The amygdaloid complex, corticotropin releasing factor and stress-induced gastric ulcerogenesis in rats

The amygdaloid complex and corticotropin releasing factor (CRF) are both important in stress reactions and we thus evaluated the effects of intra-amygdalar CRF on stress ulceration in rats. Bilateral micro-applications of CRF (0.05, 0.5 or 5.0 micrograms) into the central amygdala (CEA) attenuated cold restraint-induced gastric mucosal lesions in a dose-related manner. Similar gastric cytoprotective effects were seen with intra-CEA noradrenaline (NA; 3.0 micrograms), whereas the NA neurotoxin, DSP-4 (25 micrograms), or the beta-adrenoceptor antagonist, propranolol (1 microgram), aggravated stress ulcer pathology. Intra-CEA pretreatment with DSP-4 or propranolol clearly reversed the ulceroprotective effects of CRF during stress. These results indicate that the CEA is a neural substrate for CRF effects, and CRF-NA interactions in this limbic area are crucial for the regulation of stress ulcerogenesis.     

Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction

The effect of systemic administration of the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on noradrenaline efflux in the frontal cortex was studied in freely-moving rats using microdialysis in vivo. Five days after treatment with DSP-4 (40 mg/kg i.p.), the noradrenaline content of the frontal cortex was reduced by 75%. Yet, noradrenaline efflux in the frontal cortex was nearly two-fold greater in DSP-4 treated rats than in saline-injected controls. Local infusion of the noradrenaline-selective uptake blocker, desipramine (5 microM), via the microdialysis probe, increased noradrenaline efflux in rats from both groups. Perfusion of Ringer's solution, containing 80 mM K+, also increased noradrenaline efflux in both groups, but the increase after DSP-4 pretreatment was greater than in the controls. In contrast, removal of Ca2+ from the infusion medium reduced noradrenaline efflux in both treatment groups. These results indicate that, at this dose, DSP-4 increases the extracellular concentration of noradrenaline in rat frontal cortex despite causing a partial lesion of noradrenergic neurones. This is due to an increase in the release of noradrenaline, although reduced clearance is also likely. These data challenge the assumption that depletion of noradrenaline content after treatment with DSP-4 invariably translates into diminished noradrenergic transmission.     

Evidence from microdialysis and synaptosomal studies of rat cortex for noradrenaline uptake sites with different sensitivities to SSRIs

1. Microdialysis of the frontal cortex of freely-moving rats and uptake of [3H]noradrenaline into cortical synaptosomes were used to evaluate changes in efflux of noradrenaline in vivo and uptake of [3H]noradrenaline in vitro, respectively, induced by the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the tricyclic antidepressant, desipramine. 2. Noradrenaline efflux was increased during local infusion into the cortex of each of these drugs. All three agents also inhibited synaptosomal uptake of [3H]noradrenaline; this inhibition was unaffected by a substantial (50%) lesion of central 5-hydroxytrytaminergic neurones induced by intracerebroventricular infusion of 5,7-DHT (150 microg). 3. A noradrenergic lesion (70%), induced by pretreatment with the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 40 mg kg(-1) i.p.), 5 days earlier, abolished the increase in noradrenaline efflux caused by local infusion of fluoxetine. In contrast, the desipramine-induced increase in efflux was greater than in non-lesioned rats whereas the effect of citalopram on noradrenaline efflux was unaffected by DSP-4 pretreatment. 4. The combined results of all these experiments suggest that there could be more than one, functionally distinct, noradrenaline uptake site in rat frontal cortex which can be distinguished by their different sensitivities to desipramine and the SSRIs, fluoxetine and citalopram.     

The effect of noradrenaline, injected into the hypothalamus, on thermoregulation in the cat

1. Noradrenaline (NA) was microinjected into the anterior hypothalamic/preoptic area(AH/POA) of unanaesthetized cats held at ambient temperatures of 10, 22 or 35 degrees C. Loci in which injection of NA caused body temperature changes were also found to be sensitive to the febrile action of PGE1. 2. At all ambient temperatures, NA caused a dose-dependent fall in body temperature. However the mechanisms by which these temperature changes were brought about varied at different ambient temperatures. In cats maintained at the higher ambient temperature, NA activated heat loss mechanisms whereas in the cats maintained in the 10degrees C environment, the major effect of NA injection was an inhibition of heat conservation and heat production mechanisms. 3. We conclude that NA acts in cats not only as an inhibitor of heat conservation and production, but also acts in an excitatory manner on an active heat loss pathway within the AH/POA.     

