiated swimming activity, but no evident synergism of ECS and MR lesion could be observed. Taking into account these and other data it is concluded that central serotonin depletion might differentially affect the adaptive processes occurring in the alpha 2-adrenoceptors in the course of treatment with tricyclic antidepressants and ECS, but it does not seem to be a strong phenomenon. Moreover, it is suggested that clonidine effects in the open field and forced swimming tests may be mediated by different neuronal substrates within the rat hippocampus.     

Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat.

The forced swim test is a behavioural paradigm that is predicative of antidepressant activity in rodents. Until recently, research has focused on the ability of antidepressant drugs to decrease immobility in the forced swim test paradigm, but the neurochemical sequelae induced by swim stress, or the neurochemical basis of antidepressant-induced behavioural changes have received little attention. In this regard, we have recently demonstrated that forced swim test exposure increases serotonergic activity in the amygdala, frontal cortex and hippocampus and dopamine turnover in the striatum. In addition, forced swim test-exposure activates the hypothalamic pituitary adrenal axis. The purpose of the present study was to examine the effect of treatment with the selective noradrenaline reuptake inhibitor reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation scores in the forced swim test, and on forced swim test-induced neurochemical and hypothalamic pituitary adrenal axis changes in the rat. Reboxetine treatment (10 and 30 mg/kg) significantly decreased immobility and defaecation in the forced swim test in dose dependent manner. Furthermore, reboxetine produced a dose dependent attenuation of forced swim test-induced increases in serotonin turnover in the amygdala and frontal cortex and dopamine turnover in the striatum. Reboxetine (30 mg/kg) produced a modest, but non-significant, attenuation of forced swim test-induced increases in serum corticosterone concentrations. These data demonstrate that, in addition to the behavioural activity of reboxetine in the rat forced swim test paradigm, a dose-dependent attenuation of swim stress-induced increases in serotonergic and dopaminergic activity occurred in a region specific manner. These are the first data to demonstrate that treatment with the selective noradrenaline reuptake inhibitor, reboxetine can impact on the activity of other neurotransmitter systems in response to stress. Moreover, these data further demonstrate that this paradigm is a valuable tool in studying the effect of antidepressants, on both behaviour and swim stress-related alterations in central neurotransmitter function and hypothalamic pituitary adrenal axis activity in the rat.     

Modification of behavioral response to intra-hippocampal injections of noradrenaline and adrenoceptor agonists by chronic treatment with desipramine and citalopram: functional aspects of adaptive receptor changes

The present study investigated the effects of acute and of chronic treatment with desipramine (DI) and citalopram (CT) on the alterations in rat behavior in the open field and in the forced swim tests produced by intra-hippocampal microinjections of noradrenaline (NA) and adrenoceptor agonists. Chronic but not acute treatment with DI potentiated the stimulatory effects of NA on the rats' behavior in the open field test and in the forced swim test as well as revealed the excitatory effect of microinjections of phenylephrine at a dose producing insignificant changes when given alone. The depressive effects of clonidine in the open field test were antagonized by acute DI administration and reversed by chronic DI. No characteristic changes in the isoproterenol-induced increase in rat locomotion were observed following chronic DI since the antagonistic interaction was found after both acute and chronic DI pretreatment. Chronic though not acute administration of CT produced effects in the forced swim test similar to those of DI, i.e. excitatory effects of phenylephrine and clonidine on behavior. The data indicate a potentiation of excitatory processes in the brain limbic structure, probably mediated via alpha 1-adrenoceptors.     

Are ascending noradrenergic and serotonergic pathways necessary for effects of electroconvulsive treatment? Clonidine hypothermia and forced swim study

Are ascending noradrenergic and serotonergic pathways necessary for effects of electroconvulsive treatment? Clonidine hypothermia and forced swim study. W. DANYSZ , W. KOSTOWSKI, M. HAUPTMANN, A. BIDZINSKI. Pol. J. Pharmacol. Pharm., 1989, 41, 15-22. Influence of chemical lesions to the noradrenergic locus coeruleus (intracerebral 6-OHDA injection, systemic administration of DSP-4) and serotonergic raphe system (intracerebral 5,7-DHT) on some effects produced by electroconvulsive shock (ECS) was studied. Administration of ECS slightly but significantly attenuated clonidine (CLO)-induced hypothermia and reduced rats immobility in forced swim test. DSP-4 reduced ECS action on CLO hypothermia remaining without effect upon ECS action in the second test. Other lesions were ineffective in both tests. This finding is in contrast to results obtained previously in animals receiving desipramine. The possible difference between ECS and antidepressant drugs action is discussed.     

