Post-feeding increases in accumbal dialysate dopamine reflect persisting increases in dopamine release.

To determine whether post-feeding increases in dialysate dopamine (DA) in the nucleus accumbens are associated with persisting increases in DA release, we examined the effect of Ca++-free perfusion on post-feeding dialysate concentrations of DA. Post-feeding dialysate DA is entirely Ca++-dependent, suggesting the existence of post-feeding increases in exocytotic DA release and the ability of microdialysis to monitor dynamic changes in DA release through behaviour.

Enhanced miotic response to topical dilute pilocarpine in patients with Alzheimer's disease.

To determine whether miotic response to dilute (0.0625%, two drops) topical pilocarpine could be useful in detecting Alzheimer's disease (AD), we assessed the response in 14 AD patients and 10 control subjects. The miotic response to pilocarpine was significantly greater in AD patients than in control subjects (p < 0.001). In contrast, mydriatic response to the anticholinergic tropicamide (0.01%, one drop) failed to show a difference between the groups (p = 0.54). There was no significant correlation between the miotic and mydriatic responses in individuals. We conclude that dilute pilocarpine could be useful as a diagnostic tool in early AD.

Dopaminergic and cholinergic interaction in cataleptic responses in mice.

The cataleptogenic effects of haloperidol, a dopamine D2 receptor antagonist; SCH23390, a D1 receptor antagonist; physostigmine, a cholinesterase inhibitor; and pilocarpine, a muscarinic M1 receptor agonist, were challenged by pretreatment of mice with SKF38393, a dopamine D1 receptor agonist; apomorphine, a dopamine D1/D2 receptor agonist (mainly D2 receptor); pirenzepine, a muscarinic M1 receptor antagonist; and scopolamine, a muscarinic M1/M2 receptor antagonist. The effect of physostigmine and pilocarpine on haloperidol and SCH23390 cataleptic responses was also examined. Each of the challenging agents blocked one or more of the cataleptogenic agents, but only scopolamine blocked all four. Pirenzepine blocked cataleptic responses induced by SCH23390 and pilocarpine, but not those by haloperidol and physostigmine. The results of this study suggest that the action of physostigmine (endogenous acetylcholine) on M2 receptors might be more potent than that on muscarinic M1 receptors. A further interesting observation was that the haloperidol-induced catalepsy was enhanced by physostigmine pretreatment, but not by pilocarpine pretreatment, whereas the SCH23390-induced catalepsy showed the opposite spectrum of enhancement by the two cholinergic agonists. We conclude that, although the four cataleptogenic agents act via the dopaminergic-cholinergic systems, their pharmacological differences may be due largely to the different receptor subtypes that are involved in the mediation of catalepsy produced by each agent. Thus, dopamine receptors not only influence the cholinergic muscarinic receptors, but muscarinic M1 and M2 receptors also might mediate dopamine D1 and D2 receptor responses, respectively. The results suggest that there are, at the least, relationships between muscarinic M1 receptors and dopaminergic D1 receptors, and between muscarinic M2 receptors and dopaminergic D2 receptors. Dopamine D1 and D2 receptors may interact in a synergistic fashion on dopaminergic systems, but act independently of each other in influencing other system such as cholinergic neurons.

Behavioral effects of dilazep on cholinergic, dopaminergic, and purinergic systems in the rat.