A major T cell determinant from the influenza virus hemagglutinin (HA) can be a cryptic self peptide in HA transgenic mice

A single low dose of the neurotoxin: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results paradoxical sleep deprivation and reduction in food intake without any detectable motor deficiencies. In the present study we monitored the in vivo extracellular levels of monoamines and their metabolites following intraperitoneal (i.p.) administration of a single dose of MPTP (5 mg/kg). Microdialysates were collected from the ventrobasal thalamic nucleus (VB) of Halothane anesthetized rat. We found a significant decrease in noradrenaline (NA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) levels and a significant increase in 3,4-dihydroxyphenylalanine (DOPA) concentration whereas amino acid levels were unchanged throughout the 4-hour long perfusion. We found no significant difference in the post mortem release of NA and DOPA between the control and MPTP treated animals, suggesting that the intracellular NA pool were maintained. The above findings support the idea that the neurochemical mechanism of rapidly developing and transient behavioral changes induced by MPTP may be an immediate decrease in monoaminergic transmission and metabolism following MPTP injection.     

Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex

Noradrenaline (NA) has been shown to influence astrocytic and vascular functions related to brain homeostasis, metabolism, local blood flow, and blood-brain barrier permeability. In the current study, we investigate the possible associations that exist between NA-immunoreactive nerve terminals and astrocytes and intraparenchymal blood vessels in the rat frontoparietal cortex, both at the light and electron microscopic levels. As a second step, we sought to determine whether the NA innervation around intracortical microvessels arises from peripheral or central structures by means of injections of N-(2-chloroethyl-N-ethyl-2-bromobenzylamine) (DSP-4), a neurotoxin that specifically destroys NA neurons from the locus ceruleus. At the light microscopic level, 6.8% of all NA-immunoreactive nerve terminals in the frontoparietal cortex were associated with vascular walls, and this perivascular noradrenergic input, together with that of the cerebral cortex, almost completely disappeared after DSP-4 administration. When analyzed at the ultrastructural level in control rats, NA terminals in the neuropil had a mean surface area of 0.53 +/- 0.03 micron2 and were rarely junctional (synaptic incidence close to 7%). Perivascular terminals (located within a 3-micron perimeter from the vessel basal lamina) counted at the electron microscopic level represented 8.8% of the total NA terminals in the cortical tissue. They were smaller (0.29 +/- 0.01 micron2, P < 0.05) than their neuronal counterparts and were located, on average, 1.34 +/- 0.08 microns away from intracortical blood vessels, which consisted mostly of capillaries (65%). None of the perivascular NA terminals engaged in junctional contacts with surrounding neuronal or vascular elements. The primary targets of both neuronal and perivascular NA nerve terminals consisted of dendrites, nerve terminals, astrocytes, and axons, whereas in the immediate vicinity (0.25 micron or less) of the microvessels, astrocytic processes represented the major target. The results of the current study show that penetrating arteries and intracortical microvessels receive a central NA input, albeit parasynaptic in its interaction, originating from the locus ceruleus. Particularly, they point to frequent appositions between both neuronal and perivascular NA terminals and astroglial cells and their processes. Such NA neuronal-glial and neuronal-glial-vascular associations could be of significance in the regulation of local metabolic and vascular functions under normal and pathologic situations.     

Stoichiometric interaction of a beta-receptor blocking drug with fraction of liver cytochrome P-450 as a possible cause for its dose-dependent availability

Four daily doses of pyrazole (50 mg/kg), caused a reduction in rat brain noradrenaline (NA) of over 20% when determined 24 hrs after the final injection. Neither 4-methylpyrazole (10-50 mg/kg), nor 4-iodopyrazole (10-50 mg/kg) had any effect. In mice treated similarly, pyrazole (50-400 mg/kg) caused a dose-dependent decrease in brain NA. Neither 4-methylpyrazole, 4-bromopyrazole nor 4-iodopyrazole caused any significant change in the levels. However if the brain NA levels were examined 6 hrs after a single dose, then in addition to pyrazole, 4-methylpyrazole showed a dose-dependent ability to lower brain NA. 4-bromopyrazole and 4-iodopyrazole, given acutely, caused a dose-dependent decrease in rectal temperature and exploratory behaviour. 4-methylpyrazole in high doses (200-400 mg/kg) showed similar properties but they did not correlate with the decrease in brain NA. Pyrazole, after acute treatment, showed little ability to change rectal temperature of exploratory behaviour. It is concluded that the NA-depleting effect of pyrazole is not related to inhibition of alcohol dehydrogenase, since other 4-substituted pyrazoles which are more potent inhibitors of the enzyme have little or no effect on brain NA levels.     

