Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin

The action of ghrelin on telemetrically recorded motor activity and the transmission of the effects of this neuropeptide on spontaneous and exploratory motor activity and some related endocrine and homeostatic parameters were investigated. Different doses (0.5-5 microg) of ghrelin administered intracerebroventricularly caused significant increases in both square crossing and rearing activity in the "open-field" apparatus, while only the dose of 5 microg evoked a significant increase in the spontaneous locomotor activity recorded by telemetry. Ghrelin also induced significant increases in corticosterone release and core temperature. To determine the transmission of these neuroendocrine actions, the rats were pretreated with different antagonists, such as a corticotropin-releasing hormone (CRH) antagonist (alpha-helical CRH(9-41)), the nitric oxide synthase inhibitor Nomega-nitro-L-arginine-methyl ester (L-NAME), haloperidol, cyproheptadine or the cyclooxygenase inhibitor noraminophenazone (NAP). The open-field and biotelemetric observations revealed that the motor responses were diminished by pretreatment with the CRH antagonist and haloperidol. In the case of HPA (hypothalamic pituitary adrenal) activation, only cyproheptadine pretreatment proved effective; haloperidol and L-NAME did not modify the corticosterone response. NAP had only a transient, while cyproheptadine elicited a more permanent impact on the hyperthermic response evoked by ghrelin; the other antagonists proved to be ineffective. The present data suggest that both CRH release and dopaminergic transmission may be involved in the ghrelin-evoked behavioral responses. On the other hand, ghrelin appears to have an impact on the HPA response via a serotonergic pathway and on the hyperthermic response via a cyclooxygenase and a serotonergic pathway.     

The action of a synthetic derivative of Met5-enkephalin-Arg6-Phe7 on behavioral and endocrine responses

The neuroendocrine and behavioral effects of Tyr-d-Ala-Gly-Phe-d-Nle-Arg-Phe (DADN), a more stable derivative of the endogenous opiate Met-enkephalin related peptide Met⁵-enkephalin-Arg⁶-Phe⁷ were investigated in mice. The behavioral experiments consisted of monitoring the horizontal (square crossing) and vertical (rearing) locomotion in the open field system. To evaluate the effect of the heptapeptide on the hypothalamo-pituitary-adrenal (HPA) axis, the plasma corticosterone level was measured. DADN induced dose-dependent increases in locomotion and rearing 30 min after intracerebroventricular injection and also elicited marked activation of the hormonal stress response. To elucidate the receptors involved in the mediation of these actions, animals were pretreated with the nonselective opioid antagonist naloxone, the selective κ-receptor antagonist nor-binaltorphimine or the μ₁-receptor blocker naloxonazine. Both the HPA activation and the behavioral responses were diminished by the preadministration of naloxone. Nor-binaltorphimine did not display a significant effect, while naloxonazine completely abolished the hyperactivity and the corticosterone elevation elicited by the analog. These findings suggest that μ-receptors predominate in the mediation of the neuroendocrine actions of DADN, while κ-receptors do not play a significant role.     

Endocrine, behavioral and autonomic effects of neuropeptide AF

The actions of neuropeptide AF (NPAF), on the hypothalamic-pituitary-adrenal (HPA) axis, behavior and autonomic functions were investigated. NPAF (0.25, 0.5, 1, 2 nmol) was administered intracerebroventricularly to rats, the behavior of which was monitored by means of telemetry, open-field (OF) observations and elevated plus-maze (EPM) tests. The temperature and heart rate were recorded by telemetry, and the plasma ACTH and corticosterone levels were used as indices of the HPA activation. The dopamine release from striatal and amygdala slices after peptide treatment (100 nM and 1 μM) was measured with a superfusion apparatus. To establish the transmission of the HPA response, animals were pretreated with the corticotrophin-releasing hormone (CRH) receptor antagonist antalarmin or astressin 2B (0.5 nmol). In the OF test, the animals were pretreated with antalarmin or haloperidol (10 μg/kg), while in the EPM test they were pretreated with antalarmin or diazepam (1 mg/kg). NPAF stimulated ACTH and corticosterone release, which was inhibited by antalarmin. It activated exploratory locomotion (square crossings and rearings) and grooming in OF observations, and decreased the entries to and the time spent in the open arms during the EPM tests. The antagonists inhibited the locomotor responses, and also attenuated grooming and the EPM responses. NPAF also increased spontaneous locomotion, and tended to decrease the core temperature and the heart rate in telemetry, while it augmented the dopamine release from striatal and amygdala slices. These results demonstrate, that acute administration of exogenous NPAF stimulates the HPA axis and behavioral paradigms through CRH and dopamine release.     

