Makoto Ukai

Beneficial Effects of Acute and Repeated Administrations of σ Receptor Agonists on Behavioral Despair in Mice Exposed to Tail Suspension

In an attempt to examine whether sigma receptor agonists alleviate behavioral despair, we investigated the effects of sigma receptor agonists on the tail suspension-induced immobility in mice. The acute and repeated (14 days) administrations of sigma1 receptor agonists, such as 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) (1 and/or 3 mg/kg) and (+)-pentazocine (5.6 mg/kg), sigma1/2 receptor agonists, such as 1,3-di(2-tolyl)guanidine (DTG) (3 and/or 5.6 mg/kg), desipramine (7.5 and/or 15 mg/kg), and fluoxetine (10 and/or 20 mg/kg), reduced immobility in mice exposed to tail suspension. N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl] ethylamine monohydrochloride (NE-100), a sigma1 receptor antagonist, significantly antagonized the decrease in immobility induced by acute administrations of SA4503 (1 mg/kg) and (+)-pentazocine (5.6 mg/kg). Although not significant, NE-100 showed a tendency to inhibit the DTG (5.6 mg/kg)-induced decrease in immobility. In contrast, repeated administrations of SA4503 (1 and 3 mg/kg), (+)-pentazocine (5.6 mg/kg) or DTG (5.6 mg/kg) failed to affect the increase in body weight. These results suggest that acute and repeated stimulations of sigma, possibly a sigma1 receptor subtype, alleviate behavioral despair, unaccompanied with changes in body weight.

Dynorphin A-(1-13) markedly improves scopolamine-induced impairment of spontaneous alternation performance in mice

The effect of intracerebroventricular (i.c.v.) injection of dynorphin A-(1-13) on the memory process was examined in mice, using spontaneous alternation performance related to working memory in a Y-maze. Dynorphin A-(1-13) (1, 3 and 10 micrograms) influenced neither spontaneous alternation performance nor total arm entries, which are considered to reflect locomotor activity. In contrast, dynorphin A-(1-13) (3 and 10 micrograms) significantly improved the impairment of spontaneously alternation performance induced by scopolamine (1 mg/kg s.c.). Simultaneously, the scopolamine-induced increase in total arm entries was markedly attenuated by dynorphin A-(1-13) (10 micrograms). The effect of dynorphin A-(1-13) (3 micrograms) on the scopolamine-induced impairment of spontaneous alternation was almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms i.c.v.), a kappa-selective opioid antagonist. These findings suggest that dynorphin A-(1-13) improves through the mediation of kappa-opioid receptors the scopolamine-induced impairment of spontaneous alternation performance associated with working memory.

Multi-dimensional analyses of behavior in mice treated with U-50,488H, a purported kappa (non-mu) opioid agonist

The effects of U-50, 488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl ]-benzeneacetamide, methane sulfonate, hydrate), a purported selective kappa (non-mu) opioid agonist on spontaneous locomotor activity were investigated using a multi-dimensional behavioral analyzer (Animex II). U-50,488H (1 mg/kg) failed to affect behavior in mice, however, 3 mg/kg significantly reduced rearing and grooming. In addition, 10 mg/kg markedly reduced linear locomotion, rearing and grooming. The behavioral depression induced by U-50,488H (10 mg/kg) was reversible by the opioid antagonist Mr2266 (10 mg/kg). These results suggest that the selective activation of the kappa (non-mu) opioid receptor by U-50,488H decreases linear locomotion, rearing and grooming in mice.