Salbutamol overcomes the effect of the noradrenergic neurotoxin DSP-4 on memory function in the day-old chick

These experiments investigated the effect of the relatively selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on memory formation in day-old chicks trained on a discriminated passive avoidance task. A time course study showed that DSP-4 treatment resulted in amnesia as early as 20 min post-learning. In a second study, a series of alpha- and beta-adrenergic agonists (noradrenaline; the alpha 1 agonist phenylephrine; the beta 1 agonist dobutamine; and the beta 2 agonist salbutamol) were applied immediately after the training trial. Both noradrenaline and salbutamol were effective in ameliorating the memory deficits caused by DSP-4 treatment, and in consolidating weakly reinforced training. These studies support the notion that noradrenaline subserves a vital role in the consolidation of memory in the chick, and that the beta 2 receptor subtypes are principally involved in the intermediate phase of memory formation.     

From vasopressin receptor to water channel: intracellular traffic, constraint and by-pass

To test a potential "gating" effect of noradrenaline (NA) in the auditory cortex, the acoustic threshold was estimated by determining the rate-level function of neurons before, during, and after microiontophoretic application (5-40 nA) of NA. The rationale behind this experiment was that a gating effect should decrease the threshold for acoustic excitatory responses. From 84 recorded neurons, we observed (1) that application of NA increased the threshold for 48 of 84 cells, and (2) that, on average, the slope of the rate-level functions was unchanged. These effects on the threshold are consistent with the fact that the dominant effect of NA on the evoked response is inhibition for 34 of 84 cells; increases in evoked responses were observed for only 14 of 84 cells. GABA application (0-50 nA) also led to increased response threshold for 19 of 24 cells (unaffected, 5 of 24 cells). However, for three cells the effect of GABA application was antagonized by bicuculline application, while on the same cells bicuculline application did not prevent the noradrenergic increase in threshold. The effect induced by NA on the threshold raises questions about the generality of a gating effect of NA in sensory neocortex.     

Hyperforin as a possible antidepressant component of hypericum extracts

We demonstrate that the phloroglucinol derivative hyperforin is not only the major lipophilic chemical constituent of the medicinal plant Hypericum perforatum (St. John's wort) but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and L-Glutamate with IC50 values of about 0.05-0.10 microg/ml (5-HT, NA, DA, GABA) and about 0.5 microg/ml (L-glutamate) in synaptosomal preparations. Furthermore, potencies of two different hypericum extracts in two conventional pharmacological paradigms useful for the detection of antidepressants (behavioral despair, learned helplessness), closely correlate with their hyperforin contents. In addition, most till now known neuropharmacological properties of the clinically used hypericum extracts can also be demonstrated with pure hyperforin. It appears, therefore, that this non-nitrogenous constituent is a possible major active principle responsible for the observed clinical efficacies of the extract as an antidepressant and that it could also be a starting point for drug discovery projects engaged in the search of psychoactive drugs with novel mode of action.     

Effects of the antiparkinsonian drug budipine on neurotransmitter release in central nervous system tissue in vitro

The effects of the antiparkinsonian drugs budipine and biperiden on spontaneous and electrically evoked release of dopamine (DA), acetylcholine (ACh), GABA or noradrenaline (NA) were studied in caudate nucleus or cortex slices, respectively, of the rabbit brain. Whereas both drugs (1-10 microM) strongly increased spontaneous [3H]outflow in caudate nucleus slices preincubated with [3H]DA, budipine inhibited but biperiden facilitated the evoked DA release. In the presence of the DA-reuptake inhibitor nomifensine, a significant part of the budipine-induced basal [3H] outflow consisted of unmetabolized DA. Synaptosomal high-affinity uptake of [3H]DA was only weakly affected by budipine and biperiden (IC50 values, 11 and 9 microM, respectively). Budipine enhanced also basal [3H]outflow from cortex slices prelabeled with [3H]NA, however this outflow consisted mainly of NA metabolites even in the presence of cocaine. The evoked release of [3H]ACh in rabbit caudate nucleus slices preincubated with [3H] choline was almost unaffected by budipine but enhanced by biperiden in the absence of further drugs. In the presence of nomifensine, however, budipine inhibited, but biperiden still enhanced, the evoked ACh release. Moreover, both drugs showed antimuscarinic properties in the presence of the ACh esterase inhibitor physostigmine, i.e., they facilitated the evoked ACh release, exhibiting pA2 values of about 6.9 (budipine) and 8.3 (biperiden). Addition of the D2 receptor antagonist domperidone diminished all inhibitory effects of budipine on the evoked ACh release. The evoked overflow of [3H] in caudate nucleus slices preincubated with [3H]GABA was reduced by both budipine and biperiden. It is concluded that both anticholinergic and indirect dopaminomimetic properties contribute to the antiparkinsonian effects of budipine, whereas biperiden exhibits mainly anticholinergic effects. Moreover, both drugs might disinhibit GABA controlled neurons in the central nervous system.     

