Executive functions of postweaning protein malnutrition in mice.

It is well known that nutritional status during the fetal and/or lactation period is important for the development of the central nervous system (CNS). In contrast, the effect of malnutrition on postweaning development has not yet been thoroughly investigated. In the present study, we analyzed the behavioral and neuroanatomical effects of protein malnutrition (PM) postweaning in mice. Starting at 20-21 d of age, male ddY mice were maintained on a 5% casein diet (PM group) or 20% casein diet (control group) for 20 d. On the 20th d, body and brain weights of PM mice were lower than those of the control group. PM mice exhibited excessive alertness and spontaneous activity under novel conditions in the Irwin test. In addition, PM mice showed increased open arm exploration in the elevated plus maze compared to control mice. These results suggest that hyperactivity and reduced anxiety behavior or higher impulsiveness in PM mice could be due to an immature brain.

Effects of atomoxetine on levels of monoamines and related substances in discrete brain regions in mice intermittently deprived of rapid eye movement sleep.

An imbalance between noradrenergic and dopaminergic systems is implicated in hyperactivity disorders, such as attention deficit/hyperactivity disorder (ADHD). We previously showed that the explosive jumping behavior elicited by intermittent rapid eye movement sleep deprivation (REMSD) may serve as a useful model of ADHD (see [Biogenic Amines, 20, 99-111]). Here, we investigated whether intermittent REMSD might cause changes in monoamine turnover in the mouse forebrain. Our main findings were as follows. Intermittent REMSD led to a significant decrease in dopamine turnover and a significant increase in noradrenaline turnover in the frontal cortex. The latter effect, but not the former, was attenuated by atomoxetine, which is used clinically to treat ADHD symptoms. These results suggest (a) that intermittent REMSD induces hypernoradrenergic and hypodopaminergic states within the frontal cortex, and (b) that the therapeutic effects of atomoxetine may include an inhibition of this hypernoradrenergic state.

Involvement of the p53 tumor-suppressor protein in the development of antinociceptive tolerance to morphine.

The present study was designed to determine whether the p53 tumor-suppressor protein is involved in the development of antinociceptive tolerance to morphine. When the doses of morphine (mg/kg per injection) were subcutaneously given into mice as pretreatment twice daily for 2 days (first day (30) and second day (60)), intrathecal (i.t.) administration of morphine (0.1nmol) was inactive due to antinociceptive tolerance in the 0.5% formalin test on the third day. Tolerance to i.t. morphine was significantly suppressed by i.t. injection of pifithrin-alpha (1 and 10nmol), an inhibitor of p53 activation, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (Z-VAD-fmk) (1 and 10nmol), a non-selective caspase inhibitor, or N(G)-nitro-l-arginine methyl ester (l-NAME) (2 and 20nmol), a non-selective inhibitor of nitric oxide synthase, 5min before each morphine treatment during the induction, with none given on the test day. Moreover, p53 expression in the spinal cord had increased significantly 14h after the last morphine administration. These results indicate that the increased expression and activation of p53, and the nitric oxide and caspase systems related to p53 may contribute to the development of antinociceptive tolerance to morphine in the mouse spinal cord.

Cysteine protease inhibitors suppress the development of tolerance to morphine antinociception.

The effects of various protease inhibitors on the development of antinociceptive tolerance to morphine were examined in mice. Intrathecal (i.t.) administration of morphine (0.01-1 nmol) produced a dose-dependent and significant antinociceptive effect in the 0.5% formalin test. When the doses of morphine (mg/kg, s.c. per injection) were given as pretreatment twice daily for two days [first day (30) and second day (60)], i.t. administration of morphine (0.1 nmol) was inactive due to antinociceptive tolerance on the third day. Tolerance to i.t. morphine was significantly suppressed by the i.t. injection of N-ethylmaleimide or Boc-Tyr-Gly-NHO-Bz, inhibitors of cysteine proteases involved in dynorphin degradation, as well as by dynorphin A, dynorphin B and (-) U-50,488, a selective kappa-opioid receptor agonist. On the other hand, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, lisinopril, an angiotensin-converting enzyme inhibitor, and phenylmethanesulfonyl fluoride, a serine protease inhibitor, were inactive. These results suggest that cysteine protease inhibitors suppress the development of morphine tolerance presumably through the inhibition of dynorphin degradation.