Behavioral and neuroendocrine actions of endomorphin-2

The effects of intracerebroventricularly administered endomorphin-2 (EM2) on open-field activity and the hypothalamo-pituitary-adrenal (HPA) system were investigated. EM2 (0.25-1 microg) significantly increased both the locomotor and the rearing activity, resulting in a bell-shaped dose-response curve. EM2 also enhanced corticosterone release, with an even more profound downturn phase at higher concentrations. The corticotropin-releasing hormone (CRH) antagonist alpha-helical CRH9-41 completely abolished the EM2-evoked endocrine and behavioral responses. These findings reinforce the hypothesis that the endomorphins may play a significant role in the regulation of locomotion, rearing activity and the HPA system through the release of CRH.     

Halothane attenuated haloperidol and enhanced clozapine-induced dopamine release in the rat striatum

The effect of halothane anesthesia on changes in the extracellular concentrations of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by neuroleptics was studied using in vivo microdialysis techniques. Halothane attenuated haloperidol-induced dopamine release and enhanced clozapine-induced dopamine release in the rat striatum.A microdialysis probe was implanted into the right striatum of male SD rats. Rats were given saline or the same volume of 200 microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2) antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or 1.5%). Halothane anesthesia did not change the extracellular concentration of DA, but increased the metabolite concentrations in a dose-dependent manner. The increased DA concentration induced by haloperidol was significantly attenuated by halothane anesthesia, whereas the metabolite concentrations were unaffected. Halothane had no effect on the changes in the concentrations of DA or its metabolites induced by sulpiride. The clozapine-induced increases in DA and its metabolites were enhanced by halothane anesthesia.Our results suggest that halothane anesthesia modifies the DA release modulated by antipsychotic drugs in different ways, depending on the effects of dopaminergic or serotonergic pathways.     

Receptor selectivity of Met-enkephalin-Arg6-Phe7, an endogenous opioid peptide, in cerebral cortex of human and rat

This study was undertaken to examine the receptor selectivity of Met-enkephalin-Arg6-Phe7 (MERF) employing radioreceptor binding assays in human cerebral cortex membranes, and to elucidate the responsible receptors that mediate the regulatory action of MERF on high (20 mM) K+-stimulated release of [3H]norepinephrine ([3H]-NE) in rat cortex slices. Specific binding of [3H]MERF was inhibited by DAMGO, Tyr-D-Arg-Phe-Sar(TAPS), bremazocine and ethylketocyclazocine (EKC), but not by U69,593 (U69) and DPDPE. MERF showed high affinity for specific binding sites of [3H]DAMGO. However, MERF had little influence on the specific binding of [3H]DPDPE, [3H]U69 and [3H]diprenorphine ([3H]DIP) in the presence of 1 microM each of DAMGO, DPDPE and U69. In [3H]NE release experiments using rat cortex slices, DAMGO, MERF and EKC, in order of their potency, inhibited K+-stimulated release of [3H]NE. The inhibitory effects of MERF and DAMGO were more sensitive than that of EKC to antagonism by CTAP, nor-binaltorphimine (nor-BNI) and naloxone. These results suggested that MERF possesses high affinity for mu-receptors, but not for delta-, kappa1-, and very low affinity for kappa2-receptors in human cerebral cortex membranes. Also, the inhibitory effect of MERF on the K+-stimulated release of [3H]NE appears to be mediated by mu-receptors in rat cerebral cortex slices.     

The effects of different receptor blockers on the H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH induced inhibition of extinction of active avoidance behaviour

H-Phe-Ile-Tyr-His-Ser-Tyr-Lys-OH after intracerebroventricular (icv.) administration inhibited the extinction of active avoidance behaviour for a short period. The dopamine receptor blocker haloperidol completely blocked this effect of the heptapeptide, while the muscarinic anticholinergic agent atropine only partly inhibited it. The alpha 1-receptor blocker phenoxybenzamine and the beta-receptor blocker propranolol did not significantly influence the extinction inhibition induced by the peptide. These results suggest that the dopaminergic and, in part the cholinergic system, play important roles in this behavioural action of H-Phe-Ile-Tyr-Ser-Tyr-Lys-OH.     

