Fear Stress Research Articles

Effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in rats: dissociation of biochemical and behavioral effects

Background: We have examined the effects of nicotine pretreatment on dopaminergic and behavioral responses to conditioned fear stress in the rat. Methods: Rats were pretreated daily with saline or nicotine for 20 days then challenged with nicotine or saline on day 21. Animals were trained in a classical conditioned fear paradigm. Dopamine utilization in the medial prefrontal cortex and nucleus accumbens shell and conditioned fear stress–induced immobility responses were assessed. Results: Saline pretreated animals rapidly acquired the conditioned fear stress response as assessed by preferential activation of mesoprefrontal dopamine metabolism and tone-elicited immobility responses. Repeated, but not acute, nicotine pretreatment significantly reduced conditioned fear stress–induced dopamine metabolism in the medial prefrontal cortex and nucleus accumbens shell. Repeated nicotine pretreatment did not modify the acquisition or expression of conditioned fear stress responses, however. Conclusions: The dissimilar effects of repeated nicotine exposure on the cortical dopamine and behavioral responses to conditioned fear stress suggest that nicotine differs from other agents with anxiolytic activity that produce coordinated changes in conditioned fear stress–induced cortical dopaminergic and behavioral responses. Furthermore, compared with results of acute footshock stress, repeated nicotine pretreatment appears to have differential effects on physical versus psychological stressors. Results are discussed within the clinical context of stress-related psychopathology syndromes and comorbid nicotine dependence.

CRH Signalling in the Bed Nucleus of the Stria Terminalis is Involved in Stress-Induced Cardiac Vagal Activation in Conscious Rats

The bed nucleus of the stria terminalis (BNST) is involved in autonomic and behavioral reactions to fearful stimuli and contains corticotropin-releasing hormone (CRH) fibers and terminals. The role of CRH in the medial part of the BNST in the regulation of heart rate (HR) and PQ interval of the electrocardiogram was studied under resting conditions and conditioned fear stress in freely moving rats. Microinfusion of CRH (0.2 μg/0.6 μl) in the medial BNST under resting conditions significantly enhanced HR as compared to saline treatment, but did not reduce the PQ interval, indicating that exogenous CRH in the medial BNST can activate both the sympathetic and parasympathetic cardiac outflow. In addition, CRH induced a slight increase in gross locomotor activity, an effect that succeeded the tachycardiac response, indicating that the HR response was not a consequence of increased locomotor activity, but likely a direct effect of CRH. CF was induced by 10-min forced exposure to a cage in which the rat had experienced footshocks (5 × 0.5 mA × 3s) the day before. α-helical CRH(9–41) (αhCRH; 5 μg/0.6 μl), a non-selective CRH receptor antagonist, or saline was infused into the medial BNST of rats prior to CF. CF induced freezing behavior, associated with an increase in HR and PQ interval, indicating activation of sympathetic and vagal outflow to the heart. αhCRH significantly reduced the PQ response, but enhanced the tachycardia, suggesting inhibition of vagal activity. In addition, α-helical CRH(9–41) reduced the freezing response. Taken together, the data provide first evidence that CRH, released in the medial BNST during stress, contributes to cardiac stress responses, particularly by activating vagal outflow.

Pretreatment with diazepam suppresses the reduction in defensive freezing behavior induced by fluvoxamine in the conditioned fear stress paradigm in mice

The effects of the selective serotonin (5-hydroxytryptamine (5-HT)) reuptake inhibitor fluvoxamine, given alone or in combination with the benzodiazepine anxiolytic diazepam on the defensive freezing behavior of mice in the conditioned fear stress paradigm were examined. Fluvoxamine (5–20 mg/kg, i.p.) induced a dose-dependent reduction in freezing behavior. In contrast, while low doses of diazepam (0.125 and 0.25 mg/kg, i.p.) reduced the freezing behavior, such effects were not observed with high doses of diazepam (0.5 and 1 mg/kg, i.p.). In the combination study, fluvoxamine (20 mg/kg, i.p.) did not reduce the freezing behavior in mice that had been pretreated with diazepam (0.125–1 mg/kg, i.p.). None of the doses of fluvoxamine and diazepam used in the present study had any effects on motor activity under non-stressed conditions. These results suggest that benzodiazepines may negatively influence the clinical efficacy of selective 5-HT reuptake inhibitors in the treatment of anxiety disorders.

Monoamine oxidase inhibitors reduce conditioned fear stress-induced freezing behavior in rats

The present study examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety induced by conditioned fear stress. The selective serotonin 1A receptor agonist tandospirone (0.1–10 mg/kg) inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), N-(2-aminoethyl)-5-( m-fluorophenyl)-4-thiazole carboxamide (Ro 41-1049) (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduced anxiety or fear, while inhibition of monoamine oxidase A or B alone failed to reduce anxiety or fear.