Dynorphin A-(1-13) potently prevents memory dysfunctions induced by transient cerebral ischemia in mice

The effect of dynorphin A-(1-13), an endogenous kappa-opioid receptor agonist, on memory dysfunctions induced by transient cerebral ischemia in mice was investigated by using three different tasks, namely, spontaneous alternation, elevated plus-maze performance, and passive avoidance behavior. Transient ischemia produced a marked memory dysfunction in mice, as assessed in the three tasks, which were carried out consecutively 1 to 3 days after the ischemic insult. The i.c.v. injection of dynorphin A-(1-13) before the ischemic insult potently prevented the impairment of spontaneous alternations, the prolongation of transfer latency in the elevated plus-maze and the shortening of step-through latency in the passive avoidance task induced by transient ischemia. Dynorphin A-(1-13) (10 micrograms), however, did not affect the body temperature of the sham-operated or the ischemic mice. The protective effect of dynorphin A-(1-13) (10 micrograms) on ischemia-induced memory dysfunctions observed in the three tasks was almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms, i.c.v.), a kappa-selective opioid receptor antagonist. These results suggest that dynorphin A-(1-13) prevents memory dysfunctions in ischemic mice through the activation of kappa-opioid receptors.

U-50,488H, a κ-opioid receptor agonist, markedly prevents memory dysfunctions induced by transient cerebral ischemia in mice

Transient ischemia produced marked memory dysfunctions in mice on three different tasks, spontaneous alternation, elevated plus-maze and passive avoidance, as tested 1, 1-2, and 2-3 days after ischemic insult, respectively. U-50,488H, a kappa-opioid receptor agonist, administered 20 min before ischemic insult markedly prevented the impairment of spontaneous alternation, the prolongation of transfer latency in elevated-plus maze and the shortening of step-through latency in passive avoidance induced by transient ischemia. The protective effect of U-50,488H (30 mg/kg) on ischemia-induced memory dysfunctions observed in the three tasks was almost completely reversed by pretreatment with nor-binaltorphimine (4 micrograms, i.c.v.), a kappa-selective opioid antagonist. Although U-50,488H (30 mg/kg) did not affect body temperature in sham mice, it blocked hypothermia induced by ischemic insult. These results suggest that the protective effect of U-50,488H on memory dysfunctions in ischemic mice is associated with the activation of kappa-opioid receptors and is not based upon hypothermia.

Dynorphin A-(1-13) attenuates basal forebrain-lesion-induced amnesia in rats

The effects of dynorphin A-(1-13), an endogenous kappa opioid agonist, on basal forebrain (BF)-lesion-induced amnesia in rats were investigated using step-through-type passive avoidance task. The BF was lesioned by injecting the cholinergic neurotoxin ibotenic acid (6 micrograms/side). The number of rats achieving the cut-off time (600 s) of step-through latency (STL) in BF-lesioned group significantly decreased as compared with that in sham-operated group. Dynorphin A-(1-13) (0.3 micrograms) significantly increased the number of rats achieving the cut-off time of STL in BF-lesioned rats. These results suggest that dynorphins play an improving role in the impairment of memory processes in BF-lesioned rats.

Multi-dimensional analyses of behavior in mice treated with morphine, endorphins and [des-tyrosine1]-γ-endorphin

An investigation was made as to the effects of an intracerebral injection of morphine, endorphins and [des-tyrosine1]-gamma-endorphin (DT gamma E) on spontaneous locomotor activity in mice. This was done by exploiting a newly devised multi-dimensional behavioral analyser with a capacitance system. This apparatus simultaneously recorded nine different degrees of behavior (1/1, 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128 and 1/256) according to the movement sizes in mice. Within 15 min after injection, gamma-endorphin (5 and 10 microgram), leucine-enkephalin (200 micrograms) and methionine-enkephalin (100 micrograms) produced a significant increase in the 1/1 size of movement. Fifteen to 30 min after injection, the movement patterns induced by morphine (40 micrograms) and DT gamma E (40 micrograms) became similar, although morphine (40 micrograms) caused a significant decrease in the 1/1 and 1/2 sizes of movement. beta-Endorphin (2 micrograms) significantly decreased most of the movement sizes for 30 min compared with saline-treated group. [D-alanine2]-methionine-enkephalinamide (20 micrograms) significantly decreased almost all the movement sizes within 15 min after injection. The significant alteration in the movement sizes induced by morphine and endorphins except for DT gamma E was antagonized by pretreatment with naloxone (1 mg/kg). These results strongly suggest the qualitative difference in the behavioral effects of each of the opioids and nonopioid.