Endocrine and behavioral effects of neuromedin S

The present experiments focused on the effects of neuromedin S on hypothalamic–pituitary–adrenal (HPA) activation and behavior. The peptide (0.25–1 nmol) was administered intracerebroventricularly to rats, the behavior of which was monitored by means of telemetry, open field observations and an elevated plus-maze (EPM) test. Autonomic functions such as the temperature and the heart rate were recorded by telemetry. The action on the HPA axis was assessed via measurements of the plasma corticosterone and ACTH levels. To reveal the transmission of the endocrine responses, animals were pretreated with corticotrophin releasing hormone receptor (CRHR) antagonists (1 nmol). In the open field test, the animals were pretreated with either a CRHR₁ antagonist (antalarmin) or haloperidol (10 μg/kg), while in the EPM test they were pretreated with antalarmin or diazepam (1 mg/kg). The dopamine release from striatal and amygdala slices after peptide treatment was measured with a superfusion apparatus. Neuromedin S exerted dose-dependent effects on the HPA system, which were inhibited by antalarmin. It also activated grooming and decreased the entries to and time spent in the open arms during the EPM test. The grooming response was abolished by haloperidol and antalarmin pretreatment, while diazepam and antalarmin showed a tendency to attenuate the response evoked in the EPM test. In the superfusion studies, neuromedin S enhanced the dopamine release from the amygdala slices. These results demonstrate that neuromedin S stimulates the HPA axis through the CRHR₁ pathway and evokes stereotyped behavior and anxiety through mesolimbic dopamine and corticotrophin releasing hormone release.     

The effect of chronic levodopa on haloperidol induced behavioral supersensitivity in the guinea pig

The effect of chronic levodopa-carbidopa administration (200 mg/kg for 21 days) on guinea pigs rendered behaviorally supersensitive by the prior administration of haloperidol (.5 mg/kg for 21 days) was examined. Animals who showed an increased behavioral response to apomorphine after chronic haloperidol administration were treated with levodopa-carbidopa and then apomorphine - induced stereotypy was reexamined. Although the chronic levodopa control groups and the chronic haloperidol control remained supersensitive to the behavioral effect of apomorphine, the haloperidol-levodopa group's behavioral response to apomorphine returned to normal. Both chronic dopaminergic antagonist and agonist administration have been demonstrated to induce heightened apomorphine-induced stereotypy and this has been interpreted as a reflection of altered striatal dopamine receptor site sensitivity. The finding that the serial administration of a chronic dopaminergic antagonist followed by a chronic dopaminergic agonist results in a return to normal of a striatal dopamine receptor-dependent behavior suggests that these chronic treatments affect dopamine receptor sites by different mechanisms of action. Since neuroleptic induced dopaminergic supersensitivity in animals is an accepted model of tardive dyskinesia, levodopa may also reverse dopaminergic supersensitivity in patients and might be a potential therapeutic agent in tardive dyskinesia.     

Haloperidol increases plasma beta endorphin-like immunoreactivity and cortisol in normal human males

To investigate possible central dopaminergic regulation of beta-endorphin-like immunoreactivity (beta E-LI) and adrenocorticotropin (ACTH) release in humans, we gave the dopamine antagonist haloperidol or placebo intravenously to twelve normal male subjects and measured beta E-LI and cortisol for 120 minutes following injection. Haloperidol, but not placebo, produced significant increases in plasma beta E-LI and cortisol. These findings suggest that central dopaminergic pathways such as the tuberohypophyseal system may participate in regulation of the secretion of beta E and ACTH from the human pituitary.     

