DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain

AIM:To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. METHODS:Rats were treated with an intraperitoneal injection of MK-801 [0.08(low-dose) and 0.16(highdose) mg/kg] or NaC l(vehicle control). In a first series of experiment,the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments,the whole brain of each animal was rapidly removed at 40 min post-injection,and different regions were separated:amygdala,cerebral cortex,hippocampus,hypothalamus,midbrain and ventral striatum on ice followed by DNA microarray(4 × 44 K whole rat genome chip) analysis.RESULTS:Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency(30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number(up- and down- regulations) of gene expressions in the cerebral cortex(378),midbrain(376),hippocampus(375),ventral striatum(353),amygdala(301),and hypothalamus(201) under low-dose(0.08 mg/kg) of MK-801. Under high-dose(0.16 mg/kg),ventral striatum(811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region.CONCLUSION:Acute MK-801 treatment increases synchrony of baseline gamma oscillations,and causes very early changes in gene expressions in six individual rat brain regions,a first report.     

Locally Administered Low Nicotine-Induced Neurotransmitter Changes in Areas of Cognitive Function

The present study examined the effect of a low-dose of nicotine; below that one expects to be achieved from a single cigarette, on brain regional heterogeneity and sensitivity of catecholaminergic responses. 1 μM nicotine was infused into six brain areas via a microdialysis probe: the dorsal and ventral hippocampus, the medial temporal and prefrontal cortex, the basolateral amygdala, and the ventral tegmental area (VTA). The nicotine concentration in the brain tissue near the probe site was approximately 0.1 μM. Nicotine-induced increases and decreases could be noted in dopamine (DA), norepinephrine (NE), and serotonin (5HT) levels. In particular, DA and 5HT decreased in both hippocampal areas, while NE increased in the dorsal and decreased in the ventral hippocampus. In the cortical areas, DA and NE increased and 5HT was not significantly altered. In the amygdala all three neurotransmitters increased and in the VTA, all three decreased. Many of the nicotine-induced changes in neurotransmitter concentrations were reversed in the presence of atropine. Where nicotine induced decreases in DA and 5HT in the VTA, increases were observed in the presence of atropine. A similar reversal was seen with NE in the VTA and ventral hippocampus. In contrast, the increases in DA observed in the cortex and amygdala and the increases in NE observed in the cortex, amygdala and dorsal hippocampus were inhibited by the presence of atropine. 5HT was also significantly decreased in the amygdala and both cortical areas in the presence of atropine, where nicotine alone had no significant effect. We conclude, that at low doses, nicotine significantly alters the release of DA, NE, and 5HT – in some areas increasing, in others decreasing endogenous neurotransmitter levels. This data, in conjunction with previous experiments, indicates that the effects of nicotine are regionally heterogeneous and arise from both direct and indirect actions on various receptors and neurotransmitter systems and nicotine’s effects at low doses differ from that at higher doses. The changes in effects in the presence of atropine suggest that muscarinic acetylcholine receptors play a major role in nicotine’s actions on neurotransmitter systems.     

Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin

Ghrelin is a peptide hormone produced and secreted from the stomach. Hypothalamic injection of the peptide increases food intake but it is not known if the peptide affects other brain regions. We measured several behavioral parameters such as anxiety (elevated plus maze), memory retention (step down test), and food intake after injections of different doses of the peptide in the hippocampus, amygdala, and dorsal raphe nucleus (DRN). The injection of ghrelin in the hippocampus and DRN significantly and dose dependently increased food intake in relation to controls rats, while injections into the amygdala did not affect the food intake. We also show for the first time that ghrelin clearly and dose dependently increases memory retention in the hippocampus, amygdala, and DRN. Moreover, ghrelin at different potencies induced anxiogenesis in these brain structures while the highest dose of 3 nmol/microl was effective in all of them. The comparison of sensitivity of each brain structure indicates a specific role of them for each of the behaviors studied. The results provide new insight in to the anatomical substrate and the functional role of extrahypothalamic ghrelin targets in the CNS.     