S-(+)-fenfluramine-induced nociceptive behavior in mice: Involvement of interactions between spinal serotonin and substance P systems.

Intrathecal (i.t.) administration into mice of S-(+)-fenfluramine (0.01-0.1nmol), a serotonin (5-hydroxytryptamine, 5-HT) releaser, produced a behavioral response consisting of scratching, biting and licking. Here, we report the behavioral characteristics and the involvement of interactions between 5-HT and substance P (SP) systems in the S-(+)-fenfluramine-induced behavioral response. The S-(+)-fenfluramine-induced behavioral response peaked at 5-15min and almost disappeared at 20min after injection. The behavior induced by S-(+)-fenfluramine (0.1nmol) was dose-dependently inhibited by an intraperitoneal injection of morphine (0.02-0.5mg/kg), suggesting that the behavioral response is related to nociception. The S-(+)-fenfluramine-induced nociceptive behavior was significantly inhibited by pretreatment with 5-HT antiserum and co-administration of ketanserin, a selective 5-HT2 receptor antagonist. However, WAY-100635, a selective 5-HT1A receptor antagonist, and ramosetron, a selective 5-HT3 receptor antagonist, were not active. On the other hand, SP antiserum and RP67580, a selective neurokinin-1 (NK1) receptor antagonist, significantly inhibited S-(+)-fenfluramine-induced nociceptive behavior. These results suggest that i.t.-administered S-(+)-fenfluramine releases SP through the activation of 5-HT2 receptors subsequent to 5-HT release, and, as a result, produces nociceptive behavior.

Preventive effect of kami-untan-to on performance in the forced swimming test in thiamine-deficient mice: relationship to functions of catecholaminergic neurons.

The kampo (Japanese herbal) medicine "kami-untan-to" (KUT) has been used for a long time in the treatment of neuropsychiatric disorders. We have recently reported that mice put on a thiamine-deficient (TD) diet exhibit a depressive behavior and impairment in avoidance learning after 20 days, and that this impairment was reversed by the chronic administration of KUT. In the present study, we investigated the effect of KUT on the depressive behavior observed in TD mice by using the forced swimming test. Our results show that oral administration of KUT from the 1st day of TD feeding prevented the increased duration of immobility in TD mice. Administration of KUT from the 10th day of TD feeding also had a beneficial effect on depressive behavior. To examine the relationship between the potential effects of KUT on monoaminergic neuronal functions and the depressive behavior observed in TD mice, we measured the immunohistochemical distribution of tyrosine hydroxylase (TH) in the brain using microphotometry. The fluorescence intensity of TH decreased in the limbic cortex and brainstem in TD mice compared with pair-fed mice as the control group, while KUT treatment protected against these decreases. These results suggest that KUT treatment may prevent a sign of depressive behavior, the animal immobility time, induced by TD feeding through a mechanism that involves the decrease of TH in some brain areas of TD mice.

Alterations in cognitive function in prepubertal mice with protein malnutrition: relationship to changes in choline acetyltransferase.

