Neonatal lesions of the left entorhinal cortex affect dopamine metabolism in the rat brain.

The present study was performed to determine the effects of neonatal excitotoxic lesions of the left entorhinal cortex on dopamine (DA) metabolism and release in limbic regions of the rat brain. Quinolinic acid or phosphate buffered saline was infused into the left entorhinal cortex of rat pups on postnatal day 7 (PD7). Concentrations of DA,3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the lateral amygdala, nucleus accumbens, caudate-putamen, and medial prefrontal cortex were determined in the postmortem brains of lesioned and sham-operated rats on PD35 and PD56. On PD35, concentrations of DA in the bilateral lateral amygdala and HVA in the left lateral amygdala were significantly increased in lesioned rats compared with sham-operated animals, while no significant change was observed in the other three brain areas. On PD56, in addition to the increased concentration of DA in the left lateral amygdala, those of DA, DOPAC and HVA in the caudate-putamen, and DA in the nucleus accumbens were found to be increased, but DA concentrations in the right medial prefrontal cortex were decreased. The DOPAC/DA concentration ratio was, however, decreased in the amygdala and nucleus accumbens of the lesioned rats. In an in vivo microdialysis study, methamphetamine (MAP: 2 mg/kg, i.p.)-induced DA release in the amygdala of lesioned rats was significantly enhanced compared with sham-operated rats on both PD35 and PD56. There were no significant differences in MAP-induced DA release in the caudate-putamen between the sham-operated and lesioned rats at any time point. These findings provide evidence that neonatally induced structural abnormalities in the entorhinal cortex affect DA transmission in the limbic regions at the adolescent stage.

Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats.

To examine the effects of lesions of the entorhinal cortex on limbic dopamine (DA) metabolism, DA and its metabolites were assayed in five brain regions (the medial prefrontal cortex, anterior cingulate cortex, caudate-putamen, accumbens nucleus, and lateral amygdala), 14 and 28 days after quinolinic acid or sham lesions of the left entorhinal cortex in rats. Concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) on day 14 in the medial prefrontal cortex, accumbens nucleus, and lateral amygdala of the entorhinal cortex lesioned animals were significantly decreased compared with the controls, but they returned to control levels on day 28. The concentration of DA in the lateral amygdala and spontaneous locomotion to a novel environment were significantly increased on day 28 after the lesion. These results suggest that entorhinal cortex lesions alter mesolimbic dopamine metabolism, particularly in the amygdala.

Plasma thrombomodulin values and hepatorenal function in the elderly.

To define the clinical significance of plasma thrombomodulin (TM) values in elderly, we examined plasma TM in healthy young subjects, healthy elderly subjects and patients with cerebral infarction sequelae. We also studied the relationship with effective renal plasma flow (ERPF) and with the liver's protein-production ability. The TM values of healthy elderly subjects were higher than those of healthy young subjects. There existed an inverse correlation between TM values and ERPF. Accordingly, high TM values might significantly influence renal arteriosclerosis. From the inverse correlation identified between TM and serum cholinesterase, it was estimated that high TM might appear in conjunction with the liver's protein production ability. Patients with cerebral infarction showed higher plasma TM values. It is thought that angiopathy has been maintained in patients as the anamnesis of cerebral infarction even though it occurred in the past. The TM values of patients with diabetes mellitus (DM) were higher than those without it. Moreover, the TM values of patients with DM complicated by retinopathy were higher than those uncomplicated by retinopathy. It is therefore estimated that increased TM might occur with angiopathy resulting from DM. A possibility thus exists that plasma TM could be utilized as one of the markers for endothelial injury.

The characterization of the effect of locally applied N-methylquipazine, a 5-HT3 receptor agonist, on extracellular dopamine levels in the anterior medial prefrontal cortex in the rat: an in vivo microdialysis study.