Opioid receptor dependent long-term potentiation: Peptidergic regulation of synaptic plasticity in the hippocampus

Rapid progress has been made towards understanding the synaptic physiology of excitatory amino acid transmission in the hippocampus. By comparison, the function of opioid peptides localized to some of the same pathways which use glutamate for fast excitation is poorly understood. Here I consider new evidence specifically implicating opioid peptides in long-term potentiation (LTP) induced by high-frequency stimulation of pathways which combine glutamate and opioid neurotransmission. This form of LTP is unique in that it depends on activation of opioid receptors, and unlike many excitatory systems in brain, it does not require activation of the (NMDA) type of glutamate receptor. Thus one of the main functions of opioids in the hippocampus may be to regulate activity-dependent changes in synaptic strength and neuronal excitability. At another level, “opioid” LTP may provide basic insights into peptidergic transmission and its functional interactions with classical neurotransmitters in the brain.     

Postsynaptic effects evoked by activation of long propriospinal pathways in cervical spinal neurons in cats

Effects induced in motoneurons and interneurons of the cervical enlargements of the cat spinal cord by stimulation of the lateral and ventral funiculi at the lower thoracic level were studied under conditions producing degeneration of fibers of descending brain systems. Stimulation of this sort evoked PSPs (mainly of mixed character) in 57 of 90 motoneurons tested. In nine motoneurons the primary response consisted of monosynaptic EPSPs evoked by activity of fibers of the lateral funiculus, and in the rest it consisted of polysyanptic (at least disynaptic) EPSPs and IPSPs. Polysynaptic effects arising in the neuron in response to stimulation of the lateral and ventral funiculi usually differed only quantitatively. The intensity of excitatory synaptic action on motoneurons of the proximal muscle (especially thoracid) was much greater than that on motoneurons of distal muscles. Nearly all motoneurons with no synaptic action belonged to the latter group. Stimulation of the lateral and ventral funculi facilitated synaptic action induced in motoneurons by stimulation of high-threshold segmental afferents and led to excitation of interneurons located in the vectral quadrant, and had no effect on interneurons in the dorsal regions of gray matter. These effects are regarded mainly as the result of excitation of long ascending propriospinal pathways in the cervical parts of the cord; it is also postulated that some of them are evoked by the arrival of activity along collaterals of descending propiospinal pathways to the neurons in this region.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 11, No. 4, pp. 339–347, July–August, 1979.     

Dynamic Regulation of AMPAR Phosphorylation In Vivo Following Acute Behavioral Stress

The tuning of glutamatergic transmission is an essential mechanism for neuronal communication. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ionotropic glutamate receptors that mediate fast synaptic transmission. The phosphorylation states of specific serine residues on the GluA1 and GluA2 AMPAR subunits are considered critical post-translational modifications that regulate AMPAR activity and subcellular trafficking. While behavioral stress, via stress hormones, exerts specific alterations on such glutamatergic processes, there have been conflicting data concerning the influence of stress on AMPAR phosphorylation in different brain regions, and the post-stress signaling mechanisms mediating these processes are not well delineated. Here, we examined the dynamics of phosphorylation at three AMPAR serine residues (ser831-GluA1, ser845-GluA1, and ser880-GluA2) in four brain regions [amygdala, medial prefrontal cortex (mPFC), dorsal hippocampus, and ventral hippocampus] of the rat during the hour following behavioral stress. We also tested the impact of post-stress corticosteroid receptor blockade on AMPAR phosphorylation. Both GluA1 subunit residues exhibited elevated phosphorylation after stress, yet post-stress administration of corticosteroid receptor antagonists curtailed these effects only at ser831-GluA1. In contrast, ser880-GluA2 displayed a time-dependent tendency for early decreased phosphorylation (that was selectively augmented by mifepristone treatment in the amygdala and mPFC of stressed animals) followed by increased phosphorylation later on. These findings show that the in vivo regulation of AMPAR phosphorylation after stress is a dynamic and subunit-specific process, and they provide support for the hypothesis that corticosteroid receptors have an ongoing role in the regulation of ser831-GluA1 phosphorylation during the post-stress interval.     