Endocrine and behavioral effects of neuromedin S

The present experiments focused on the effects of neuromedin S on hypothalamic–pituitary–adrenal (HPA) activation and behavior. The peptide (0.25–1 nmol) was administered intracerebroventricularly to rats, the behavior of which was monitored by means of telemetry, open field observations and an elevated plus-maze (EPM) test. Autonomic functions such as the temperature and the heart rate were recorded by telemetry. The action on the HPA axis was assessed via measurements of the plasma corticosterone and ACTH levels. To reveal the transmission of the endocrine responses, animals were pretreated with corticotrophin releasing hormone receptor (CRHR) antagonists (1 nmol). In the open field test, the animals were pretreated with either a CRHR₁ antagonist (antalarmin) or haloperidol (10 μg/kg), while in the EPM test they were pretreated with antalarmin or diazepam (1 mg/kg). The dopamine release from striatal and amygdala slices after peptide treatment was measured with a superfusion apparatus. Neuromedin S exerted dose-dependent effects on the HPA system, which were inhibited by antalarmin. It also activated grooming and decreased the entries to and time spent in the open arms during the EPM test. The grooming response was abolished by haloperidol and antalarmin pretreatment, while diazepam and antalarmin showed a tendency to attenuate the response evoked in the EPM test. In the superfusion studies, neuromedin S enhanced the dopamine release from the amygdala slices. These results demonstrate that neuromedin S stimulates the HPA axis through the CRHR₁ pathway and evokes stereotyped behavior and anxiety through mesolimbic dopamine and corticotrophin releasing hormone release.     

Effect of CNS-active drugs on TRH-induced prolactin release

The effects of several central acting drugs upon thyrotropin-releasing hormone (TRH)-induced increases in prolactin (PRL) release were compared in estrogen-primed male rats. Administration of the serotonin antagonist, p-chlorophenylalanine, or the opiate antagonist, naltrexone, did not alter TRH-induced release of PRL. Pre-treatment with either the dopamine agonist, piribedil, or the cholinergic agonist, pilocarpine, resulted in significantly reduced TRH-induced PRL release. Pilocarpine did not inhibit the TRH-induced increase in PRL release when rats were first pre-treated with the dopamine receptor blocker, haloperidol. These results indicate that the dopaminergic and cholinergic systems can modify TRH-induced release of PRL in vivo.     

Role of Corticotropin-Releasing Factor (CRF) Receptor-1 on the Catecholaminergic Response to Morphine Withdrawal in the Nucleus Accumbens (NAc)

Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine (DA) levels in brain regions receiving dense VTA input. Since the role of stress in drug addiction is well established, the present study examined the possible involvement of CRF1 receptor in the interaction between morphine withdrawal and catecholaminergic pathways in the reward system. The effects of naloxone-precipitated morphine withdrawal on signs of withdrawal, hypothalamo-pituitary-adrenocortical (HPA) axis activity, dopamine (DA) and noradrenaline (NA) turnover in the nucleus accumbens (NAc) and activation of VTA dopaminergic neurons, were investigated in rats pretreated with vehicle or CP-154,526 (selective CRF1R antagonist). CP-154,526 attenuated the increases in body weight loss and suppressed some of withdrawal signs. Pretreatment with CRF1 receptor antagonist resulted in no significant modification of the increased NA turnover at NAc or plasma corticosterone levels that were seen during morphine withdrawal. However, blockade of CRF1 receptor significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin (ACTH) levels, DA turnover and TH phosphorylation at Ser40 in the NAc. In addition, CP-154,526 reduced the number of TH containing neurons expressing c-Fos in the VTA after naloxone-precipitated morphine withdrawal. Altogether, these results support the idea that VTA dopaminergic neurons are activated in response to naloxone-precipitated morphine withdrawal and suggest that CRF1 receptors are involved in the activation of dopaminergic pathways which project to NAc.     

Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders

Increasing evidence suggests that the neuroendocrine changes seen in psychiatric patients, especially in those suffering from affective disorders, may be causally related to the psychopathology and course of these clinical conditions. The most robustly confirmed neuroendocrine finding among psychiatric patients with affective disorders is hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, resulting from hyperactive hypothalamic corticotropin-releasing hormone (CRH) neurons. A large body of preclinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA system abnormalities. Further, normalization of HPA system regulation was shown to be a prerequisite for favorable treatment response and stable remission among depressives. Preclinical data based on animal models including selectively bred rat lines and mouse mutants support the notion that CRH neurons are hyperactive also in neuroanatomical regions that are involved in behavioral regulation but are located outside the neuroendocrine system. This raises the question of whether more direct interventions such as CRH receptor antagonists would open a new lead in the treatment of stress-related disorders such as depression, anxiety and sleep disorders. Recent clinical observations support this possibility.     