In this study, we examined the effect of n-methylquipazine (NMQ), which is a putative 5-hydroxytryptamine3(5-HT3)receptor agonist, on the extracellular concentrations of dopamine (DA) and one of its metabolites, dihydroxyphenylacetic acid (DOPAC), in the anterior medial prefrontal cortex (AmPFc) of awake, freely moving rats. The administration of NMQ via the perfusion fluid produced a concentration-dependent (10-1,000 microM) increase in extracellular DA levels in the AmPFc. In contrast, NMQ produced a decrease in the extracellular concentrations of DOPAC. The increase in extracellular DA levels returned to baseline after the removal of NMQ from the perfusate. The increase in extracellular DA levels in the AmPFc produced by 100 microM of NMQ was markedly attenuated by either the coadministration of tetrodotoxin (1 microM), which inhibits axonal impulse flow, or the depletion of extracellular Ca2+ by removing CaCl2 and adding EDTA to the perfusate. The intradialysate administration of the 5-HT3 antagonist BRL 46470A produced a concentration-dependent (10-1,000 microM) decrease in extracellular DA levels, and this effect was reversible on removal from the perfusate. In contrast, ondansetron (500 and 1,000 microM), which is another 5-HT3 receptor antagonist, produced a transient increase followed by a sustained decrease in extracellular DA levels. The preinfusion of 10 microM of BRL 46470 followed by coperfusion of BRL 46470A with 50 or 100 microM of NMQ via the dialysis probe did not significantly attenuate the increase of NMQ in extracellular DA levels in the AmPFc. The administration of the selective 5-HT2 receptor MDL 100907 (1 mg/kg, i.p.) also did not alter the increase in basal DA levels produced by 100 microM of NMQ. The pretreatment of rats with alpha-methyl-p-tyrosine produced a significant attenuation in the NMQ-induced increase in extracellular DA levels, suggesting that the elevation by NMQ of DA levels is dependent on newly synthesized stores of DA. Overall, these results suggest that the increase in AmPFc DA levels by NMQ is probably not mediated by its interaction with the 5-HT3 receptor.

Brain SPECT of Creutzfeldt-Jakob disease.

SPECT imaging with I-123 IMP or Tc-99m HMPAO was performed in two patients with Creutzfeldt-Jakob disease to evaluate abnormalities in brain perfusion. In the first patient, there was decreased perfusion of the left frontal, parietal, and temporal lobes. CT and MRI were negative. In the second patient, there was patchy perfusion and slightly decreased perfusion of the right hemisphere. MRI revealed slight brain atrophy and bilateral high intensity areas in the basal ganglia on T2 weighted images. Subsequent SPECT imaging revealed severely decreased perfusion of the entire brain. Subsequent MRI demonstrated severe brain atrophy.

Hypofrontality does not occur with 6-hydroxydopamine lesions of the medial prefrontal cortex in rat brain.

This study examined the effect of lesions of dopamine (DA) nerve terminals the medial prefrontal cortex on local cerebral glucose utilization (LCGU) and dopamine metabolism in the rat brain. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the medial prefrontal cortex. Twenty-eight days after the lesion, concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in eight brain regions with a high-performance liquid chromatographic assay. LCGU was assessed by [14C]2-deoxy-D-glucose autoradiography. The lesion produced a striking reduction in DA (to 6% of the control value), and a moderate reduction in DOPAC and HVA in the medial prefrontal cortex. The ratio of DOPAC to DA in the medial prefrontal cortex was significantly elevated in the 6-OHDA lesioned animals. In contrast to DA depletion, LCGU in the medial prefrontal cortex of the lesioned rats was unaltered when compared with the control. These findings suggest that decreased energy metabolism in the frontal cortex, i.e., hypofrontality, does not occur with decreased DA innervation of that site.

Comparative study of dopamine metabolism with local cerebral glucose utilization in rat brain following the administration of haloperidol decanoate.

The effects of haloperidol decanoate on dopamine (DA) metabolism in discrete regions of rat brain were investigated and compared with changes in local cerebral glucose utilization (LCGU). The concentration of DA and its metabolite, homovanillic acid, and the alpha-methyl-p-tyrosine (alpha-MT)-induced decline of DA were measured in 6 brain regions by a high-performance liquid chromatographic assay. LCGU in 26 brain regions were examined by [14C]2-deoxy-D-glucose autoradiography. At 24-hr after intramuscular injection of haloperidol decanoate (60 mg eq/kg to haloperidol), the concentration of homovanillic acid in the prefrontal cortex, caudate-putamen, accumbens nucleus, lateral amygdala, and medial thalamus showed significant increase compared with control values. On day 21, the increase in these regions was significantly attenuated with no significant difference from the controls. Furthermore, chronic haloperidol rats showed alpha-MT-induced decline of DA to a similar extent in the control rats. LCGU on day 21 showed significant decrease in the parietal cortex, and a tendency toward decrease in the prefrontal cortex, lateral amygdala and medial thalamus compared with the controls. There was no significant change in LCGU in the caudate-putamen or accumbens nucleus. Chronic haloperidol would thus appear to affect energy metabolism mainly in the cortico-thalamo-limbic circuits, and this may not correspond well to presynaptic DA metabolism.

Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactivity, stereotypy and ataxia in the rat.

Intracerebroventricular injection of the D-forms of alanine (Ala; 2-200 micrograms/rat) and serine (Ser; 20-2000 micrograms/rat) caused a dose-dependent inhibition of the ability of 10 mg/kg of phencyclidine (PCP; given i.p.) to increase automatically quantitated locomotor counts and cumulated scores of locomotion, stereotypy and ataxia for 90 min after PCP administration. D-Ala and D-Ser were found to be more potent than the corresponding L-isomers in attenuating the PCP-induction of these behavioral abnormalities. Although L-, but not D-Ser, at moderate doses (400 micrograms/rat) produced a slight decrease in cumulative ataxia scores after a 10-mg/kg PCP administration, D-, but not L-Ser, reduced the behavioral scores at large doses (more than 1000 micrograms/rat). Similarly, bilateral i.c.v. infusion of D-Ala (140 micrograms/rat) reduced the increasing effects of a lower dose of PCP (5 mg/kg i.p.) on locomotion, stereotypy and ataxia scores, whereas the L-form of Ala (140 micrograms/rat) lacked the inhibitory influence. The stereo-selectivity of the antagonism by Ala and Ser of PCP-induced abnormal behavior parallels that of the potencies of these amino acids as agonists for the strychnine-insensitive glycine site linked to the N-methyl-D-aspartate type excitatory amino acid receptor. Furthermore, the decreasing effects of D-Ala (200 micrograms/rat i.c.v.) and D-Ser (2000 micrograms/rat i.c.v.) on PCP-induced hyperactivity were antagonized by i.c.v. application of 5,7-dichlorokynurenate and 7-chlorokynurenate which are selective antagonists of the glycine modulatory site.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in local cerebral glucose utilization and dopamine metabolism in the rat brain following acute administration of haloperidol.

The effects of acute administration of haloperidol on local cerebral glucose utilization (LCGU) in 26 discrete regions of the rat brain were examined by the quantitative autoradiographic [14C] 2-deoxy-D-glucose technique and compared with the changes in dopamine (DA) metabolism in 13 brain regions examined by a high performance liquid chromatographic assay. A moderate dose (0.25 mg/kg) of acute haloperidol significantly reduced LCGU in a few brain regions; a high dose (1.0 mg/kg) reduced LCGU in 11 regions including the prefrontal cortex, thalamus and other subcortical structures, but not in the caudate putamen or accumbens nucleus. However, the levels of DA metabolite in the caudate-putamen, accumbens nucleus, prefrontal cortex, and medial thalamus were strikingly elevated with both doses of haloperidol. Thus, the changes in LCGU did not parallel presynaptic DA metabolism in terms of direction or distribution, and they might represent mainly the activities of postsynaptic sites.

Differential effects of tight and loose 2-hour restraint stress on extracellular concentrations of dopamine in nucleus accumbens and anteromedial frontal cortex.

Changes in the extracellular dopamine (DA) concentrations were examined in the nucleus accumbens (NAS) and anteromedial frontal cortex (AMFCx) during either 2-hr loose or tight restraint stress by means of a microdialysis method. Loose restraint induced significant 100% and 30% increases in DA release in the AMFCx and NAS, respectively, and the increased DA levels returned to the control values despite continued stress. Tight restraint induced an almost constant 100-130% increase during stressing in the AMFCx and a 30% reduction in the NAS. Transient increases in DA release were observed in both regions soon after the cessation of loose, but not tight, restraint.

Stereoselective inhibition by D- and L-alanine of phencyclidine-induced locomotor stimulation in the rat.

Bilateral injection of D-alanine, but not L-alanine, (10-100 micrograms per side for each amino acid) into the lateral ventricle reduced the increasing effect of phencyclidine (PCP, 10 mg/kg, given intraperitoneally) on locomotor activity in the rat in a dose dependent manner. This stereoselectivity agrees with the potency of these agents as agonists for the strychnine-insensitive glycine receptor in the N-methyl-D-aspartate receptor complex, suggesting that stimulation of the allosteric regulation site may antagonize the ability of PCP to produce hyperactivity.

Effects of chronic treatment with haloperidol and methamphetamine on hippocampal kindled seizures in the cat.