Repeated neonatal separation stress alters the composition of neurochemically characterized interneuron subpopulations in the rodent dentate gyrus and basolateral amygdala

Emotional experience during early life has been shown to interfere with the development of excitatory synaptic networks in the prefrontal cortex, hippocampus, and the amygdala of rodents and primates. The aim of the present study was to investigate a developmental "homoeostatic synaptic plasticity" hypothesis and to test whether stress-induced changes of excitatory synaptic composition are counterbalanced by parallel changes of inhibitory synaptic networks. The impact of repeated early separation stress on the development of two GABAergic neuronal subpopulations was quantitatively analyzed in the brain of the semiprecocial rodent Octodon degus. Assuming that PARV- and CaBP-D28k-expression are negatively correlated to the level of inhibitory activity, the previously described reduced density of excitatory spine synapses in the dentate gyrus of stressed animals appears to be "amplified" by elevated GABAergic inhibition, reflected by reduced PARV- (down to 85%) and CaBP-D28k-immunoreactivity (down to 74%). In opposite direction, the previously observed elevated excitatory spine density in the CA1 region of stressed animals appears to be amplified by reduced inhibition, reflected by elevated CaPB-D28k-immunoreactivity (up to 149%). In the (baso)lateral amygdala, the previously described reduction of excitatory spine synapses appears to be "compensated" by reduced inhibitory activity, reflected by dramatically elevated PARV- (up to 395%) and CaPB-D28k-immunoreactivity (up to 327%). No significant differences were found in the central nucleus of the amygdala, the piriform, and somatosensory cortices and in the hypothalamic paraventricular nucleus. Thus during stress-evoked neuronal and synaptic reorganization, a homeostatic balance between excitation and inhibition is not maintained in all regions of the juvenile brain.     

Intracerebral beta-endorphin, met-enkephalin and morphine: kindling of seizures and handling-induced potentiation of epileptiform effects

The effects of repeated infusion of small, initially subconvulsive amounts of beta-endorphin, met-enkephalin or morphine sulfate into the amygdala and hippocampus were investigated. beta-endorphin and met-enkephalin evoked epileptiform spiking when infused into the posterior amygdala or ventral hippocampus. Morphine evoked epileptiform spiking when infused into the anterior amygdala. Naloxone blocked or terminated the spiking. Repetition of the infusions led to the gradual development of bilateral generalized convulsions by beta-endorphin and met-enkephalin and to the development of tolerance to morphine. An unexpected observation was that handling, immobilization or conspecific threat potentiated the epileptiform effects of beta-endorphin and morphine in many cases. These results suggest that endogenous opiate mechanisms might play a role in convulsive seizures and that stressful stimuli can exacerbate opiate seizures.     

Acute stress induces contrasting changes in AMPA receptor subunit phosphorylation within the prefrontal cortex, amygdala and hippocampus

Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation is involved with these stress effects. Using an acute inescapable stress protocol with rats, we found opposite effects on AMPA receptor phosphorylation in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) compared to the amygdala and ventral hippocampus (VH). After stress, the phosphorylation of Ser831-GluA1 was markedly decreased in the mPFC and DH, whereas the phosphorylation of Ser845-GluA1 was increased in the amygdala and VH. Stress also modulated the GluA2 subunit with a decrease in the phosphorylation of both Tyr876-GluA2 and Ser880-GluA2 residues in the amygdala, and an increase in the phosphorylation of Ser880-GluA2 in the mPFC. These results demonstrate that exposure to acute stress causes subunit-specific and region-specific changes in glutamatergic transmission, which likely lead to the reduced synaptic efficacy in the mPFC and DH and augmented activity in the amygdala and VH. In addition, these findings suggest that modifications of glutamate receptor phosphorylation could mediate the disruptive effects of stress on cognition. They also provide a means to reconcile the contrasting effects that stress has on synaptic plasticity in these regions. Taken together, the results provide support for a brain region-oriented approach to therapeutics.     

Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior

In the present study, the influence of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala on anxiety-related behaviour was investigated in rats. As a model of anxiety, the elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used. Bilateral microinjection of different doses of morphine (2.5, 5 and 7.5 microg/rat) into the ventral hippocampus or the nucleus accumbens increased the percentage of open arm time (%OAT) and open arm entries (%OAE) but not locomotor activity, indicating an anxiolytic response. However, intra-central amygdala administration of the opioid did not show any response. On the other hand, microinjection of a dose of naloxone into the ventral hippocampus (2 microg/rat) or the nucleus accumbens (1 microg/rat) increased open arm time (%OAT), but not open arm entry (%OAE) which may indicate an anxiolytic effect. Pre-treatment administration of naloxone (0.5, 1 and 2 microg/rat) reversed the anxiolytic effect of morphine (7.5 microg/rat) injected into the ventral hippocampus in a dose-dependent manner. A dose of the antagonist (1 microg/rat) also reduced the morphine response (2.5 microg/rat) when injected in the nucleus accumbens. In conclusion, it seems that the opioidergic system in the ventral hippocampus and the nucleus accumbens are involved in anxiety-related behaviors and the ventral hippocampus may be the main site of action of the anxiolytic properties of morphine.     

Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine

Calcitonin gene-related peptide (CGRP) plays an important role in peripheral and central sensitization. CGRP also is a key molecule in the spino-parabrachial-amygdaloid pain pathway. Blockade of CGRP1 receptors in the spinal cord or in the amygdala has antinociceptive effects in different pain models. Here we studied the electrophysiological mechanisms of behavioral effects of CGRP in the amygdala in normal animals without tissue injury. Whole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in rat brain slices showed that CGRP (100 nM) increased excitatory postsynaptic currents (EPSCs) at the parabrachio-amygdaloid (PB-CeLC) synapse, the exclusive source of CGRP in the amygdala. Consistent with a postsynaptic mechanism of action, CGRP increased amplitude, but not frequency, of miniature EPSCs and did not affect paired-pulse facilitation. CGRP also increased neuronal excitability. CGRP-induced synaptic facilitation was reversed by an NMDA receptor antagonist (AP5, 50 μM) or a PKA inhibitor (KT5720, 1 μM), but not by a PKC inhibitor (GF109203X, 1 μM). Stereotaxic administration of CGRP (10 μM, concentration in microdialysis probe) into the CeLC by microdialysis in awake rats increased audible and ultrasonic vocalizations and decreased hindlimb withdrawal thresholds. Behavioral effects of CGRP were largely blocked by KT5720 (100 μM) but not by GF109203X (100 μM). The results show that CGRP in the amygdala exacerbates nocifensive and affective behavioral responses in normal animals through PKA- and NMDA receptor-dependent postsynaptic facilitation. Thus, increased CGRP levels in the amygdala might trigger pain in the absence of tissue injury.     

Effects of morphine administration and its withdrawal on rat brain aminopeptidase activities