This study examined the effects of 1,4-bis[3-(3,4,5-trimethoxy benzoyloxy)-propyl] perhydro-1,4-diazepine (dilazep; Comelian) on central dopaminergic, cholinergic, and purinergic neuronal systems in rats. Intraperitoneal injections of dilazep (1-5 mg/kg) produced yawning responses, the most effective dose being 2 mg/kg. Dilazep potentiated physostigmine-induced yawning but not pilocarpine- and bromocriptine-induced yawning. Dilazep-induced yawning was not affected by low doses of haloperidol or sulpiride, but was completely inhibited by atropine, a muscarinic M1 receptor antagonist. Dilazep-induced yawning, as well as physostigmine-induced yawning, were markedly inhibited by pretreatment with SK & F 38393, a dopamine D1 receptor agonist, and were potentiated by SCH23390, a dopamine D1 receptor antagonist that alone does not elicit yawning. Caffeine, an adenosine receptor antagonist, inhibited dilazep- and physostigmine-induced yawning responses but N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl, adenosine (L-PIA), adenosine A1 receptor agonists, were inactive. These results suggest that because the effects of dilazep on central cholinergic neurons are similar to those of physostigmine dilazep may potentiate indirectly the action of endogenous acetylcholine. Cholinergic neurons activated by dilazep may be modulated by postsynaptic dopamine D1 receptor activity but may not be affected by dopamine D2 receptor activity. Furthermore, the stimulatory effects of dilazep on cholinergic neuron may not be due to an inhibition of dopamine D1 receptors via purinergic (adenosine A1 receptor) stimulation by dilazep.

Interleukin-2 receptor in peripheral blood lymphocytes of Alzheimer's disease patients.

In this study, we investigated the differences in the incidence rate of human leukocyte antigen-DR (HLA-DR) and interleukin 2 receptor (IL-2R) in the peripheral blood lymphocytes of 13 women who were diagnosed clinically as having Alzheimer's disease (AD group), and 13 healthy women with no mental disorders (control group). As a result, the AD group showed a markedly higher rate of lymphocyte subsets of CD4+HLA-DR+, CD4+IL-2R+, CD8+HLA-DR+, CD8-HLA-DR+ and CD8+IL-2R+. This finding indicates a possible immune reaction occurring in the peripheral blood of AD patients. In addition, these higher rates correlate well with the changes in the immune system reported in the postmortem brains of AD patients. Our findings indicate that immunological interactions exist between the central nervous system and the peripheral blood lymphocytes of AD patients, and AD might be induced by an immune reaction occurring in the brain.

Psychological stress increases dopamine turnover selectively in mesoprefrontal dopamine neurons of rats: reversal by diazepam.

The effects of psychological stress on catecholamine and indoleamine metabolism were examined in various brain regions of rats. Psychologically stressed rats were exposed to emotional responses of foot-shocked rats, but were themselves prevented from receiving foot-shock. Psychological stress for 30 min resulted in significant increases of both 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in the medial prefrontal cortex (MPFC), but not in other dopamine (DA) terminal fields. The levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were unaffected in all brain regions examined after 30 min of psychological stress. A small but significant increase of DOPAC levels in the ventral tegmental area (VTA) was observed after a shorter (10 min) duration of stress. Moreover, an increase of DOPAC levels in the MPFC 30 min after psychological stress was attenuated by diazepam (5 mg/kg), and this attenuating effect was antagonized by Ro 15-1788 (15 mg/kg). These results suggest that mesoprefrontal DA neurons are selectively activated by psychological stress, and that the activation of the A10 cell body site (VTA) may precede that of the terminal field (MPFC). Moreover, diazepam was found to possess an inhibitory effect on the activation of mesoprefrontal DA neurons induced by psychological stress, and this effect may be partly mediated by benzodiazepine (BZD) receptors and implicated in the specific anxiolytic action of BZDs.

Effects of mianserin on negative symptoms in schizophrenia.

The efficacy of mianserin as a supplement in treating chronic schizophrenia was tested in 20 inpatients with schizophrenia who were receiving fixed doses of neuroleptics. Mianserin was given for six weeks with a starting dose of 60 mg/day. A brief psychiatric rating scale (BPRS) was completed before starting mianserin and thereafter BPRS scoring was carried out once weekly. The total BPRS score and the score for negative symptoms were decreased by mianserin treatment as compared to the pre-treatment values. Plasma 5-HIAA concentrations were increased after medication in both responding patients and nonresponding patients. However, the 5-HIAA values of responders were lower than those of nonresponders. Plasma HVA levels were slightly increased by mianserin in the responders. There were no significant changes in MHPG levels. These results suggest that the negative symptoms of schizophrenia may be improved by mianserin treatment.

[Effects of muscimol on aggressive behaviors induced by clonidine in mice].