Substance P is a possible neurotransmitter in the rat spinothalamic tract

In order to shed some light on the neurotransmitters in the spinothalamic tract (STT), we examined, biochemically and immunohistochemically, the contents of various neurotransmitter candidates in the terminal field of the STT after cervical hemi-chordotomy (HC) and dorsal quadrant-chordotomy (dQC) in the rat. Substance P (SP), calcitonin gene-related peptide (CGRP), enkephalin, neuropeptide Y, neurotensin, oxytocin and dynorphin A were analyzed immunohistochemically. The contents of neuropeptides (SP, CGRP and cholecystokinin octapeptide) were measured by radioimmunoassay and those of amino acids (aspartic acid, glutamic acid, gamma-aminobutyric acid (GABA) and glycine) and noradrenaline were determined using high-performance liquid chromatography. Cervical hemi-chordotomy, but not dQC, caused significant decreases of the SP-like immunoreactivity in and SP content of the ventral thalamus on the ipsilateral side, compared with that on the contralateral side and of rats subjected to sham-operation. However, neither HC nor dQC resulted in any changes in the ventral thalamic contents of other putative neurotransmitters examined. These results suggest that, in rats, the STT contains SP and that SP-positive fibers run in the ventral half of the ascending spinal tract at the cervical level.     

Effect of selegiline against selective neurotoxins

The complexity of the pharmacological activity of selegiline cannot be considered only as a result of a simple MAO-B inhibition. The mechanism of its neuroprotective action against the noradrenergic neurotoxin DSP-4 was widely studied (-)-p-fluoro-deprenyl (PFD), the chemical derivative of selegiline, with its possible metabolites were also involved into these studies. The results suggested that the uptake inhibitory effect of selegiline, and mainly that of its metabolite (-)-methylamphetamine (MA), played an essential role in the protection. MA was more potent to inhibit the uptake of noradrenaline and dopamine, than the parent compound. Neither selegiline nor its metabolite inhibited the reuptake of serotonin. In respect of the protection against DSP-4 induced toxicity PFD and its metabolites behaved similarly to selegiline, but their effects were more lasting than that of selegiline. After oral treatment selegiline undergoes an intensive "first pass" metabolism, which leads to an enhanced formation of MA. The better understanding of the fate of selegiline in the body, including its pharmacokinetic behaviour and metabolism, may contribute to a better knowledge of the complex pharmacological activity of the drug. The results could be summarised as follows. a) MAO-B inhibition-which is due to the parent compound-is an irreversible "hit and run" effect, the level of which after an initial phase is independent of the presence of the substance which caused it. b) The uptake inhibition is a reversible process and strictly proportional to the concentration of the substance responsible for the effect. In this respect the uptake inhibitory action of the metabolites exceeds that of the parent compounds. The role of the reversible uptake inhibition in neuroprotection may partly explain the need of the daily administration of selegiline to parkinsonian patients in spite of the irreversible MAO-B inhibitory action of the drug.     

Daily and momentary mood and stress are associated with binge eating and vomiting in bulimia nervosa patients in the natural environment.