The endogenous opioid neuropeptide system seems to be involved in the neural processes which underlie drug addiction. Several studies have reported that the administration of morphine induces changes in the levels and/or activity of endogenous opioid peptides (enkephalin, dynorphin) and their precursors in specific brain regions of the adult CNS. The aim of this work was to study the effects of chronic morphine exposure and its withdrawal on certain aminopeptidases capable of degrading opioid peptides in brain areas including the amygdala, hypothalamus, hippocampus, striatum and brain cortices. In animals treated with morphine, aminopeptidase N presented higher enzyme activity levels in the striatum, the hypothalamus and the amygdala compared to control animals, although statistically significant differences were observed only in the case of the striatum. In addition, the activity of soluble puromycin-sensitive aminopeptidase (PSA) was found to be higher in the frontal cortex of these rats. In contrast, rats experiencing withdrawal symptoms presented decreased levels of aminopeptidase activity in certain brain areas. Thus, the activity of aminopeptidase N in the hippocampus and soluble puromycin-sensitive aminopeptidase in the frontal cortex were found to be lower in rats experiencing naloxone precipitated withdrawal symptoms, compared to the corresponding controls. Finally, the activity of the three studied aminopeptidases in vitro was unaltered by incubation with morphine, suggesting that the observed effects are not due to a direct action of this opioid upon the aminopeptidases. The results of the present report indicate that aminopeptidases may play an important role in the processes of tolerance and withdrawal associated with morphine administration.     

In vivo cellular responses to electrophoretically applied dynorphin in the rat hippocampus

Recent immunohistochemical and radioimmunochemical observations have demonstrated a differential distribution of immunoreactive dynorphin (DYN) in rat brain. The presence of DYN immunoreactivity in a major intrinsic fiber pathway within the rat hippocampus (the mossy fiber system) has led us to evaluate the possible role of DYN and other closely related peptides in this structure. Single cell activity and hippocampal field potentials have been recorded from the CA1-CA3 cellular fields in halothane or urethane anesthetized rats. DYN, DYN1-13, DYN1-8, and alpha-neo-endorphin had an excitatory effect on most CA1-CA3 neurons encountered as has been previously observed for opiates and other opioid peptides. This response could be blocked by naloxone or by co-administration of Mg++ ion suggesting an indirect (synaptic) mechanism of excitation similar to that hypothetized for enkephalin. A significant number of CA3 neurons, however, exhibited a non-naloxone sensitive inhibitory response to DYN, related opioid peptides, and the kappa agonist WIN 35-197 (ethylketocyclazocine). Field potential analysis of CA1-CA3 neuronal responses to mossy fiber activation also indicated an excitatory, Mg++ reversible, action of iontophoretically applied DYN. These observations support our cytochemical and assay studies indicating diverse opioid systems within the rat hippocampus. In addition, these functional studies are congruent with other evidence suggesting multiple opioid mechanisms in this structure.     

Distribution of kappa opioid receptors in the brain of young and old male rats

The experiments to be described have been designed in order to: (a) provide new information on the concentrations of opioid kappa receptors in different regions of the brain of the male rats; and (b) to analyze whether the density of brain kappa receptors might be modified by the process of aging. The concentration of kappa receptors was investigated in the hypothalamus, amygdala, mesencephalon, corpus striatum, hippocampus, thalamus, frontal poles, anterior and posterior cortex collected from male rats of 2 and 19 months of age. 3H-bremazocine (BRZ) was used as the ligand of kappa receptors, after protection of mu and delta receptors respectively with dihydromorphine and d-ala-d-leu-enkephalin. The results obtained show that: (1) in young male rats, the number of kappa opioid receptors is different in the various brain areas examined: the hypothalamus and the striatum have a concentration of kappa binding sites which is significantly higher than that found in the mesencephalon and in the amygdala; much lower concentrations of kappa binding sites have been found in the thalamus, the frontal poles, the hippocampus, the anterior and posterior cerebral cortex. (2) Aging exerts little influence on the number of kappa receptors in the majority of the brain structures considered. However in the amygdala and in the thalamus the number of kappa receptors was increased in old animals. To the authors' knowledge, the data here presented are the first ones which suggest that age may increase rather than decrease the number of neurotransmitter receptors in the brain.     

