The effect of amygdaloid ablation or stimulation on plasma corticosterone levels in the male rat

Participation of the amygdaloid complex in pituitary-adrenal function was assessed by measuring plasma corticosterone levels after a variety of ablative or stimulatory procedures in male rats. Transection of the stria terminalis, ablation of the basolateral amygdalopiriform region or subtotal amygdalectomy did not alter a.m. or p.m. non-stress plasma corticosterone levels. Likewise, stress-induced increments in plasma corticosterone concentrations in experimental rats were not different from those in controls after 3 min exposure to ether vapor or immobilization in a supine position. As a corollary to the ablation studies, rats bearing chronically implanted electrodes were subjected to sham or electrical stimulation. In non-anesthetized (freely moving) rats electrical stimulation of the corticomedial amygdala, and basolateral amygdala, dorsal hippocampus and arcuate nucleus resulted in plasma corticosterone levels significantly (P < 0.05) greater than from those in sham stimulated controls. In contrast, in pentobarbital anesthetized rats plasma corticosterone concentrations in the amygdaloid and hippocampal stimulated animals were not different from those of sham stimulated rats; only stimulation of the arcuate nucleus produced plasma corticosterone levels greater (P < 0.05) than those in sham stimulated rats.These data indicate that in the male rat the amygdala is capable of influencing ACTH secretion. However, the finding that pituitary-adrenal function was not compromised by either selective or extensive amygdaloid ablation suggests that the amygdala is not essential for pituitary-adrenal function as we assessed this function.     

Pituitary-adrenal and dopaminergic modulation of schedule-induced polydipsia: behavioral and neurochemical evidence.

Five experiments investigated in rats the effects of increasing or decreasing plasma corticosterone levels on schedule-induced polydipsia and dopamine efflux in the nucleus accumbens. The results indicate that the acquisition of schedule-induced polydipsia could be decreased by adrenalectomy, blockade of corticosterone synthesis, or administration of corticosterone. Performance of established schedule-induced polydipsia was also decreased by adrenalectomy. The effects of corticosterone administration on established schedule-induced polydipsia depended on the level of performance. High levels of drinking were enhanced by a high dose of corticosterone, whereas low rates of drinking were increased by a low dose. Similar injections of corticosterone also significantly increased dopamine efflux. The relative involvement of pituitary-adrenal activity and dopamine neurotransmission in the nucleus accumbens in the acquisition and performance of SIP is discussed and related to contemporary hypotheses of schedule-induced behavior.     

The rat corticosterone response: Habituation and modification by chlordiazepoxide

The rat plasma corticosterone response was measured in 3 novel situations that differed in the extent to which the rat's own behavior determined its sampling of novel stimuli. All 3 tests induced a significant rise in corticosterone concentrations and on repeated exposures the corticosterone significantly decreased. Acute administration of chlordiazepoxide (5 mg/kg) significantly reduced the corticosterone response to novelty and after 5 days of drug pretreatment chlordiazepoxide was even more effective at reducing the corticosterone response to novel situations. The corticosterone response to the stress of cold and restraint was reduced by an acute dose of 50 mg/kg chlordiazepoxide, and after 5 days of pretreatment by doses of 10 and 50 mg/kg. In all but one test tolerance developed to the corticosterone-blocking action of chlordiazepoxide after 10 days of drug treatment.     

Adrenocortical response following acute neurogenic stimuli is mediated by CRF-41

The present study examined whether neurogenic stimuli activate the pituitary-adrenal axis via CRF-41. Adult male rats were exposed to photic, acoustic or sciatic nerve stimulation. At 4, 15, and 30 min following the onset of stress, animals were sacrificed, trunk blood collected and the median eminence removed. At 4 min following the stress onset, there was a significant decrease in CRF-41 content of the median eminence, which persisted for 30 min. Concomitant with the decrease in CRF-41 content, serum adrenocorticotropic hormone (ACTH) and corticosterone levels increased. Thus, this study demonstrates that CRF-41 released from the median eminence plays a dynamic role in mediating the ACTH and corticosterone response to neurogenic stimuli.     