Effects of the dopamine D3 receptor agonist, R(+)-7-hydroxy- N,N-di-n-propyl-2-aminotetralin, on memory processes in mice

The putative dopamine D3 receptor agonist, R(+)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (R(+)-7-OH-DPAT) (0.1-100 microg/kg, s.c.), administered before training, immediately after training, and before retention significantly shortened step-down latency of passive avoidance learning, indicating the amnesic effects of R(+)-7-OH-DPAT. Neither the dopamine D1 receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine maleate R(+)-SCH23390) (2.5 and 5 microg/kg, i.p.), nor the dopamine D2 receptor antagonist, S(-)-sulpiride (10 and 30 mg/kg, i.p.), markedly influenced the R(+)-7-OH-DPAT (10 and 100 microg/kg, s.c.)-induced amnesia. In addition, only a 1000 microg/kg dose of R(+)-7-OH-DPAT decreased locomotor activity; 1 and 100 microg/kg doses of the drug were ineffective. These results suggest that the amnesic effects of the dopamine D3 receptor agonist, R(+)-7-OH-DPAT, are not mediated via dopamine D1 or D2 receptors in the brain.

Stimulation of δ1- and δ2-opioid receptors produces amnesia in mice

Abstract The effects of intracerebroventricular administration of δ 1 - and δ 2 -selective opioid receptor agonists on spontaneous alternation performance, elevated plus-maze behavior and passive avoidance learning including step-down and step-through types were examined in mice. Although the δ 1 -selective opioid receptor agonist, [ d -Pen2, l -Pen5]enkephalin (DPLPE) (1–10 μ g) or the δ 2 -selective opioid receptor agonist, [ d -Ala 2 ]deltorphin II (deltorphin) (1–10 μ g) did not markedly affect spontaneous alternation performance or elevated plus-maze behavior, DPLPE (1, 3 and/or 10 μ g) and deltorphin (3 and 10 μ g) inhibited passive avoidance learning including step-down and step-through types. The δ 1 -selective opioid receptor antagonist, 7-benzylidenenaltrexone (3.5 ng), and the δ 2 -selective opioid receptor antagonist, naltriben (19 ng), significantly antagonized the inhibitory effects of DPLPE (3 μ g) and deltorphin (3 μ g) on passive avoidance learning, respectively. In contrast, DPLPE (3 μ g) or deltorphin (3 μ g) did not markedly influence behavioral responses induced by electroshocks during training of passive avoidance learning. Moreover, DPLPE (0.3–3 μ g) or deltorphin (0.3–3 μ g) failed to significantly affect the radiant heat-induced nociceptive responses. These results suggest that stimulation of δ 1 - and δ 2 -opioid receptors produces amnesia, depending on the learning tasks used.

Effects of pre-germinated brown rice on depression-like behavior in mice.

We investigated the antidepressant-like effects of pre-germinated brown rice (PGBR) and polished rice (PR) pellets, respectively, in comparison with control (AIN-93G) pellets in the forced swimming test and the learned helplessness paradigm in mice. Mice were fed respective pellets for 30 days. The immobility time on the 2nd day of the forced swimming test was shorter in mice fed with PR or PGBR pellets than in mice fed with control pellets. In the learned helplessness paradigm, the number of escape failures in mice fed with PGBR pellets was significantly smaller than that in mice fed with control pellets. Compared to the control group, an increase in serotonin (5-HT) levels, but not in 5-hydroxyindoleacetic acid (5-HIAA) levels, and a decrease in the 5-HIAA/5-HT ratio were observed in the frontal cortex of the PGBR group. There were no differences among the three groups in terms of 5-HT and 5-HIAA levels and their ratios in the hippocampus and striatum. The levels of noradrenaline and 3-methoxy-4-hydroxyphenylglycol were not affected by the food pellets in all the brain regions tested. Additionally, we could not detect any differences in the expression of the 5-HT1A receptor and the 5-HT transporter in the frontal cortex of the three groups. These results suggest that the increase of 5-HT levels in the mouse frontal cortex contributes to the antidepressant-like effects of PGBR pellets.