强啡肽A和CCK—8对大鼠脊髓突触小体摄取^45Ca的影响

为了探讨血管紧张素Ⅱ(AⅡ)和八肽胆囊收缩素(CCK-8)这两种肽的抗阿片作用机理,本实验中观察了三种阿片类物质(吗啡、强啡肽和 DPDPE)和两种抗阿片物质(AⅡ和 CCK-8)对大鼠脊髓突触小体摄取~(45) Ca 的影响。结果表明:(1)在脊髓腹柱突触小体上,10nmol/L—1μmol/L 的吗啡、强啡肽 A(Dyn A)和 DPDPE 对~(45)Ca 摄取均有较弱的抑制作用;(2)CCK-8在浓度高达lμmol/L 时对~(45)Ca 摄取有较弱的抑制作用;(3)AⅡ在浓度高达lμmol/L时也不影响腹柱突触小体摄取~(45)Ca;(4)在背柱的突触小体制备中,上述阿片物质中 Dyn A 对~(45)Ca 摄取有较强的抑制作用,并被 k 受体阻断剂 nor-BNI 所阻断。10和100nmol/L 的 CCK-8能翻转lμmol/L Dyn A 对~(45)Ca 摄取的抑制作用;(5)A Ⅱ不能翻转Dyn A 的抑制作用。以上结果提示,CCK-8阻断 Dyn A 抑制脊髓背柱突触小体摄取 Ca~(2+)的作用可能是其行为学中抗阿片作用的机理之一。AⅡ对脊髓 Ca~(2+)摄取和 Dyn A 抑制脊髓 Ca~(2+)摄取的作用皆无影响,与行为学中观察到的 AⅡ在脊髓内不能对抗阿片镇痛的现象一致,进一步说明 CCK-8和AⅡ拮抗阿片类物质对神经末梢 Ca~(2+)摄取的影响可能是其抗阿片作用的重要机理之一。     

Acute and Repeated Systemic Amphetamine Administration: Effects on Extracellular Glutamate, Aspartate, and Serine Levels in Rat Ventral Tegmental Area and Nucleus Accumbens

Abstract: Recent work indicates an important role for excitatory amino acids in behavioral sensitization to amphetamine. We therefore examined, using in vivo microdialysis in awake rats, the effects of amphetamine on efflux of glutamate, aspartate, and serine in the ventral tegmental area and nucleus accumbens, brain regions important for the initiation and expression of amphetamine sensitization, respectively. Water-pretreated and amphetamine-pretreated rats were compared to determine if sensitization altered such effects. In both brain regions, Ca²⁺-dependent efflux of glutamate accounted for ∼20% of basal glutamate efflux. A challenge injection of water or 2.5 mg/kg of amphetamine did not significantly alter glutamate, aspartate, or serine efflux in the ventral tegmental area or nucleus accumbens of water- or amphetamine-pretreated rats. However, 5 mg/kg of amphetamine produced a gradual increase in glutamate efflux in both regions that did not reverse, was observed in both water- and amphetamine-pretreated rats, and was prevented by haloperidol. Although increased glutamate efflux occurred with too great a delay to mediate acute behavioral responses to amphetamine, it is possible that repeated augmentation of glutamate efflux during repeated amphetamine administration results in compensatory changes in levels of excitatory amino acid receptors in the ventral tegmental area and nucleus accumbens that contribute to development or expression of amphetamine sensitization.     

The influence of neuromodulators on the synaptic plasticity in dopaminergic structures of the midbrain (hypothetical mechanism)