The behavioral profile of zolpidem, a novel hypnotic drug of imidazopyridine structure

The imidazopyridine zolpidem has previously been shown to displace benzodiazepines from their receptors, with a preferential activity at BZ1 sites, and to exert hypnotic activity in man. Zolpidem's pharmacological profile includes anticonvulsant, antipunishment and behavioral depressant actions. However, unlike benzodiazepines, zolpidem exerts sedative actions at relatively low doses. In drug discrimination experiments differences between the internal stimuli produced by chlordiazepoxide and zolpidem were identified. These differences appeared to be qualitative rather than quantitative with the stimulus properties of zolpidem being related to the drug's sedative action. In condition where tolerance developed rapidly to the depressant activity of benzodiazepines little tolerance was seen with zolpidem. The behavioral profile of consistent with the suggestion that this compound may have selective sedative action produced by activity at a sub-type of benzodiazepine receptor.     

Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine

The present study examined the effects of constant nicotine infusions on dopamine overflow in the nucleus accumbens and on locomotor activity and compared them with the changes evoked by repeated daily injections (one injection per day for 5 days) of the drug. The putative anxiolytic properties of nicotine have also been examined using the elevated plus-maze test of anxiety. Repetitive daily subcutaneous injections of nicotine (0.4 mg/kg) enhanced (P < 0.01) the overflow of dopamine evoked by a challenge dose of the drug (0.4 mg/kg) and increased (P < 0.01) its stimulatory effects on locomotor activity. The constant infusion of nicotine, at doses of 1 and 4 mg/kg per day, abolished (P < 0.05) the effects of a bolus injection of nicotine on extracellular dopamine and attenuated (P < 0.01) the enhanced locomotor response evoked by daily pretreatment with nicotine boli. The mesolimbic dopamine response to a bolus injection of nicotine was not significantly attenuated by nicotine infusions when the dose was reduced to 0.25 mg/kg per day. The locomotor responses in these rats were significantly (P < 0.05) less than those seen in the animals pretreated with nicotine injections alone but were also higher (P < 0.05) than those seen in saline-treated control rats given a bolus injection of nicotine. Neither the constant infusion (4 mg/kg per day) nor the injection of nicotine (0.4 mg/kg) evoked an anxiolytic or anxiogenic effect in the elevated plus-maze test. However, the nicotine infusions did abolish the locomotor stimulant effects of the drug in this apparatus. They also abolished the plasma corticosterone response to nicotine and attenuated the plasma corticosterone response to the maze. The data suggest that constant infusions of nicotine, at doses of 1 mg/kg per day or more, may cause desensitisation of the nicotinic receptors which mediate the stimulatory effects of the drug on mesolimbic dopamine release and locomotor activity. The data also suggest that the receptors which mediate the increase in plasma corticosterone, seen in animals given nicotine boli, may also be desensitised by nicotine infusions, and that these receptors may be implicated in the adrenocortical response to anxiogenic stimuli.Abbreviations DA dopamine - NAcc nucleus accumbens Correspondence to: M.E.M. Benwell     