We have found that protein malnutrition (PM) causes a significant impairment of memory-related behavior on the 15th and 20th day after the start of PM (5% casein) feeding in prepubertal mice but not in postpubertal mice, as measured by a passive-avoidance task. This impairment was almost completely reversed by merely switching to a standard protein (20% casein) diet on the 10th day after the start of PM. However, the reversal was not observed when the switching to a standard protein regimen was done on the 15th day of the PM diet. Interestingly, the impairment of memory-related behavior on the 20th day was improved by the chronic administration of physostigmine (0.1 mg/kg/day x last 10 days, i.p.), a cholinesterase inhibitor. To correlate brain cholinergic neuron function with the memory-related behavior impairment induced by PM, microphotometry was used to determine the histological distribution of the imunofluorescence intensity for choline acetyltransferase (ChAT), a functional marker of presynapse in cholinergic neurons. The change in the intensity of fluorescence indicated that ChAT protein was decreased in the hippocampus (CA1, CA3 and dentate gyrus) on the 20th day after PM feeding in comparison with controls. These results suggest the possibility that the memory-related behavior deficits observed in prepubertal mice with PM are caused by a dysfunction of the cholinergic neurons in the hippocampus.

Pronociceptive role of dynorphins in uninjured animals: N-ethylmaleimide-induced nociceptive behavior mediated through inhibition of dynorphin degradation.

Intrathecal (i.t.) administration into mice of N-ethylmaleimide (NEM), a cysteine protease inhibitor, produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by NEM was inhibited by the intraperitoneal injection of morphine. We have recently reported that dynorphin A and, more potently big dynorphin, consisting of dynorphins A and B, produce the same type of nociceptive response whereas dynorphin B does not [Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C, Sakurada T, Bakalkin G, Terenius L, Kisara K. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 2002;952:7-14]. The NEM-induced nociceptive behavior was inhibited by pretreatment with dynorphin A- or dynorphin B-antiserum and each antiserum also reduced the nociceptive effects of i.t.-injected synthetic big dynorphin. The characteristic NEM-evoked response was not observed in prodynorphin knockout mice. Naloxone, an opioid receptor antagonist, had no effects on the NEM-induced behavior. Ifenprodil, arcaine and agmatine, antagonists at the polyamine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and MK-801, an NMDA ion-channel blocker inhibited the NEM-induced effects. Ro25-6981, an antagonist of the NMDA receptor subtype containing NR2B subunit was not active. NEM completely inhibited degradation of dynorphin A by soluble and particulate fractions of mouse spinal cord. Collectively, the results demonstrate that endogenous prodynorphin-derived peptides are pronociceptive in uninjured animals, and required for the NEM-induced behavior. The NEM effects may be mediated through inhibition of the degradation of endogenous dynorphins, presumably big dynorphin that in turn activates the NMDA receptor ion-channel complex by acting on the polyamine recognition site.

Differential effects of N-peptidyl-O-acyl hydroxylamines on dynorphin-induced antinociception in the mouse capsaicin test.

In the capsaicin test, intrathecal (i.t.) dynorphins are antinociceptive. Cysteine protease inhibitors such as p-hydroxymercuribenzoate (PHMB) given i.t. augment and prolong their activity. The effect of two novel cysteine protease inhibitors, N-peptidyl-O-acyl hydroxylamines, on the antinociception induced by i.t. administered dynorphin A or dynorphin B has been investigated. When administered i.t. 5 min before the injection of capsaicin (800 ng) into the plantar surface of the hindpaw, dynorphin A (62.5-1000 pmol) or dynorphin B (0.5-4 nmol) produced a dose-dependent and significant antinociceptive effect. The effect of dynorphin A (1 nmol) and dynorphin B (4 nmol) disappeared completely within 180 and 60 min, respectively. PHMB (2 nmol) and Boc-Tyr-Gly-NHO-Bz (BYG-Bz) (2 nmol) co-administered with dynorphin A or dynorphin B significantly prolonged antinociception induced by both. On the other hand, Z-Phe-Phe-NHO-Bz (ZFF-Bz) (1 and 2 nmol) only prolonged antinociception induced by dynorphin A. The results suggest that Z-Phe-Phe-NHO-Bz is an inhibitor of cysteine proteases preferring cleavage of dynorphin A, with less specificity towards dynorphin B in the mouse spinal cord.

Immunohistochemical fluorescence intensity reduction of brain somatostatin in the impairment of learning and memory-related behaviour induced by olfactory bulbectomy.