Antidepressant-like effects of NMDA-receptor antagonist injected into the dorsal hippocampus of rats

Exposure to uncontrollable stressors causes behavioral changes that have been related to depressive states in humans. Poststress intrahippocampal administration of amino-7-phosphonoheptanoic acid (AP-7), a glutamate NMDA-receptor antagonist, attenuated the restraint-induced decreased exploration of an elevated plus maze 24 h later. The objective of the study was to test if this treatment would also attenuate the increased immobility seem in the forced swim test (FST) due to preexposition to this stressful situation. Male Wistar rats with cannulae aimed at the dorsal hippocampus were submitted to 15 min of forced swimming and tested 24 h later. They received bilateral intrahippocampal injections of AP-7 (10 nmol) either before or after the pretest swimming session or before the test. Poststress treatment increased latency to display the first episode of immobility and tended to reduce total immobility time. The drug was ineffective when given before stress or before test and in nonstressed animals. This suggests that glutamate NMDA receptors located in the dorsal hippocampus are involved in the behavioral changes observed in the FST.     

Neuropeptide-Y exerts antidepressant-like effects in the forced swim test in rats

The effects of neuropeptide-Y were examined in the forced swim model of depression in rats. Following a 15-min preswim, four groups of rats were given three intracerebroventricular (i.c.v.) injections of neuropeptide-Y (0.5, 5, or 10 microg) or saline over a 24-h period. Several behaviors were subsequently measured during a 5-min forced swim. Neuropeptide-Y treatment dose dependently increased swimming and decreased immobility. The pattern of results is consistent with that produced by serotonergic antidepressant drugs in this model.     

A stimulatory effect of intraaccumbens injections of noradrenaline on the behavior of rats in the forced swim test

Intraaccumbens injections of catecholamines noradrenaline and dopamine, though not of serotonin, stimulated locomotion by rats in an open field, 10–15 min later. Similar effects were observed 5 min after microinjection of apomorphine whereas clonidine only attenuated locomotor activity. On the other hand, intraaccumbens administration of phenylephrine, isoproterenol and quipazine, in doses similar to an effective dose of noradrenaline, did not alter rat open field behavior. The escape-directed activity of rats in the forced swim test (FST) was stimulated 5 min after local administration of noradrenaline, phenylephrine, isoproterenol or apomorphine only. No effects in the FST were observed 15 min after noradrenaline injection or after intracaudate noradrenaline administration. The stimulatory effects of intraaccumbens noradrenaline injection in the FST were antagonized by the local pretreatment of rats with phentolamine, though not with propranolol. Accordingly, it is possible to conclude that both catecholamines, but not serotonin, play complex and probably distinct roles within the nucleus accumbens in the stimulation of activity by rats in the FST and the open field test.     

On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression

Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test. Chronic DMI action on the rat immobility was reduced by 6-hydroxydopamine lesions of the LC: other lesions (electrolytic, DSP-4) were ineffective. Electrical stimulation of the LC increased the rat activity in the forced swim paradigm, producing an effect similar to that of antidepressants. The anti-immobility effect of DMI as well as LC stimulation were antagonized by drugs blocking alpha-adrenoceptors (phenoxybenzamine, prazosin) but not by propranolol, a non-selective antagonist of beta-adrenoceptors. On the other hand, the anti-immobility action of AMI was unchanged by all adrenolytics used in that study. The results indicate that the LC system and alpha 1-adrenoceptors play an important role in the antidepressive action of DMI, but not AMI, in the forced swim test.     

Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms.

The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline-containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex). The ECoG effects were continuously analysed and quantified by means of a Berg-Fourier analyser as total power and as power in preselected bands of frequency. Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose-dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus. Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex. The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of alpha 2-adrenoceptors but not by alpha 1-adrenoceptor antagonists. Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective alpha 2-adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after microinjection of phentolamine into the same sites. No significant effects on behaviour and ECoG activity were evoked after intraventricular injection or microinfusion into the locus coeruleus of prazosin or methoxamine.     