The relation of mood and stress to binge eating and vomiting in the natural environments of patients with bulimia nervosa (BN) was examined using real-time data collection. Women (n = 131; mean age = 25.3 years) with BN carried a palmtop computer for 2 weeks and completed ratings of positive affect (PA), negative affect (NA), anger/hostility (AH), and stress (STRS); they also indicated binge or vomit episodes (BN-events) 6 times each day. Mixed models were used to compare mood and STRS between and within days when BN-events occurred. Between-days analyses indicated that binge and vomit days both showed less PA, higher NA, higher AH, and greater STRS than days with no BN-events. Within-day, decreasing PA, and increasing NA and AH, reliably preceded BN-events. Conversely, PA increased, and NA and AH decreased following BN-events. Demonstration of the temporal sequencing of affect, STRS, and BN-events with a large BN sample may help advance theory and clinical practice, and supports the view that binge and purge events hold negatively reinforcing properties for women with BN. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of vigabatrin correlated with whole brain gamma-aminobutyric acid metabolism in audiogenic sensitive rats

The present study evaluates dose-dependent behavioral effects of acutely or subacutely administered single doses of vigabatrin (gamma-vinyl gamma-aminobutyric acid, gamma-vinyl GABA, CAS 60643-86-9) in audiogenic sensitive rats, in correlation with whole brain GABA metabolism. There was a discrepancy in timing between behaviorally observed maximal antiepileptic protection (4 h after i.p. administration of gamma-vinyl GABA) and on the other hand maximal inhibition of GABA-transaminase activity and maximal increase of whole brain GABA content (24 h after i.p. administration of gamma-vinyl GABA). This suggests that the antiepileptic properties of gamma-vinyl GABA not only depend on GABA-ergic neurotransmission. A possible explanation is a gamma-vinyl GABA-induced decrease of excitatory amino acids or increased glycine concentrations in the brain.     

DNA triple helix formation at oligopurine sites containing multiple contiguous pyrimidines

We have used DNase I footprinting to assess the formation of triple helices at 15mer oligopurine target sites which are interrupted by several (up to four) adjacent central pyrimidine residues. Third strand oligonucleotides were designed to generate complexes containing central (X.TA)nor (X.CG)n triplets (X = each base in turn) surrounded by C+.GC and T.AT triplets. It has previously been shown that G.TA and T.CG are the most stable triplets for recognition of single TA and CG interruptions. We show that these triplets are the most useful for recognizing consecutive pyrimidine interruptions and find that addition of each pyrimidine residue leads to a 30-fold decrease in third strand affinity. The addition of 10 microM naphthylquinoline triplex-binding ligand stabilizes each complex so that all the oligonucleotides produce footprints at similar concentrations (0.3 microM). Targets containing two pyrimidines are only bound by oligonucleotides generating (G.TA)2 and (T.CG)2 with a further 30-fold decrease in affinity. (G.TA)2 is slightly more stable than (T.CG)2. In the presence of the triplex-binding ligand the order of stability is (G.TA)2 > (C.TA)2 > (T.TA)2 > (A.TA)2 and (T.CG)2 > (C.CG)2 > (G.CG)2 = (A.CG)2. No oligonucleotide footprints are generated at target sites containing three consecutive pyrimidines, though addition of 10 microM triplex-binding ligand produces stable complexes with oligonucleotides generating (G.TA)3, (T.CG)3 and (C.CG)3, with a further 30-fold reduction in affinity. No footprints are generated at targets containing four Ts, though the ligand induces a weak interaction with the oligonucleotide generating (T.CG)4.     

Rapid and sensitive determination of catecholamines and the metabolite 3-methoxy-4-hydroxyphen-ethyleneglycol using HPLC following novel extraction procedures

In the present study assays were improved for the determination of free catecholamines and 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), the major metabolite of peripheral and central noradrenaline. The compounds were extracted by a fluid phase extraction: a diphenyl boric acid method for the purification of catecholamines and an ethyl acetate extraction for MHPG were used, respectively. High-performance liquid chromatography with electrochemical detection was employed for quantitative analysis. In previous studies, significant differences between plasma concentrations of these substances in normal volunteers and hospital patients were demonstrated. Therefore, we established valid reference values for a hospital population. Blood and urine samples of 59 patients without disorders and medication affecting catecholamine synthesis and metabolism or the activity of the sympatho-adrenal system were collected and analyzed for free and total (free plus conjugated) MHPG, noradrenaline (NA), adrenaline (A) and dopamine (DA); total MHPG was assayed after enzymatic hydrolysis of conjugates. Our data clearly demonstrate that these methods are sensitive, specific, rapid, and can easily be standardized. The intra- and inter-assay precision were high (CV 2.6-5.3% and 4.3-6.9% for plasma, CV 3.8-4.9% and 5.1-8.2% for urine, respectively). For plasma, the mean concentrations +/- SD were determined to be 20.82+/-4.70 pmol/ml for free MHPG, 68.43+/-16.21 pmol/ml for total MHPG, 2.11+/-0.24 pmol/ml for NA and 0.31+/-0.08 pmol/ml for A. For 24h-urine the mean concentrations +/-SD were determined to be 0.44+/-0.13 mmol/24h for free MHPG, 8.79+/-2.13 mmol/24h for total MHPG, 169.8+/-58.25 nmol/24h for NA, 62.19+/-21.79 nmol/24h for A and 757.2+/-382.6 nmol/24h for DA. In summary, these novel and rapid methods can clearly be employed in a routine clinical setting.     