Differential plasma corticosterone responses to hippocampal stimulation

Summary The effect of limbic forebrain stimulation on pituitary-adrenal function was assessed by evaluating plasma corticosterone obtained prior to and following sham or electrical stimulation of urethane (1.20 g/kg) anesthetized female rats. Cortical electroencephalogram (EEG), electrocardiogram (ECG), heart rate (HR), mean arterial blood pressure (MAP), and respiration were routinely monitored. Timed blood samples (0.25 ml) were obtained from a catherized femoral artery. The HR (Bts/min), MAP (mm of Hg), and corticosterone levels (g/dl) for 7 non-stimulated rats averaged over 6 sampling periods were 385±19, 95±6, and 70.3±5.8 respectively. In electrically or sham stimulated rats, blood samples were taken just prior to stimulation (biphasic square waves, 100 A, 50 or 60 Hz, 1 ms, 1 s on/1 s off for 15 or 30 min) and 5, 10, 15, and 30 min after initiation of stimulation.Significant changes in plasma corticosterone levels were obtained following stimulation of hippocampal and amygdaloid areas. In contrast, no change in corticosterone concentration was observed following stimulation of cortex, corpus callosum, fornix and a variety of other CNS areas. Detailed analysis of hippocampal influence on urethane stimulated plasma corticosterone levels showed increased plasma corticosterone levels following stimulation of CA1. In contrast, stimulation of CA3, dentate (includes CA4) and the subiculum produced significant decreases in plasma corticosterone levels. No change in corticosterone levels was observed following sham stimulation. Collectively, these data indicate that consideration must be given to the possibility that differential neuroendocrine regulatory mechanisms reside within various limbic forebrain complexes and that electrical stimulation of limbic forebrain sites of urethane anesthetized rats may provide information regarding sites inhibitory to pituitary-adrenal activity.     

Effects of eating,meal cues and ventromedial hypothalamic lesions on serum corticosterone,glucose and free fatty acid concentrations

Male hooded rats were fed once daily for 14 days with 1-hr access to food mash and water to establish the stimuli of the experimenter's entrance into the animal quarters (Experiment 1) or placement of the rat's cage into a chamber (Experiment 2) as cues for a meal. Rats without brain lesions failed to exhibit changes in serum concentrations of glucose or free fatty acids (FFA) to meal cues while exhibiting declines in serum corticosterone concentration. In response to meal consumption, these rats exhibited robust increases in glucose and decreases in FFA and corticosterone levels. VMH lesions (Experiment 2) accentuated glucose declines and diminished corticosterone declines in response to meal consumption or a meal cue. The results suggest a role of the VMH in pituitary-adrenal inhibition, but also indicate the importance of considering the roles of anticipatory metabolic activity and emotional reaction in the regulation of metabolic substrates and pituitary-adrenal activity.     

On the role of brain noradrenaline and the pituitary-adrenal axis in avoidance learning. I. Studies with corticosterone

A marked impairment of the acquisition of a one-way active avoidance response was observed in rats after a 6-hydroxydopamine-induced lesion of the ascending (dorsal) noradrenaline bundle to the cortex cerebri in combination with adrenalectomy. The deficit in acquisition was prevented by low daily doses of corticosterone. Neither adrenalectomy nor lesions of the dorsal noradrenaline bundle alone caused a deficit. It is suggested that brain noradrenaline neurons and the pituitary-adrenal axis may interact in the control of active avoidance behavior. Finally, noradrenaline neurons appear not to play any role in extinvtion of punished behavior.     

Evidence that Piracetam has an anxiolytic action

In the social interaction test of anxiety Piracetam (100 mg/kg) had an anxiolytic profile very similar to that seen after 5 days of administration of chlordiazepoxide (5 mg/kg). Piracetam (50-300 mg/kg) produced no signs of sedation and it was therefore suggested that it might be a non-sedative anxiolytic drug. Piracetam (100 mg/kg) produced significantly higher cortical concentrations of 5-hydroxytryptamine and lower concentrations of 5-hydroxyindoleacetic acid, indicating a reduced 5-HT turnover. There were no drug-induced changes in noradrenaline or dopamine in any brain region, either with or without pretreatment with alpha-methylparatyrosine. The cortical concentrations of 7 amino acids were measured and were unchanged by treatment with Piracetam.     