We assessed the effects of chronic treatment with haloperidol (0.5-2 mg/kg/day, p.o., 17 days) and methamphetamine (1-2 mg/kg/day, p.o., 17 days; 4 mg/kg/day, p.o. 9 days) on hippocampal kindled seizures using a kindling procedure with low-frequency (about 3 Hz) electrical stimulation in cats. The number of stimulating pulses required to trigger epileptic afterdischarge (pulse-number threshold, PNT) was considered an indicator of seizure threshold. Haloperidol, 0.5 and 1.0 mg/kg, reduced the duration of epileptic afterdischarge (afterdischarge duration, ADD) without affecting PNT, and 2.0 mg/kg strongly reduced PNT and ADD. Methamphetamine, 2.0 mg/kg, reduced PNT and ADD, and 4.0 mg/kg preferentially reduced PNT. The effects of the two drugs on hippocampal kindled seizures were found to be partially opposite to those on amygdala kindled seizures, suggesting the different response of these limbic structures to dopamine receptor manipulation.

Phencyclidine increases extracellular dopamine metabolites in rat medial frontal cortex as measured by in vivo dialysis.

An acute intraperitoneal injection of phencyclidine (PCP) caused a tetrodotoxin-reversible increase in extracellular release of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dialysates from the medial frontal cortex of the rat. Moreover, there was an increase in the tissue content of DOPAC and HVA with acceleration of dopamine (DA), but not noradrenaline, utilization in the cortical area after systemic administration of PCP. These results suggest that PCP facilitates DA metabolism in the medial frontal cortex by increasing impulse flow in the DA neurons projecting to the prefrontal region.

Frontal decortication decreases the affinity of N-(1-[2-thienyl]cyclohexyl)[3H]piperidine binding to rat striatum.

Bilateral ablation or transection of the corticostriatal pathways of the rat caused a reduction in N-(1-[2-thienyl]cyclohexyl)[3H]piperidine ([3H]TCP) binding to the striatum at 5-7, but not 3 and 14-28, days postlesion with a persistent decrease in striatal glutamate content 3-28 days after the decortication. This reduction was found to be due to an increase in Kd without changes in Bmax of the [3H]TCP binding. The present findings suggest that interruption of striatal glutamatergic transmission following frontal decortication may produce a temporal reduction in the affinity of phencyclidine receptor in the striatum.

Changes in amitriptyline distribution in rat brain during a 14-day continuous infusion.

The amitriptyline (ATL) distribution in 12 rat brain regions was examined during 2-, 7- and 14-day continuous ATL infusion, starting with 18 mg/kg/day on the first day. The concentration of nortriptyline, a demethylated metabolite of ATL, in brain and serum was very low in comparison with ATL. The brain/serum concentration ratio of ATL and absolute ATL concentration in the brain were lower on the 2nd day than on the other 2 days. On the other hand, the ATL serum level on the 2nd day was higher than on the other 2 days. The ATL distribution in brain was heterogeneous on each of the three days and there were changes with time in its distribution in two brain portions, the anterior basal ganglia and the medulla oblongata + pons.

Distribution of clomipramine in various brain regions of rats under steady-state serum concentrations.

The clomipramine (CMP) distribution in 12 regions of rat brain was investigated 2 and 7 days after subcutaneous minipump implantation. The results of serial blood samplings during 7 days indicated that steady-state CMP serum levels were achieved from experimental day 2. The regional CMP distributions in the brains were uneven on both the 2nd and 7th experimental days. On both test days the CMP concentrations were higher in the cerebral cortex and hippocampus than those in the other regions, and those in the cerebellum and bulbus olfactorius and septum were lower. When the serial fluctuations of the CMP levels were examined in 12 brain regions, there were significant differences between days 2 and 7 in the following four regions: the anterior basal ganglia, hypothalamus, bulbus olfactorius + septum and amygdala.

Acute effect of some psychotropic drugs on low-frequency amygdaloid kindled seizures.

We assessed the acute effects of some psychotropic drugs on amygdaloid-kindled seizures produced by low-frequency stimulation. We used the number of stimulating pulses required for the induction of epileptic afterdischarge (pulse-number threshold, PNT) as an indicator for the seizure-generating threshold, and the duration of the epileptic afterdischarge (AD duration, ADD) as an indicator for the duration of the induced seizures. Methamphetamine and atropine elevated the PNT and reduced the ADD. Haloperidol reduced the PNT at all tested doses and reduced the ADD at high dosage. Imipramine elevated the PNT at low doses and reduced the PNT at high dosage. Imipramine also reduced the ADD. Reserpine at high dose elevated the PNT without affecting the ADD.