Galanin and spatial learning in the rat. Evidence for a differential role for galanin in subregions of the hippocampal formation

Anatomical, neurochemical and behavioural evidence support a role for galanin in hippocampally mediated functions such as spatial learning and memory. To obtain more precise information on this role, galanin (3 nmol/rat) was infused via bilateral chronic cannulae into different areas of the hippocampal formation which are characterized by different galanin receptor subtypes and also by different galanin innervation patterns. The effects of infused galanin on spatial learning were examined in the Morris swim maze. Infusions of galanin into both the dorsal and ventral dentate gyrus, which mainly contain GAL-R2 receptor mRNA and a high degree of galanin-noradrenaline coexistence, significantly retarded spatial acquisition without affecting swim speed or performance in the visible platform test. This spatial learning deficit was fully blocked by pretreatment with the non-selective galanin antagonist M35. Analysis of retention performance suggested that the major effect of intrahippocampal galanin is mediated via a specific disruption of acquisition mechanisms of importance for performance in the probe trial. Galanin infused into the ventral CA1 (a mainly GAL-R1 receptor mRNA expressing region) or into anterior, ventral CA3 regions did not produce any deficits in spatial learning compared to control animals. These results suggest that galanin mediates its action on spatial learning mainly through the GAL-R2 receptor subtype in areas where most of the galanin is present in noradrenergic terminals. A possible role for the GAL-R1 receptor subtype in cognition in the dorsal and ventral hippocampus remains to be defined. The results suggest a differential functional role for galanin and galanin receptor subtypes within subregions of the hippocampal formation.     

Comparative studies on antidepressant action of alprazolam in different animal models

Alprazolam, a new benzodiazepine from triazolobenzodiazepine group, produced anxiolytic action in the conflict test with potency similar to that of diazepam. The myorelaxant activity of the drug was relatively weak. Unlike desipramine, alprazolam failed to reduce the immobility of rats in the forced swim test and was unable to prevent clonidine-induced hypothermia. Alprazolam, unlike desipramine, failed also to potentiate behavioral effect of noradrenaline injected into the hippocampus. Alprazolam after acute but not chronic administration antagonized the synchronizing effect of clonidine on EEG pattern. On the other hand, alprazolam similarly to tricyclic antidepressants, prevented the suppression of dominance behavior by clonidine in rats competing for food. The results indicate that alprazolam acts only weakly upon noradrenergic mechanisms related to depression and to antidepressant action of drugs.     

Production of limbic motor seizures and brain damage by systemic and intracerebral injections of paraquat in rats.

The behavioural and neuropathological effects of both systemic and intrahippocampal injections of paraquat dichloride (1,1'-dimethyl 4,4'-bipyridinium dichloride) were studied in rats. Paraquat (0.1-1.0 mumol) injected into the dorsal hippocampus, produced limbic motor seizures within a few minutes of injection followed by neuronal damage in the CA1 and CA3 pyramidal cell layers, pyriform cortex, dentate granule cell layer and in the hilus fascia dentata at 24 hr (n = 9 rats). A smaller dose of paraquat (10 nmol) was ineffective. The effects of intrahippocampal injections of paraquat (1 mumol) were prevented by administering it together with atropine (50 nmol; n = 6 rats) or by giving it 60 min. after MK 801 (0.3 mg.kg-1 intraperitoneally). Systemic injections of paraquat (20-100 mg.kg-1) also produced forelimb clonus and rearing in 10 out of 15 animals. Neuronal cell death was found 24 hr later in 9 of these rats and was restricted to the pyriform cortex, the brain region with the highest concentrations of paraquat. Atropine (150 mg.kg-1 intraperitoneally given 60 min. previously) completely prevented the motor seizures but cell death still occurred in 2 of the 6 animals tested. In conclusion, both systemic and intrahippocampal injections of paraquat produced behavioural excitation accompanied 24 hr later by brain damage and antagonist studies suggested involvement of muscarinic and NMDA receptors in the neurotoxic mechanism.     

Increased anxiety and "depressive" symptoms months after MDMA ("ecstasy") in rats: drug-induced hyperthermia does not predict long-term outcomes

Rationale There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour. Objective The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration. Method Male Wistar rats were treated with MDMA (4×5 mg/kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28°C) or a low ambient temperature (16°C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC. Results MDMA treatment caused a clear and consistent hyperthermia at 28°C and hypothermia at 16°C. Months later, rats pre-treated with MDMA at either 16 or 28°C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and increased immobility in the forced swim test. MDMA pre-treatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28°C. Rats pre-treated with MDMA showed loss of 5-HT in the hippocampus, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippocampus was greater in rats pre-treated at 28°C. Dopamine in the striatum was also depleted in rats given MDMA. Conclusions These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.     