Neurosteroids Ameliorate Conditioned Fear Stress: An Association with Sigma1 Receptors

Mice exhibited a marked suppression of motility (conditioned fear stress) when placed in an environment in which they had previously received an electric footshock. This conditioned fear stress response was dose-dependently attenuated by neurosteroids such as dehydroepiandrosterone sulfate (DHEAS; 25 and 50 mg/kg, s.c.) and pregnenolone sulfate (PREGS; 10–50 mg/kg, s.c.), and by a putative sigma1 receptor agonist, (+)-N-allylnormetazocine ((+)-SKF-10,047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; 10–50 mg/kg, s.c.) and allopregnanolone (5 and 20 mg/kg, s.c.) had no effect on this stress response. The attenuating effects of DHEAS (50 mg/kg, s.c.), PREGS (50 mg/kg, s.c.), and (+)-SKF-10,047 (6 mg/kg, s.c.) were reversed by NE-100 (5 mg/kg, i.p.), a sigma1 receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with (+)-SKF-10,047 (3 mg/kg) at doses that do not affect the conditioned fear stress response by themselves, motor suppression was significantly attenuated. In mice showing the conditioned fear stress response, the serum concentration of DHEAS was lower than that in non-shocked mice. These results suggest that the attenuating effects of DHEAS and PREGS on the conditioned fear stress response are mediated via sigma1 receptors and that PROG has a sigma1 receptor antagonistic property. Further, the endogenous DHEAS may be involved in the expression of conditioned fear stress response in mice.

Suppression of conditioned fear by administration of CRF receptor antagonist CP-154,526.

In order to examine the involvement of corticotropin-releasing hormone (CRF) receptor in the formation of anxiety, we investigated whether CRF receptor antagonist CP-154,526 suppressed conditioned fear stress. First, rats were individually subjected to 30 min of footshock. Twenty-four hours after footshock, the rats were again placed in the chamber and observed for 5 min without shock. CP-154,526 was administered 30 min before placing the rats in the chamber again. After that, CP-154,526 was once more administered 30 min before applying footshock. Administration of CP-154,526 30 min both before conditioned fear stress (placing the rats inside the cage but not applying footshock) and before actual footshock significantly reduced freezing behavior. These results show that CP-154,526 blocked both the acquisition and expression of conditioned fear, thus suggesting that the CRF receptor might be related to anxiety.

Involvement of ??-Opioid Receptor in the Salsolinol-Associated Place Preference in Rats Exposed to Conditioned Fear Stress

Involvement of ??-Opioid Receptor in the Salsolinol-Associated Place Preference in Rats Exposed to Conditioned Fear Stress

Involvement of mu-Opioid Receptor in the Salsolinol-Associated Place Preference in Rats Exposed to Conditioned Fear Stress

Salsolinol, a condensation product of dopamine with acetaldehyde (the initial oxidation product of ethanol), has long been discussed as an endogenous opioid system-activating factor contributing to the etiology of alcoholism. Moreover, psychological stress has been considered to play an important role in the development of alcoholism. Male Sprague Dawley rats were subjected to conditioned fear stress (at 24 hr after electric footshock exposure), and then salsolinol or saline was injected intraperitoneally. For conditioning, rats were immediately confined to the nonpreferred compartment after salsolinol injection and to the preferred compartment after saline injection on alternate days. This conditioning session was repeated twice daily (for 8 days). Test session was carried out 1 day after the last conditioning session. Salsolinol [10 mg/kg, but not 1, 3, or 30 mg/kg, intraperitoneally (ip)] without conditioned fear stress induced a slight, but significant, place preference. In contrast, salsolinol (1, 3, and 10 mg/kg, ip) with conditioned fear stress induced a marked and significant place preference. The nonselective opioid receptor antagonist naloxone hydrochloride (which can pass into the brain), but not the nonselective peripheral opioid receptor antagonist naloxone methiodide (which cannot pass into the brain), significantly attenuated the salsolinol (3 mg/kg, ip)-induced place preference under conditioned fear stress. Moreover, the selective mu-opioid receptor antagonist beta-funaltrexamine significantly attenuated the salsolinol-induced place preference. Furthermore, 0.3 mg/kg salsolinol (which produced no significant place preference) combined with the mu-opioid receptor agonist morphine [0.1 mg/kg, subcutaneously (sc)], at the dose which alone produced no significant place preference, produced a marked and significant place preference. Both naloxone hydrochloride and beta-funaltrexamine significantly attenuated the salsolinol plus morphine-induced place preference. Salsolinol may have some rewarding effect, and its rewarding effect may be potentiated by psychological stress. In addition, the rewarding effect of salsolinol especially under psychological stress may involve the endogenous central opioid system, i.e., mu-opioid receptor.