A behavioral study was carried out to clarify a relationship between the GABAergic and purinergic central system in aggressive behaviors induced by clonidine in mice. Mice administered a high dose of clonidine (20 mg/kg, i.p.) exhibited aggressive behaviors such as biting and attacking. These behaviors are inhibited by L-PIA (N6-L-phenylisopropyl adenosine) and stimulated by caffeine, which suggest that a blockade of adenosine receptors is involved in these behaviors. Muscimol (0.5-2 mg/kg, i.p.), a GABA-a receptor agonist, not only markedly potentiated clonidine (20 mg/kg i.p.)-induced aggressive behaviors but also elicited characteristic behaviors such as gnawing, reinforced irritability, and self-mutilation. Bicuculline (1, 2 mg/kg, i.p.), a GABA-a receptor antagonist, or picrotoxin (1 mg/kg, i.p.), a chloride channel blocker, did not significantly affect clonidine (20 mg/kg, i.p.)-induced aggressive behaviors. The potentiating effects of muscimol (0.5, 1 mg/kg, i.p.) on clonidine-induced aggressive behaviors were antagonized by bicuculline (1, 2 mg/kg, i.p.), but not affected significantly by picrotoxin (1 mg/kg, i.p.). L-PIA (0.2 mg/kg, i.p.) reduced clonidine-induced aggressive behaviors and also reversed the potentiating effects of muscimol. Stereotyped gnawing behaviors induced by combined treatment of muscimol (0.5, 1 mg/kg, i.p.) and clonidine (20 mg/kg, i.p.) were not affected by bicuculline (2 mg/kg, i.p.). The results suggest that the potentiating effects of muscimol on clonidine-induced aggressive behaviors may be induced via the stimulation of GABA-a receptors, although not necessarily associated with chloride channel functions, and may involve certain interactions between the stimulation of GABA-a receptors and the inhibition of adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dilazep (Comelian) on the central purinergic system: inhibitory effects on clonidine-induced aggressive behavior.

Mice given clonidine (20-50 mg/kg i.p. and 5 micrograms i.c.v.) exhibited aggressive behavior. Dilazep as well as N6-(L-phenylisopropyl) adenosine (adenosine agonist) inhibited this behavior. Dilazep combined with N6-(L-phenylisopropyl) adenosine markedly inhibited the behavior at low doses that were without effect when given alone whereas the inhibitory effect of dilazep on the behavior was reversed by caffeine and 8-phenyltheophylline, which are adenosine antagonists. The results suggest that the inhibitory action of dilazep on clonidine-induced aggressive behavior can be substantially attributed to central purinoceptor stimulation.

[Effects of bifemelane on central dopaminergic and cholinergic systems in rats].

The study served to examine the effects of bifemelane on central dopaminergic-cholinergic neuronal mechanisms in rats. Bifemelane (5-20 mg/kg) evoked yawning responses, the frequency being low. Bifemelane (10 mg/kg) as well as bromocriptine (2.5 mg/kg) potentiated physostigmine (0.2 mg/kg)-, bromocriptine (2.5 mg/kg)- or apomorphine (0.1 and 0.5 mg/kg)-induced yawning but completely inhibited pilocarpine-induced yawning. Pretreatment with sulpiride (20 mg/kg) and a low dose of haloperidol (0.02 mg/kg) reversed the stimulatory effect of bifemelane on physostigmine-induced yawning and the inhibitory effect of the drug on pilocarpine-induced yawning, whereas atropine (5 mg/kg) diminished these yawning responses. SK&38393 (2.0 mg/kg), a dopamine D-1 receptor agonist, markedly potentiated bifemelane- and bromocriptine-induced yawning but inhibited physostigmine-induced yawning, and did not affect pilocarpine-induced yawning. The increased yawning responses were blocked by atropine and a low dose of haloperidol. Bifemelane (10 mg/kg) and bromocriptine (2.5 mg/kg) tended to increase apomorphine (5 mg/kg)-induced oral stereotypy, such as licking and biting, but the increase was not significant. These results suggest that the effects of bifemelane on central dopaminergic and cholinergic neurons may be similar to those of bromocriptine.