Repeated electroconvulsive stimuli increase brain-derived neurotrophic factor in ACTH-treated rats

Electroconvulsive therapy is considered to be an effective treatment for severe depression. We have already shown that the antidepressant-like effects of tricyclic antidepressants in the rat forced swim test are blocked by repeated treatment with adrenocorticotropic hormone (ACTH). In the present study, we investigated the effect of repeated electroconvulsive stimuli on the forced swim test and on brain-derived neurotrophic factor (BDNF) protein levels in ACTH-treated rats. Electroconvulsive stimuli (50 mA, 0.2 s) was administered 30 min after ACTH treatment (100 microg/rat, s.c.) once daily for 14 days. In both saline and ACTH-treated rats, repeated electroconvulsive stimuli for 6 or 14 days decreased the immobility time in the forced swim test and increased the BDNF protein levels in the hippocampus. However, repeated imipramine administration (10 mg/kg, i.p. for 14 days) had no effect on the hippocampus BDNF protein levels in ACTH-treated rats. These results suggest that electroconvulsive stimuli has decreasing effects of immobility time in the forced swim test in the tricyclic antidepressant-resistant depressive model of rats induced by repeated ACTH treatment, and that increased BDNF may be involved in this phenomenon.     

Effect of cyclophosphamide on gene expression of cytochromes p450 and beta-actin in the HL-60 cell line

The novel antidepressant reboxetine is a selective norepinephrine reuptake inhibitor. In this study, the antidepressant-like effects of reboxetine were characterized in a modified rat forced swim test. Further, in order to investigate the role of the locus coeruleus and lateral tegmental noradrenergic systems in the mediation of reboxetine's effects, the impact of different chemical lesions of these two pathways was examined on the behavioral responses induced by reboxetine in the forced swim test. Reboxetine (5-20 mg/kg, s.c.) dose-dependently decreased immobility and swimming behavior in the forced swim test while it simultaneously increased climbing behavior. These effects were similar to those previously demonstrated with tricyclic antidepressants and are indicative of reboxetine's effects on the noradrenergic system. Discrete local injections of the neurotoxin 6-hydroxydopamine were employed to lesion the ventral noradrenergic bundle arising from cells located in the lateral tegmentum. This resulting lesion completely prevented reboxetine (10 mg/kg, s.c.)-induced decreases in immobility and increases in climbing behavior, demonstrating that an intact ventral noradrenergic bundle is required for the manifestation of reboxetine-induced antidepressant-like behavior in the test. In contrast, lesions of the dorsal noradrenergic bundle which consists of neurons arising from the nucleus locus coereleus, were achieved by systemic pretreatment with the selective noradrenergic neurotoxin N-(2-chloroethyl)-N-2-bromobenzylamine (DSP-4; 50 mg/kg, i.p.). The ability of reboxetine (10 mg/kg, s.c.) to increase climbing and decrease immobility was augmented by DSP-4 pretreatment. Furthermore, neither lesions of the dorsal noradrenergic bundle nor the ventral noradrenergic bundle altered baseline immobility scores in the forced swim test. Taken together, these data suggest that forebrain regions innervated by these two distinct noradrenergic pathways exert opposing influences on the behavioral response to reboxetine in the rat forced swim test.     

Corticosterone Is Permissive to the Anxiolytic Effect That Results From the Blockade of Hippocampal Mineralocorticoid Receptors

The effects of RU 28318, a mineralocorticoid receptor antagonist (A-MR), and RU 38486, a glucocorticoid receptor antagonist (A-GR) on behavior in three animal models of anxiety were assessed after microinjection into the dorsal hippocampus. Significant anxiolytic effects were observed after intrahippocampal injection of 0.5, and 1 ng of A-MR in thigmotaxic behavior in the open field, in the elevated plus-maze, and in the defensive burying test. Lower (0.2 ng) or higher (5 ng) doses of A-MR were ineffective, as were comparable injections of A-GR or microinjections of combined A-MR and A-GR. The anxiolytic effect of intrahippocampal A-MR administration observed in the elevated plus-maze and in the open field was not observed in adrenalectomized animals or in animals pretreated with a systemic injection of dexamethasone (80 mg/kg). Intrahippocampal injection of 1 ng of A-MR or A-GR prevented the return to basal corticosterone levels observed 90 min after restraint stress. This effect was reversed in dexamethasone-pretreated animals. The results are discussed in light of recent findings implicating the role of the MR in the hippocampus in adaptive behavioral responses to an aversive or threatening environment, and further implicate the permissive role of corticosterone in A-MR-induced behavioral responses.     