Ethanol, But Not the Anxiolytic Drugs Buspirone and Diazepam, Produces a Conditioned Place Preference in Rats Exposed to Conditioned Fear Stress

The present study was designed to investigate the role of an anxiolytic effect in the development of a drug-associated place preference in rats exposed to conditioned fear stress, using the conditioned place-preference paradigm. The administration of a low dose of ethanol (300 mg/kg, IP) and the anxiolytic drugs, buspirone (1 and 2 mg/kg, IP) and diazepam (1.25 and 2.5 mg/kg, IP), did not produce a place preference in rats that were not exposed to conditioned fear stress. In rats that were exposed to conditioned fear stress, ethanol produced a significant place preference, while buspirone and diazepam failed to produce a place preference. In addition, ethanol, buspirone, and diazepam produced no place preference in rats treated with an anxiogenic dose of pentylenetetrazole (20 mg/kg, IP). A significant decrease in locomotor activity was observed in rats exposed to conditioned fear stress. Ethanol, but not buspirone and diazepam, significantly recovered or increased locomotor activity in rats exposed to conditioned fear stress. Further, the locomotor-stimulating effect of ethanol was markedly enhanced by repeated exposure to conditioned fear stress. These results suggest that the stimulating effect may be strongly related to the development of the rewarding effect of a low dose of ethanol under psychological stress, and that the conditioned place preference paradigm with conditioned fear stress may be useful for studying the rewarding mechanism of ethanol with regard to the interaction between ethanol and psychological stress.

The mechanism of alteration of monoamine metabolism in brain regions in marble burying behavior-isolated housing mice and effect of oren-gedoku-to on this alteration

The mechanism of the alteration in marble burying behavior-isolated housing (MBB-IH) mice was investigated. The determination of hypothalamus monoamine and serum corticosterone contents indicated that MBB-IH mice readily responded to the stress stimuli in conditioned fear stress. Six drugs, such as buspirone (10 mg/kg, p.o.), zimelidine (10 mg/kg, p.o.), clomipramin (10 mg/kg, p.o.), yohimbine (5 mg/kg, p.o.), ethyl beta-carboline-3-carboxylate (beta-CCE, 5 mg/kg, p.o.) and flumazenil (15 mg/kg, p.o.) were singly and/or three times administered to MBB-IH mice. Their inhibitory activity on the MBB-IH mice was considered by the use of activity profiles consisting of spontaneous locomotor activity, marble burying behavior and hypothalamus monoamine content. Using these profiles, we calculated the activities as vector in three-dimensional space, and compared the distance from the control point (DCP). DCPDOPAC and DCP5-HIAA were shortened by single administration of beta-CCE and flumazenil. Oren-gedoku-to (30 and 300 mg/kg, p.o.) shortened the DCPDOPAC and DCP5-HIAA similarly to beta-CCE. The blended crude drugs in Oren-gedoku-to, Coptis rhizome (636.0 mg/kg, p.o.), Scutellaria root (644.4 mg/kg, p.o.) and Gardenia fruit (894.8 mg/kg, p.o.) shortened the DCPDOPAC. Coptis rhizome and Scutellaria root also shortened the DCP5-HIAA. These results suggest that GABA neuron function intensely affects the alteration of MBB-IH and Oren-gedoku-to has the intrinsic benzodiazepine-like activity.

Effect of microinjection of serotonergic anxiolytics to the basolateral neucleus of the amygdala on conditioned fear stress

Effect of microinjection of serotonergic anxiolytics to the basolateral neucleus of the amygdala on conditioned fear stress

Suppression of conditioned fear by administration of CCKB receptor antagonist PD135158

In order to examine the involvement of CCK in the formation of anxiety, we have investigated whether CCKB receptor antagonist PD135158 suppressed conditioned fear stress. Rats were individually subjected to 30 min of inescapable electric footshock in a chamber with a grid floor. First, the rats were individually subjected to 30 min of footshock. Twenty-four h after the footshock, the rats were again placed in the chamber and observed for 5 min without shocks. PD135158 was administered 30 min before placing the rats in the chamber again. Secondly, PD135158 was administered 30 min before footshock. Thirdly, PD135158 was administered 5 min after footshock. Administration of PD135158 30 min before conditioned fear stress significantly reduced freezing behavior. Administration of PD135158 30 min before footshock also significantly reduced freezing behavior. But, administration of PD135158 5 min after footshock did not significantly reduce freezing behavior. PD135158 blocked not only the acquisition but also the expression of conditioned fear. These results suggest that the CCKB receptor might play an important role in conditioned fear stress and that it might be related to anxiety.