Immune-neuroendocrine interactions during aging: age-dependent thyrotropin-inhibiting activity of thymosin peptides

Thymosin fraction 5 (TF-5), a partially purified thymic preparation, has been previously shown to have luteinizing hormone-releasing hormone (LH-RH)-releasing activity in perfused rat hypothalamus as well as in vivo stimulatory effect on the pituitary-adrenal axis in prepubertal monkeys. We report here the effect of TF-5 on the TSH-thyroid axis in young (3 months) and old (25 months) Sprague-Dawley male rats. Conscious free-moving animals carrying an indwelling atrial cannula received a single dose of 5 mg/kg body wt. of either bovine serum albumin (BSA) or TF-5 via the cannula. In the young rats, TF-5 induced a marked reduction of plasma thyrotropin (TSH) which was significantly greater than the normal circadian decline observed in the BSA-treated controls. The old males displayed high basal levels of TSH which showed no circadian rhythmicity, and did not respond to TF-5. Thyroxine (T4), triiodothyronine (T3), corticosterone, and prolactin levels were not affected by TF-5 at the dose levels tested. The old rats had significantly lower basal levels of T4, but not T3, than their young counterparts. The synthetic peptides thymosin alpha-1 and serum thymic factor, which are components of TF-5, had no effect on the above hormones when injected in doses up to 5 micrograms/kg body wt. Acute thymectomy in 3-month-old males induced a significant increase in basal levels of TSH without affecting plasma T4 or T3. These results suggest that the thymus has an inhibitory action on TSH in the rat, which is not mediated by the thyroid gland.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt's test

The objective of this study was to investigate whether bilateral dopamine depletion within the medial prefrontal cortex affects depression state, as well as the antidepressant efficacy of desipramine, in the forced swimming test. The rat's behaviour was evaluated by quantifying duration of immobility, climbing, swimming and diving. Immobility latency was also quantified and proved to be a suitable novel parameter. Monoamine levels within the medial prefrontal cortex were measured by high-performance liquid chromatography during Porsolt's test, as well as one week after it. While Porsolt's test was followed by a typical depression-like profile in sham rats, depletion of prefrontocortical dopamine (86% vs sham controls) reduced immobility and enhanced swimming, which is consistent with a diminished depression tonus. The observed enhancement of swimming was correlated with a high prefrontocortical serotonergic neurotransmission. On the other hand, desipramine induced antidepression-like effects in sham rats by increasing prefrontocortical noradrenaline and serotonin neurotransmisson, but also by blocking the normal increase in dopamine activity during the swimming test. Interestingly, desipramine behaved in a quite different manner in lesioned rats. Thus, immobility duration was not further reduced and only climbing, but not swimming, was enhanced. These effects were correlated with a preferential enhancement of noradrenaline neurotransmission. In conclusion, the results indicate that: (i) dopamine neurotransmission within the medial prefrontal cortex is a factor involved in depression, since dopamine reduction led to a low depression tonus; (ii) desipramine induces antidepression not only by enhancing prefrontocortical noradrenaline and serotonin neurotransmission, but also by blocking the normal increase in dopamine neurotransmission during a depressant situation; (iii) a selective enhancement of prefrontocortical serotonin neurotransmission mediates swimming; and (iv) a selectively augmented prefrontocortical noradrenaline activity mediates climbing during Porsolt's test.     

The sensitivity of the rat corticosterone response to environmental manipulations and to chronic chlordiazepoxide treatment

Rats that were exposed for 20 mins to an unfamiliar room had significant increases in plasma corticosterone concentrations, that were greater if the room was brightly lit than if it was dimly lit. Chlordiazepoxide (5 mg/kg for 5 days) significantly reduced the corticosterone response to a novel room, but was without effect on the levels in rats left undisturbed in the animal house. When pairs of rats were placed for 10 mins in an unfamiliar test box there was an increase in plasma corticosterone that was greater when the box was brightly lit; chlordiazepoxide (5 mg/kg for 5 days) significantly reduced these corticosterone responses. In rats repeatedly exposed to the same apparatus there was significant, but not complete, habituation of the corticosterone response in both singly tested rats and in those tested in pairs; manipulation of light levels no longer had a significant effect on the corticosterone levels; and chlordiazepoxide did not block the corticosterone response in these habituated rats.     