The role of brain somatostatin (SST) on memory function after olfactory bulbectomy (OBX) was investigated by using the passive-avoidance task and immunohistochemical analyses in mice. The present study indicated that the learning and memory-related behaviour was impaired on the 7th and 14th day, but not on the 1st day after OBX. The impairment of learning and memory-related behaviour on the 14th day after OBX was dose-dependently reversed by intracerebroventricularly administered SST (1 microg per mouse). To ascertain the correlation between SST in mouse brain and the impairment of learning and memory-related behaviour induced by OBX, the immunohistochemical distribution of brain SST was determined by fluorescence intensity using two-dimensional microphotometry. The intensity of SST fluorescence was low in the hippocampus on the 14th day after OBX in comparison with Sham controls. These results suggest that SST in the hippocampus is related to the impairment of learning and memory-related behaviour induced by OBX.

Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy.

Memory function after olfactory bulbectomy (OBX) was examined in two tasks, namely, step-through passive avoidance task and elevated plus-maze task. OBX mice showed a significant impairment of learning and memory-related behavior on the 7th and 14th day, as measured by passive avoidance task but not elevated plus maze task. The impairment of learning and memory-related behavior on the 14th day was improved by administration of the cholinesterase inhibitor physostigmine (0.1 mg/kg, i.p.), the non-selective muscarinic agonist oxotremorine (0.1 mg/kg, i.p.) or the selective muscarinic M(1) agonist McN-A-343 (10 microg/mouse, i.c.v.). In contrast, administration of the nicotinic agonist lobeline (5-9.8 mg/kg, i.p.) or the selective muscarinic M(2) antagonist methoctramine (2.25-18 microg/mouse, i.c.v.) has no effect on the impairment of learning and memory-related behavior induced by OBX. In addition, we have demonstrated that the intensity of choline acetyltransferase (ChAT) fluorescence is significantly decreased in the cortex, hippocampus and amygdala on the 14th day after OBX. These results suggest that the impairment of learning and memory-related behavior induced by OBX may be caused by degeneration of cholinergic neurons and muscarinic M(1) receptors play an important role in the improvement process.

Nociceptive behavior induced by poly-L-lysine and other basic compounds involves the spinal NMDA receptors.

We have previously shown that spermine, a basic polyamine, and big dynorphin, a basic polypeptide, induce nociceptive behavior if injected intrathecally (i.t.) in mice (see [Pain 86 (2000) 55-61] and [Brain Res. 952 (2002) 7-14]). This suggests that other basic molecules might have the same effects. Here, i.t. administration of poly-L-lysine (12 and 36 pg) to mice was found to produce the same characteristic behavioral response, biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 0-10 min after injection. The behavior induced by poly-L-lysine (12 pg) was dose-dependently inhibited by intraperitoneal injection of morphine (0.25-4 mg/kg) and also dose-dependently, by i.t. co-administration of D-(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine hydrogen maleate (MK-801) (0.0156-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 nmol), an antagonist of the polyamine recognition site and the NR2B-containing NMDA receptor subtype. On the other hand, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe7, d-His9]-substance P (6-11), a specific antagonist for substance P (NK1) receptors, or MEN-10,376, a tachykinin NK2 receptor antagonist, had no effect. These results confirm the observations obtained with other basic molecules and suggest that the behavior induced by poly-l-lysine is mediated through the activation of the NMDA receptor ion-channel complex acting either on the polyamine recognition site or on the NR2B subunit.

Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism.

Intrathecal (i.t.) administration of big dynorphin (1-10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5-15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1-30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-2 mg/kg) and also dose-dependently, by i.t. co-administration of D(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe(7),D-His(9)]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.

Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice.