Effect of subchronic lithium carbonate treatment on anxiolytic-like effect of citalopram and MKC-242 in conditioned fear stress in the rat

We investigated the effect of citalopram [selective serotonin (5-HT) reuptake inhibitor] and MKC-242 (5-[3-{(2 S)-(1,4-Benzodioxan-2-ylmethyl) amino}propoxy]-1, 3-benzo-dioxol hydrochloride; a selective 5-HT 1A receptor agonist) on the expression of conditioned freezing, an index of anxiety, following treatment with subchronic lithium carbonate (LiCO 3). Male Sprague–Dawley rats were used in these experiments. Acute administration of citalopram (subcutaneously, s.c.) reduced freezing significantly at a high dose (30 mg/kg), while showing no effect at lower doses (3 and 10 mg/kg). Acute administration of MKC-242 (s.c.; 0.1–10 mg/kg) dose dependently reduced freezing. Subchronic LiCO 3 treatment (1 week; 0.05% or 0.2% LiCO 3 in diet; p.o.) showed no effect on freezing behavior. Acute treatment with both citalopram (3 and 30 mg/kg) and MKC-242 (1 mg/kg) after subchronic treatment with the higher, but not the lower concentration of LiCO 3 (1 week), reduced freezing markedly and significantly, as compared with either drug alone. These results suggest that subchronic LiCO 3 treatment enhanced the anxiolytic-like effects of these serotonergic drugs by facilitating central 5-HT neurotransmission at clinically therapeutic plasma lithium levels.

Effects of the benzodiazepine antagonist flumazenil on conditioned fear stress in rats

1. 1. The authors investigated the effect of the benzodiazepine receptor antagonist flumazenil on freezing behavior induced by conditioned fear stress and used a time-sampling procedure. 2. 2. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. 3. 3. Subcutaneous administration of flumazenil (10 mg/kg) 30 min before conditioned fear stress reduced conditioned freezing, while flumazenil (1–10 mg/kg) 30 min before footshock did not. This indicates that flumazenil reduced the expression of conditioned fear, suggesting an anxiolytic effect of flumazenil. 4. 4. This effect may be attributable to antagonism by flumazenil to endogenous inverse agonist-like ligands for benzodiazepine receptors. It is suggested that endogenous inverse agonist-like ligands for benzodiazepine receptors are involved in the expression of conditioned fear stress.

Effects of conditioned fear stress on serotonin neurotransmission and freezing behavior in rats

In an attempt to clarify the role of the brain serotonergic system in the psychopathology of anxiety, we examined the effect of a psychological stress, conditioned fear stress, on extracellular serotonin (5-hydroxytryptamine, 5-HT) concentrations in the rat medial prefrontal cortex using the method of in vivo microdialysis, while simultaneously observing conditioned fear stress-induced freezing behavior, an index of anxiety. Conditioned fear stress increased extracellular 5-HT levels in the medial prefrontal cortex, and this 5-HT level increase was followed by a resolution of the freezing behavior. A dose of 10 mg/kg of a selective 5-HT reuptake inhibitor, citalopram, administered 60 min before exposure to conditioned fear stress increased extracellular 5-HT concentrations immediately and potently, reducing freezing behavior. These findings strongly suggest that facilitation of brain 5-HT neurotransmission decreases anxiety, which is in agreement with the clinical reports that selective 5-HT reuptake inhibitors are effective in the treatment of anxiety disorders.

Involvement of dopamine D 1 and D 2 receptors in the ethanol-associated place preference in rats exposed to conditioned fear stress