Corticosterone response in the chick separation-stress paradigm

Corticosterone response to separation stress and its sensitivity to the anxiolytic, chlordiazepoxide (CDP), were examined in 7-day-old domestic fowl (Gallus gallus). Saline or CDP (8.0 mg/kg) was injected intramuscularly 30 min before tests. Chicks were placed in isolation either with or without mirrors for a 15-min observation period, in which distress vocalizations were recorded. After testing, chicks were euthanized and blood was collected for the corticosterone assay. Chicks tested in the No-Mirror condition displayed an increase in vocalizations that was attenuated by CDP. Similarly, corticosterone levels were highest in chicks tested in the No-Mirror condition; however, CDP only modestly attenuated corticosterone levels. The present findings demonstrate that corticosterone levels parallel the behavioral marker of distress vocalizations in this paradigm, but this biological marker may be less sensitive than the behavioral marker to benzodiazepine anxiolytic manipulations.     

Septal driving of hippocampal theta rhythm: role of gamma-aminobutyrate-benzodiazepine receptor complex in mediating effects of anxiolytics

In free-moving male rats, when the hippocampal theta rhythm is artificially driven by stimulation in the septum at frequencies between 5 and 10 Hz, the function relating frequency to the threshold current required to drive the theta rhythm has a minimum at 7.7 Hz. This minimum is eliminated by anxiolytic drugs. Dose-response curves for this effect are reported for chlordiazepoxide, diazepam and meprobamate. The effect of meprobamate was reversed by two gamma-aminobutyrateA antagonists, picrotoxin and bicuculline, which have previously been shown to be without effects of their own. The gamma-aminobutyrateB agonist, baclofen, also without effect on its own, blocked the elimination of the 7.7-Hz minimum caused by the gamma-aminobutyrateA agonist, muscimol. The beta-carboline, ethyl-beta-carboline-3-carboxylate, had mixed agonist/antagonist properties, blocking the effects of chlordiazepoxide, diazepam and muscimol (though not sodium amylobarbitone) but itself acting like a benzodiazepine. Coupled with earlier data, these findings support a role for gamma-aminobutyrate receptors in mediating the effects of anxiolytic drugs.     

Environmental control of suppression of the pituitary-adrenal system

Rats having access to food and water for 1 hr daily show elevated plasma corticosterone levels prior to feeding and drinking. The activity of the pituitary-adrenal system was studied in animals receiving food and water, food or water alone or an empty drinking bottle. Within 5 min there was a 35% drop in the concentration of plasma corticosterone. This decline reached 50% by 10 min. In those rats receiving water alone or the empty drinking tube, the time course was biphasic. Thus, following the initial drop, the pituitary-adrenal system was activated. It appears therefore that rapid suppression of the pituitary-adrenal system can occur and be conditioned to stimuli associated with prior reinforcement.     

Psychomotor and rewarding properties of the neurosteroids dehydroepiandrosterone sulphate and androsterone: effects on monoamine and steroid metabolism

The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and reward in male Wistar rats, and on steroid and monoamine metabolism in the hippocampus and striatum. In the open field test, DHEAS injections (10, 40, 80 mg/kg, i.p.) 30 min prior the test had no significant effect on ambulation, but androsterone (10 mg/kg) increased general locomotion and at doses 1-10 mg/kg, increased central field activity, suggestive of an anxiolytic action. In the conditioned place preference test, both steroids had a biphasic effect: DHEAS was rewarding at doses of 10 and 40 mg/kg, but not at 80 mg/kg, while androsterone was rewarding at doses of 1 and 10 mg/kg, but aversive at 40 mg/kg. Monoamine and steroid concentrations were analyzed in homogenates from the hippocampus and striatum of DHEAS and androsterone injected rats. DHEAS reduced the hippocampal dopamine level, increased striatal homovanilic acid (HVA) and decreased the striatal serotonin concentrations. Androsterone did not affect dopamine levels or turnover, but increased noradrenaline concentration and serotonin turnover in the hippocampus. DHEAS administration augmented concentrations of DHEA, pregnenolone, androstendiol and androstentriol in both brain structures, while androsterone injections increased brain levels of androsterone, epiandrosterone, 5α-dihydrotestosterone, and androstandiol. Present data document that although psychobehavioral and neurochemical effects of DHEAS and androsterone differ in several aspects; both neurosteroids have rewarding properties at certain dose ranges, suggesting their likely involvement in addictions, which entail different mechanisms.     