A mechanism underlying the effects of neuromodulators on long-term changes in the efficacy of excitatory and inhibitory inputs to dopaminergic and inhibitory cells of the substantia nigra and ventral tegmental area is suggested. According to this mechanism, activation of Gi/0 protein-coupled dopamine D2 autoreceptors and opioid kappa (mu) receptors on dopaminergic (inhibitory) cells promotes the LTD of excitatory inputs to these cells and decrease in their activity. Activation of Gq/11 protein-coupled alpha1 adrenoreceptors, muscarinic M1, neurokinin NK3 (alpha1, M3, NK1, serotonin 5-HT2) receptors on dopaminergic (inhibitory) cells as well as activation of Gs protein-coupled D1 receptors on inhibitory cells promotes the LTP of excitatory inputs to these cells and increase in their activity. Augmenting (lowering) GABA release can be provided by activation of presynaptic D1 and M3 receptors (mu, 5-HT1, and adenosine A1) receptors. Increase (decrease) in GABA concentration due to modulation of inhibitory cell activity and/or GABA release will promote the induction of LTD (LTP) of excitatory inputs to target dopamine cells. The model agree with known experimental data describing the involvement of neuromodulators in modification of dopamine cell activity and dopamine release. The suggested model can be useful in understanding the operation of neuronal networks, which include the basal ganglia.     

Effect of electroacupuncture on electroconvulsive shock--an autoradiographic study for opioid receptors

Radioreceptor-binding assay combined with autoradiography technique in the brain slices of rats was used to investigate cerebral areas related to electroconvulsive shock (ECS) and to analyze changes of opioid receptors of these areas in electroacupuncture (EA) anticonvulsion. The results from image processing and detection of optic density (O.D.) showed that repeated ECS resulted in an increase of opioid receptor densities in the caudate nucleus, hippocampus, habenulae nucleus and amygdala. In the group of EA plus ECS, however, the opioid receptor densities in the hippocampus, habenula nucleus and amygdala decreased as compared with that in ECS group. In addition, the receptor density in the caudate nucleus showed a decrease tendency. The results provided morphological evidence of the involvement of opioid receptors in these cerebral areas in the process of ECS and EA anticonvulsion.     

Anatomical substrates for the discriminative stimulus effects of methamphetamine in rats

Methamphetamine is a psychostimulant drug acting on central monoaminergic neurons to produce both acute psychomotor stimulation and long-lasting behavioral effects including addiction and psychosis. Drug discrimination procedures have been particularly useful in characterizing subjective effects of addictive drugs. In the present study, to identify potential anatomical substrates for the discriminative stimulus effects of methamphetamine, we investigated the drug discrimination-associated Fos expression in Sprague-Dawley rats trained to discriminate methamphetamine from saline under a two-lever fixed ratio 20 (FR-20) schedule of food reinforcement. The rats that fulfilled the criteria for learning the discrimination were anesthetized and perfused 2 h after the drug discrimination test, and Fos immunoreactivity was examined in 15 brain regions. Fos expression in the brains of rats that discriminate methamphetamine from saline was significantly increased in the nucleus accumbens (NAc) and the ventral tegmental area (VTA), but not in other areas including the cerebral cortex, caudate putamen, substantia nigra, hippocampus, amygdala and habenulla, as compared with the expression in control rats that were maintained under the FR-20 schedule. The present findings suggest a role for the VTA and NAc as possible neuronal substrates in the discriminative stimulus effects of methamphetamine.     

Changes in glucose metabolism from discrete regions of rat brain and its relationship to reproductive failure during experimental diabetes

This study reports the effects of alloxan induced diabetes on glucose metabolism enzymes viz. Hexokinase, Lactate dehydrogenase, and Glucose-6-phosphate dehydrogenase from discrete brain regions. Enzymes activity was assayed from hypothalamic areas such as medial preoptic area and median eminence-arcuate region which have gonadotropin releasing hormone cell bodies and their terminals, respectively and other brain regions like septum, amygdala, hippocampus, and thalamus. In all the areas studied, induction of diabetes resulted in a significant decrease in particulate bound HK activity, whereas soluble HK, LDH and G6PDH activity showed increase at 3, 8, 15 and 28 days intervals. Insulin treatment of diabetic rats led to recovery in enzyme activity. Blood glucose levels increased significantly after induction of diabetes and recovery was seen after insulin treatment. The present results suggest that altered cerebral glucose metabolism may also be responsible for reproductive failure observed in diabetic rats. (Mol Cell Biochem141: 97–102, 1994)