Serotonin1A-receptor agonism attenuates the cocaine-induced increase in serotonin levels in the hippocampus and nucleus accumbens but potentiates hyperlocomotion: an in vivo microdialysis study

The hippocampus and the nucleus accumbens (Nac) are important structures for the modulation of spontaneous locomotor activity. Both structures receive a serotonergic (5-HT) innervation. We have previously reported that the 5-HT(1A)-receptor antagonist WAY 100635 blocked cocaine-induced hyperactivity, while potentiating cocaine-induced 5-HT increases in the hippocampus and the Nac. In order to further investigate the relationship between extracellular 5-HT concentration and cocaine-induced behaviour, we used in vivo microdialysis to measure the effects of the 5-HT(1A)-receptor agonist 8-OH-DPAT on cocaine-induced changes in the extracellular 5-HT concentration in the hippocampus and the Nac and on behavioural activity. Following a pilot pretest in which we determined the lowest effective dose of 8-OH-DPAT for potentiating cocaine-induced hyperlocomotion, four groups of rats were given one of the following drug treatments: 8-OH-DPAT (0.2 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), 8-OH-DPAT (0.2 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 30 min apart. We found that the 5-HT(1A)-receptor agonist 8-OH-DPAT attenuated the cocaine-induced increases in 5-HT in the hippocampus and the Nac, but potentiated cocaine-induced hyperlocomotion. 5-HT metabolite measurements revealed a complex role for the 5-HT(1A)-receptor in the broad spectrum of cocaine's neurochemical effects. Altogether, these observations support an important role of the 5-HT(1A)-receptor in the hippocampus and Nac in the modulation of cocaine stimulant effects.     

Effects of swim stress and alpha-MSH acute pre-treatment on brain 5-HT transporter and corticosterone receptor

The forced swim test (FST) can lead to stress-related diseases such as depression, through activation of hypothalamic-pituitary-adrenal axis (HPAA) and corticosteroid disregulation. Among the proopiomelanocortin (POMC)-derived peptides, alpha-melanocyte-stimulating hormone (alpha-MSH) has been shown to regulate long-lasting behavioral responses. Moreover, serotonergic pathways in various brain areas are activated by stressors, a feature that suggests a role for serotonin in both stress-induced HPAA disregulation and depressive physiopathology. Taking all together these data, we investigated the effects of the FST exposure and the effects of pre-treatment with alpha-MSH on cortical synaptosomal serotonin transporter (SERT) activity, corticosterone (CORT) plasma levels and on glucocorticoid receptor (GR) occupancy and expression in rat hippocampus. Young male rats were divided into three groups treated with saline or with alpha-MSH at doses of 1 or 4 microg/rat, 15 min prior to FST. Our data show that FST increased CORT secretion; GR levels in hippocampus decreased in density after stress without variations in affinity; GR redistributed from the cytosolic to the nuclear tissue fraction; finally, SERT activity strongly increased. All these effects were blocked by pre-treatment with alpha-MSH at the higher dose.     

Role of serotonergic and noradrenergic systems in a model of visceral pain

The effects of selective manipulations of activity of the serotonergic and noradrenergic systems were examined in the rat model of visceral pain. It was found that neither p-chlorophenylalanine(p-CPA)- nor N-chloro-ethyl-2,2--bromo-benzylamine(DSP-4)-induced strong and selective depletion of the brain and spinal cord serotonin and noradrenaline, respectively, changed in a significant way rat visceral pain perception. On the other hand, 8-OH-DPAT, a full selective 5-HT1A receptor agonist, prazosin, an alpha1-adrenoceptor antagonist, clonidine, an alpha2-adrenoceptor agonist, and two beta-adrenoceptor antagonists: propranolol and metoprolol, dose-dependently reduced the number of body writhes induced by intraperitoneally administered 2% solution of acetic acid (the writhing test). The results obtained with selective receptor ligands, DSP-4 and p-CPA, indicate that the noradrenergic and serotonergic innervation of the central nervous system contribute in a complex way to the animal behavior in the writhing test. The 5-HT1A receptors and alpha2-adrenoceptors play an inhibitory role in the expression of rat behavior in this model of visceral pain. On the other hand, adrenergic alpha1 and beta1 receptors facilitate the behavioral effects of the irritant agent.