Behavioural and biochemical measures of stress in hooded rats from different sources

Striking differences in social interaction and in exploratory and motor activity were observed between hooded rats obtained from 3 different sources. The group of rats showing the lowest levels of social interaction, exploration and motor activity and having the highest level of defecation had raised plasma corticosterone concentrations, increased adrenal weights, and decreased hypothalamic noradrenaline concentrations.     

Differential effects of mecamylamine on the nicotine induced changes in amine levels and turnover in hypothalamic dopamine and noradrenaline nerve terminal systems and in the secretion of adenohypophyseal hormones in the castrated female rat. Evidence for involvement of cholinergic nicotine-like receptors

The effects of mecamylamine on the nicotine induced changes in hypothalamic catecholamine (CA) levels and turnover in female rats ovariectomized for one month have been evaluated using a quantitative microfluorimetric approach to measure CA levels in sections of brains treated according to the Falck-Hillarp procedure for the cellular demonstration of CA. In the same group of animals the serum prolactin, LH, FSH, TSH, GH and corticosterone levels were measured using radioimmunoassay procedures. The nicotine treatment induced a significant depletion of amine stores and an increase of amine turnover in dopamine (DA) and noradrenaline (NA) nerve terminals of the median eminence and of the peri- and paraventricular and dorsomedial NA systems of the hypothalamus using the tyrosine hydroxylase (TH) inhibition model. Mecamylamine (2 X 1 mg/kg) partly counteracted the nicotine induced reduction of amine stores in peri- (anterior part) and paraventricular NA nerve terminal systems as well as the nicotine induced increase of NA turnover in these systems, but not the action of nicotine on the CA systems of the median eminence. Nicotine (4 X 2 mg/kg) significantly and markedly reduced prolactin, LH, TSH, and GH secretion increased corticosterone secretin but did not influence FSH secretion. These effects were partly counteracted by mecamylamine (2 X 1 mg/kg) in the case of prolactin, LH and TSH secretion but not in the case of GH and corticosterone secretion. Taken together the results show that mecamylamine treatment (2 X 1 mg/kg) differentially counteract nicotine induced changes of amine levels and turnover in peri- (anterior part) and paraventricular NA nerve terminal systems indicating that the cholinergic nicotine-like receptors located in peri- (anterior part) and paraventricular areas may be more susceptible to the blocking activity of mecamylamine than those located in the median eminence area. Furthermore, the inhibitory effects of nicotine on prolactin, LH and TSH secretion are differentially counteracted by mecamylamine. In conclusion, other inhibitory systems than the tuberoinfundibular DA neurons in the MPZ and LPZ must also be involved in mediating the inhibitory effects of nicotine on prolactin, LH and TSH secretion and different types of cholinergic nicotine-like receptors may exist.     

Influence of shock-induced fighting and social factors on pituitary-adrenal activity, prolactin and catecholamine synthesizing enzymes in rats

The present experiment investigated changes in pituitary-adrenal activity, prolactin and catecholamine synthesizing enzymes in rats exposed to electric shocks in pairs or individually, in comparison to animals receiving no shock and tested in pairs or alone. Pairs of rats repeatedly exposed to electric shocks displayed a lower activation of the pituitary-adrenal system but a stronger activation of the sympathetic-adrenal medullary system than rats shocked individually. There was no differential release of prolactin according to the social setting in which shock occurred. Social factors by themselves influenced plasma corticosterone levels but not plasma levels of ACTH and prolactin nor catecholamine synthesis. The results are discussed in relation to the postulated beneficial effects of fighting on physiological activation produced by electric shock.