The present study was designed to investigate: (1) the involvement of dopamine D 1 and D 2 receptors, and (2) the roles of these receptors and endogenous opioid systems (endorphinergic and enkephalinergic systems) in the ethanol-induced place preference in rats exposed to conditioned fear stress using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference. The selective D 1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H3-benzazepine)hydrochloride (SCH23390; 0.01 and 0.03 mg/kg, s.c.) and the selective D 2 receptor antagonist S(−)-5-(aminosulfonyl)- N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride; 20 and 40 mg/kg, s.c.) significantly attenuated the ethanol-induced place preference. The administration of ethanol (75 mg/kg, i.p.) tended to produce a place preference, but this effect was not significant. SCH23390 (0.03 mg/kg, s.c.) and sulpiride (40 mg/kg, s.c.) significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the μ-opioid receptor agonist morphine (0.1 mg/kg, s.c.). In addition, SCH23390 (0.03 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by the selective δ-opioid receptor agonist 2-methyl-4 aα-(3-hydroxyphenyl)-1,2,3,4,4 a,5,12,12 aα-octahydroquinolino[2,3,3,- g]isoquinoline (TAN-67; 20 mg/kg, s.c.). On the other hand, sulpiride (40 mg/kg) had no significant effect on the enhancement of the ethanol (75 mg/kg, i.p.)-induced place preference produced by TAN-67. These results suggest that D 1 and D 2 receptors may be involved in the rewarding mechanism of ethanol under psychological stress. In addition, D 1 receptors may participate in the rewarding effect of ethanol modulated by the activation of μ- and δ-opioid receptors, whereas D 2 receptors may participate in the rewarding effect of ethanol modulated by the activation of μ-opioid receptors, but not in that modulated by the activation of δ-opioid receptors.

Roles of 5-HT 3 and opioid receptors in the ethanol-induced place preference in rats exposed to conditioned fear stress

The effect of the selective 5-HT 3 receptor antagonist ondansetron on the ethanol-induced place preference in rats exposed to conditioned fear stress, which stimulates the release of endogenous opioid peptides (β-endorphin and enkephalins), was investigated using the conditioned place preference paradigm. In addition, we also examined the effect of ondansetron on the ethanol-induced place preference enhanced by the administration of μ- and δ-opioid receptor agonists (exogenous opioids). The administration of ethanol (300 mg kg , I.p.) induced a significant place preference in rats exposed to conditioned fear stress. Pretreatment with ondansetron (0.01 and 0.1 mg kg , S.c.) effectively attenuated this ethanol-induced place preference. When the μ-opioid receptor agonist morphine (0.1 mg kg , s.c.) or the selective δ-opioid receptor agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg kg , s.c.) was administered in combination with 75 mg kg ethanol (which tended to produce a place preference), the ethanol-induced place preference was significantly enhanced. The selective μ-opioid receptor antagonist β-funaltrexamine at a dose of 10 mg kg significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Ondansetron (0.1 mg kg , s.c.) also significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Furthermore, the selective δ-opioid receptor antagonist naltrindole at a dose of 3 mg kg significantly attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. Ondansetron (0.1 mg kg , s.c.) slightly, but significantly, attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. These results suggest that 5-HT 3 receptors may be involved in the rewarding mechanism of ethanol under psychological stress, and may play an important role in the rewarding effect of ethanol through the activation of μ- and δ-opioid receptors.

Different roles of μ-, δ- and κ-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress

The present study was designed to investigate the role of the endogenous opioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previously with electric foot shock), using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated this ethanol-induced place preference. Moreover, the selective μ-opioid receptor antagonist β-funaltrexamine (3 and 10 mg/kg, i.p.) and the selective δ-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) significantly attenuated ethanol-induced place preference. In contrast, the selective κ-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) significantly enhanced ethanol-induced place preference. Furthermore, 75 mg/kg ethanol (which tended to produce place preference) combined with the μ-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective δ-opioid receptor agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino [2,3,3,- g] isoquinoline (TAN-67; 20 mg/kg, s.c.), at doses which alone did not produce place preference, produced significant place preference. However, co-administration of the selective κ-opioid receptor agonist trans-3,4-dichloro- N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethanol (300 mg/kg, i.p.) dose dependently attenuated ethanol-induced place preference. Moreover, conditioned fear stress shifted the response curve for the aversive effect of U50,488H to the left. These results suggest that μ- and δ-opioid receptors may play critical roles in the rewarding mechanism of ethanol, and that κ-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress.

Developmental and pharmacological features of mouse emotional piloerection.

We demonstrated emotional piloerection in mice given conditioned fear stress by means of a pass-through apparatus. The emotional piloerection was first assessed in mice of different ages. The results showed that the piloerection changed with age. Pharmacological studies showed that the piloerection was inhibited by an alpha 1-adrenoceptor antagonist prazosin, but, surprisingly, was not inhibited by anxiolytic diazepam. These findings strongly suggest that the neuronal system of piloerection is different from that of freezing behavior, and that the neuronal system of piloerection develops with age.

Sigma-receptor ligands and anti-stress actions

The functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma1-receptors have been shown to play an important role in antidepressive effects since selective sigma1-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma1-receptor agonists is antagonized by NE-100, a sigma1-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma2-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin-sensitive sigma1-receptor agonists such as (+)-SKF-10,047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoin-sensitive sigma1 receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma1 receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma1-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.