The inhibitory effect of repetitiously administered loperamide, a peripheral mu-opioid receptor agonist and well-recognized antidiarrheal agent, on mouse gastrointestinal transit was compared with that of morphine in order to examine the development of tolerance to mu-opioid receptor agonist-induced constipation (antitransit effect). When administered subcutaneously 15 min before the oral injection of charcoal meal, loperamide (0.1-30 mg/kg) and morphine (1-8 mg/kg) dose-dependently and significantly inhibited gastrointestinal transit of charcoal with the ID(50) values of 1.6 (0.3-7.1) mg/kg and 3.6 (1.5-8.5) mg/kg, respectively. When loperamide (30 mg/kg) was administered twice daily for 2 days, the antitransit effect was significantly reduced. On the other hand, morphine did not develop tolerance in even more severe conditions than those of loperamide. It is known that P-glycoprotein, an ATP-dependent drug efflux pump, is involved in the development of tolerance to morphine analgesia. The tolerance observed with loperamide was significantly prevented by cyclosporin (30 mg/kg, i.p.), a P-glycoprotein inhibitor, thus the ID(50) value in loperamide-tolerant mice was markedly reduced from >1000 mg/kg to 40 (2.7-603.0) mg/kg by cyclosporin. These results indicate that loperamide, different from morphine, readily develops tolerance to the inhibitory effect on mouse gastrointestinal transit, and the P-glycoprotein may be involved in the development of tolerance to the antitransit effect of loperamide.

Pharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: involvement of dopamine D2 and 5-HT2A receptors.

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25-20mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3mg/kg) and haloperidol (0.5mg/kg), the selective D(2) antagonist sulpiride (40 mg/kg) and 5-HT(2A/2C) antagonist ketanserin (2 and 4 mg/kg) but not with the selective D(1) antagonist SCH23390 (0.05 and 0.1mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D(2) or 5-HT(2A) receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.

Influence of olfactory bulbectomy on maternal behavior and dopaminergic function in nucleus accumbens in mice.

Olfactory bulbectomy (OBX) induces behavioral, physiological, and neurochemical alterations resembling clinical depression and is widely used as an animal model of depression. It has been reported that depression is a critical cause of child abuse and neglect and that maternal behavior involves dopaminergic neurons of the mesolimbic pathway. In a previous study we found that OBX mice show maternal behavior deficits which are improved by administration of apomorphine, a non-selective dopamine agonist. Therefore, in this study, we investigated the effect of l-3,4-dihydroxyphenylalanine (l-DOPA) on maternal behavior deficits to examine the influence of pre-synaptic dopaminergic function in OBX mice. Furthermore, we measured tyrosine hydroxylase (TH) levels using microphotometry and quantified dopamine D1- and D2-like receptors using autoradiography in the nucleus accumbens (NAc). As a result, 25mg/kg l-DOPA with 12.5mg/kg benserazide improved disrupted maternal behavior in OBX mice and there are no changes in TH levels or number of D1- and D2-like receptors between sham and OBX mothers. The behavioral data support the hypothesis that changed dopaminergic function may contribute to maternal behavior deficits in OBX mice. However, our findings concerning dopaminergic function suggest that the deficits in OBX mice are not simply due to changes in TH levels or dopamine receptor number in the NAc.

Effect of non-selective dopaminergic receptor agonist on disrupted maternal behavior in olfactory bulbectomized mice.

Olfactory bulbectomy (OBX) animals are considered a putative model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. Depression is a critical cause of child abuse and neglect, and it has been reported that maternal behavior involves dopaminergic neurons of the mesolimbic pathway. In this study, we investigated the effect of apomorphine, a non-selective dopaminergic receptor agonist, on maternal behavior to examine the influence of activated brain dopaminergic function in OBX mice. In addition, we conducted the sucrose preference test to examine the reward system which has a critical relationship to mesolimbic dopaminergic function and maternal behavior. Maternal behavior was observed on postnatal day (PND) 0 and 4. OBX female mice showed a reduction in sucrose preference 2 weeks post surgery. OBX dams showed maternal behavior deficits on PND 0, and these deficits were ameliorated by administration of apomorphine. These results suggest that maternal behavior deficits in OBX dams may involve brain hypodopaminergic function in the central nervous system induced by OBX.