Dopaminergic regulation of theta activity of septohippocampal neuron in the awake rabbit

The effects of dopamine reuptake blocker nomifensine and nonselective antagonist of dopamine receptors haloperidol on the theta rhythmicity of the medial septal neurons and hippocampal EEG were investigated in the rabbit. Bilateral intracerebroventricular infusion of nomifensine (9 micrograms in each ventriculus) produced an increase in both the rate of firing and the theta modulation of medial septal neurons; the theta power of the hippocampal EEG also augmented. The degree of neuronal theta stability (time constant of damping, tao theta) significantly increased. The frequency of rhythmic bursts in the neuronal firing also substantially elevated. The amplitude, regularity and frequency of theta waves in the hippocampal EEG also increased. The antagonist haloperidol (12.5 mg) caused the opposite effect. The theta activity of medial septal neurons and the theta power of the hippocampal EEG decreased after haloperidol injection. Theta rhythmicity of septal neurons significantly diminished, the rate of rhythmic bursts in the neuronal firing also decreased, although not substantially. The theta amplitude and regularity in the hippocampal EEG also decreased. Effects of both drugs built up rapidly and then gradually attenuated. Nomifensine infusion against the background of exposure to haloperidol provoked neither increasing neuronal firing rate, nor elevating theta activity. These finding suggest that dopaminergic system produces activation of the septohippocampal system in situations that require selective attention to functionally important information.     

Dissecting the genetic effect of the CRH system on anxiety and stress-related behaviour

Corticotropin-releasing hormone (CRH) plays a central role in the adaptation of the body to stress. CRH integrates the endocrine, autonomic and behavioural responses to stress acting as a secretagogue within the line of the hypothalamic pituitary adrenocortical (HPA) system and as a neurotransmitter modulating synaptic transmission in the central nervous system. Accumulating evidence suggests that the neuroendocrine and behavioural symptoms observed in patients suffering from major depression are at least in part linked to a hyperactivity of the CRH system. Genetic modifications of the CRH system by conventional and conditional gene targeting strategies in the mouse allowed us to study the endogenous mechanisms underlying HPA system regulation and CRH-related neuronal circuitries involved in pathways mediating anxiety and stress-related behaviour.     

Possible involvement of dopamine and dopamine2 receptors in the inhibitions of gastric emptying by escin Ib in mice

It was previously reported that escin Ib isolated from horse chestnut inhibited gastric emptying (GE) in mice, in which the capsaicin-sensitive sensory nerves (CPSN), the central nervous system and endogenous prostaglandins (PGs) were involved. In the present study, the possible involvement of dopamine and dopamine receptors in the inhibition of GE by escin Ib were investigated in mice. GE inhibition by escin Ib (25 mg/kg, p.o.) was attenuated after pretreatment with a single bolus of DL-alpha-methyl-p-tyrosine methyl ester (400 mg/kg, s.c., an inhibitor of tyrosine hydroxylase), reserpine (5 mg/kg, p.o., a catecholamine depletor), 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor). Furthermore, pretreatment with spiperone (0.5-5 mg/kg, s.c., a dopamine2 receptor antagonist), haloperidol (0.5-10 mg/kg, s.c.) and metoclopramide (1-10 mg/kg, s.c.) (centrally acting dopamine2 receptor antagonists) attenuated the effect of escin Ib. Domperidone (0.1-5 mg/kg, s.c., a peripheral-acting dopamine2 antagonist) showed a weak attenuation, but SCH 23390 (1-5 mg/kg, s.c., a dopamine, receptor antagonist) did not. It is postulated that escin Ib inhibits GE, at least in part, mediated by CPSN, to stimulate the synthesis and/or release of dopamine, to act through central dopamine2 receptor, which in turn causes the release of PGs.     

Effects of neonatal ventral hippocampal lesion in rats on stress-induced acetylcholine release in the prefrontal cortex