Central administration of p-hydroxyamphetamine produces a behavioral stimulant effect in rodents: evidence for the involvement of dopaminergic systems.

RATIONALE AND OBJECTIVES: It is well-known that amphetamine induces increased locomotor activity in rodents. We previously found that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA), an amphetamine metabolite, increases synaptic dopamine (DA) levels in the striatum. In the present study, we investigated the effect of p-OHA on locomotor activity in rodents. RESULTS: In mice, i.c.v. administration of p-OHA significantly increased locomotor activity in a dose-dependent manner. p-Hydroxynorephedrine, another amphetamine metabolite, did not increase locomotor activity. This effect of p-OHA was inhibited by pretreatment with nomifensine, a dopamine-uptake inhibitor, but not by fluoxetine, a serotonin-uptake inhibitor, or diethyldithiocarbamate, a dopamine-beta-hydroxylase inhibitor. Furthermore, we tested the effects of microinjections of p-OHA into the rat nucleus accumbens (NAc) on locomotor activity. Local infusion of p-OHA into the NAc significantly increased locomotor activity. As in mice, the increased locomotor activity induced by p-OHA microinjection into the NAc in rats was inhibited by nomifensine. CONCLUSIONS: These data suggest that dopaminergic systems in the NAc may play important roles in p-OHA-induced locomotor activity in rodents.

p-Hydroxyamphetamine causes prepulse inhibition disruptions in mice: contribution of dopamine neurotransmission.

It is well known that amphetamine induces disrupted prepulse inhibition (PPI) in humans and rodents. We have previously reported that intracerebroventricular (i.c.v.) administration of p-hydroxyamphetamine (p-OHA) induces multiple behavioral responses, such as increased locomotor activity and head-twitch response in rodents. To reveal the characteristics of p-OHA on sensorimotor function in rodents, herein we tested the effects of p-OHA on PPI in mice. i.c.v. administration of p-OHA dose-dependently induced PPI disruptions for all prepulse intervals tested. This effect of p-OHA on PPI was attenuated by pretreatment with haloperidol or clozapine. p-OHA-induced PPI disruptions were also attenuated by pretreatment with L-741,626 (a selective D(2) receptor antagonist), L-745,870 (a selective D(4) receptor antagonist) or 6-hydroxydopamine (a neurotoxin which targets DA-containing neurons), but not by SCH 23390 (a selective D(1) receptor antagonist), eticlopride (a D(2)/D(3) receptor antagonist) or GBR 12909 (a DA-reuptake inhibitor). These results indicate that selective blockade of either the D(2) or D(4) receptor subtype may prevent disruption of PPI induced by p-OHA via presynaptic DA release.

Suppressive effects by cysteine protease inhibitors on naloxone-precipitated withdrawal jumping in morphine-dependent mice.

The effects of various protease inhibitors on naloxone-precipitated withdrawal jumping were examined in morphine-dependent mice. The doses of morphine were subcutaneously given twice daily for 2 days (day 1, 30 mg/kg; day 2, 60 mg/kg). On day 3, naloxone (8 mg/kg) was intraperitoneally administered 3h after final injection of morphine (60 mg/kg), and the number of jumping was immediately recorded for 20 min. Naloxone-precipitated withdrawal jumping was significantly suppressed by the intracerebroventricular administration of N-ethylmaleimide (0.5 nmol) and Boc-Tyr-Gly-NHO-Bz (0.4 nmol), inhibitors of cysteine proteases involved in dynorphin degradation, 5 min before each morphine treatment during the induction phase, with none given on the test day, as well as by dynorphin A (62.5 pmol) and dynorphin B (250 pmol). However, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, caused no changes. The present results suggest that cysteine protease inhibitors suppress naloxone-precipitated withdrawal jumping in morphine-dependent mice, presumably through the inhibition of dynorphin degradation.