Excitotoxic neonatal ventral hippocampus (NVH) lesions in rats result in characteristic post-pubertal hyper-responsiveness to stress and cognitive abnormalities analogous to those described in schizophrenia and suggestive of alterations in dopamine (DA) neurotransmission. Converging lines of evidence also point to dysfunctions in the cortical cholinergic system in neuropsychiatric disorders. In previous studies, we observed alterations in dopaminergic modulation of acetylcholine (Ach) release in the prefrontal cortex (PFC) in post-pubertal NVH-lesioned rats. These two neurotransmitter systems are involved in the stress response as PFC release of DA and Ach is enhanced in response to some stressful stimuli. As adult NVH-lesioned rats are behaviorally more reactive to stress, we investigated the effects of NVH lesions on tail-pinch stress-induced Ach and DA release in the PFC. Using in vivo microdialysis, we observed that tail-pinch stress resulted in significantly greater increases in prefrontal cortical Ach release in post-pubertal NVH-lesioned rats (220% baseline) compared with sham-operated controls (135% baseline). Systemic administration of the D1-like receptor antagonist SCH 23390 (0.5 mg/kg i.p.) or the D2-like receptor antagonist haloperidol (0.2 mg/kg i.p.), as well as intra-PFC administration of the D2-like antagonist sulpiride (100 microm), reduced stress-induced Ach release in PFC of adult NVH-lesioned rats. By contrast, intra-PFC administration of SCH 23390 (100 microm) failed to affect stress-induced Ach release in PFC of NVH-lesioned rats. Interestingly, using in vivo voltammetry, stress-induced stimulation of PFC DA release was found to be attenuated in adult NVH-lesioned rats. Taken together, these data suggest developmentally specific reorganization of prefrontal cortical cholinergic innervation notably regarding its regulation by DA neurotransmission.     

Nitric oxide mediates the interleukin-1beta- and nicotine-induced hypothalamic-pituitary-adrenocortical response during social stress.

We investigated the role of nitric oxide (NO) in the interleukin 1beta (IL-1beta) and nicotine induced hypothalamic-pituitary-adrenal axis (HPA) responses, and a possible significance of CRH and vasopressin in these responses under basal and social stress conditions. Male Wistar rats were crowded in cages for 7 days prior to treatment. All compounds were injected i.p., nitric oxide synthase (NOS) inhibitors, alpha-helical CRH antagonist and vasopressin receptor antagonist 15 min before IL-1beta or nicotine. Identical treatment received control non-stressed rats. Plasma ACTH and serum corticosterone levels were measured 1 h after IL-1beta or nicotine injection. L-NAME (2 mg/kg), a general nitric oxide synthase (NOS) inhibitor, considerably reduced the ACTH and corticosterone response to IL-1beta (0.5 microg/rat) the same extent in control and crowded rats. CRH antagonist almost abolished the nicotine-induced hormone responses and vasopressin antagonist reduced ACTH secretion. Constitutive endothelial eNOS and neuronal nNOS inhibitors substantially enhanced the nicotine-elicited ACTH and corticosterone response and inducible iNOS inhibitor, aminoguanidine, did not affect these responses in non-stressed rats. Social stress significantly attenuated the nicotine-induced ACTH and corticosterone response. In crowded rats L-NAME significantly deepened the stress-induced decrease in the nicotine-evoked ACTH and corticosterone response. In stressed rats neuronal NOS antagonist did not alter the nicotine-evoked hormone responses and inducible NOS inhibitor partly reversed the stress-induced decrease in ACTH response to nicotine. These results indicate that NO plays crucial role in the IL-1beta-induced HPA axis stimulation under basal and social stress conditions. CRH and vasopressin of the hypothalamic paraventricular nucleus may be involved in the nicotine induced alterations of HPA axis activity. NO generated by eNOS, but not nNOS, is involved in the stress-induced alterations of HPA axis activity by nicotine.     

Role of interleukin-1 in stress responses

Recently, the central roles of interleukin-1 (IL-1) in physical stress responses have been attracting attention. Stress responses have been characterized as central neurohormonal changes, as well as behavioral and physiological changes. Administration of IL-1 has been shown to induce effects comparable to stress-induced changes. IL-1 acts on the brain, especially the hypothalamus, to enhance release of monoamines, such as norepinephrine, dopamine, and serotonin, as well as secretion of corticotropin-releasing hormone (CRH). IL-1-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis in vivo depends on secretion of CRH, an intact pituitary, and the ventral noradrenergic bundle that innervates the CRH-containing neurons in the paraventricular nucleus of the hypothalamus. Recent studies have shown that IL-1 is present within neurons in the brain, suggesting that IL-1 functions in neuronal transmission. We showed that IL-1 in the brain is involved in the stress response, and that stress-induced activation of monoamine release and the HPA axis were inhibited by IL-1 receptor antagonist (IL-1Ra) administration directly into the rat hypothalamus. IL-1Ra has been known to exert a blocking effect on IL-1 by competitively inhibiting the binding of IL-1 to IL-1 receptors. In the latter part of this review, we will attempt to describe the relationship between central nervous system diseases, including psychological disorders, and the functions of IL-1 as a putative neurotransmitter.