Central DSP-4 treatment decreases norepinephrine levels and courtship behavior in male zebra finches

In zebra finches, gonadal steroids activate male courtship, including singing, and also strongly modulate norepinephrine (NE) levels and turnover in brain areas regulating courtship behavior. In a previous study, systemic administration of DSP-4 caused significant decreases in courtship singing. These behavioral decrements were correlated with the degree of NE depletion in several vocal control nuclei. In the present study, we attempted to further decrease brain NE levels while minimizing systemic effects by infusing DSP-4 directly into the third ventricle. DSP-4 treatment significantly reduced NE levels in three of six vocal control nuclei and both hypothalamic nuclei sampled without significantly altering dopamine or serotonin levels in any areas. DSP-4-treated males took longer to begin singing and performed fewer song bouts and courtship displays. Interestingly, behavioral deficits were limited to courtship song displays, other behavior patterns, including female-directed behaviors like approach and follow, were unaffected by DSP-4 treatment. DSP-4 treatment appeared to affect singing behavior by causing deficits in initial attentiveness to females and initiation of singing rather than by affecting song structure.     

Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by hippocampal muscarinic blockade in rats

To clarify the interactions between hippocampal cholinergic and adrenergic systems in working memory function of rats, the effects of hippocampal muscarinic receptor blockade combined with noradrenaline depletion on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task, whereas the 0.32 microgram/side dose of scopolamine did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg IP caused a marked reduction in hippocampal noradrenaline concentration, but it had no effect on working memory errors. Intrahippocampal administration of 0.32 microgram/side scopolamine, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted animals. These results suggest that hippocampal muscarinic/noradrenergic interactions are involved in neural processes mediating working memory function of rats.     

Rat brain neurotransmitter turnover rates altered during withdrawal from chronic cocaine administration

This experiment utilized neurotransmitter turnover rates to assess the effects of withdrawal from chronic cocaine on the brain. A triad-littermate design was used to evaluate the importance of response dependency on the effects of withdrawal from chronic cocaine administration upon brain biogenic monoamine and amino acid putative neurotransmitter turnover rates. Each member of a triad was exposed to one of three conditions. Cocaine infusions (0.33 mg/inf) were used to engender and maintain lever pressing by one rat under an FR 2 schedule, while the second and third rats received simultaneous infusions of either cocaine or saline, respectively. After a minimum of 15 days exposure to the three treatment conditions and 24 h after the start of the last drug session, the triads were pulse labeled with [14C]glucose, [3H]tyrosine and [3H]tryptophan and killed 60 or 90 min later by total immersion in liquid nitrogen, The frozen brains were removed and dissected at -20 degrees C into 22 areas. The content and specific radioactivities for dopamine (DA), noradrenaline (NA), serotonin (5-HT), aspartate (Asp), glutamate (Glu), glycine (Gly) and gamma-aminobutyric acid (GABA) were determined in each brain region using high pressure liquid chromatography with electrochemical (biogenic monoamines) or fluorescence (amino acids) detection followed by liquid scintillation spectrometry. Turnover rates (TOR) were calculated and compared across treatment conditions. The significant decreases in TOR resulting from chronic cocaine exposure included 5-HT in the frontal cortex, DA in the cingulate cortex, entorhinal-subicular and motor-somatosensory cortices and NA in the inferior colliculus. Significant increases in TOR were also observed which included 5-HT in the preoptic-diagonal band region, DA in the hippocampus and NA in the pyriform and temporal-auditory cortices, the dentate gyrus and brainstem. GABA TOR was also increased in the preoptic-diagonal band region, dentate gyrus and brainstem of both groups receiving cocaine as was Glu TOR in the pyriform cortex and cerebellum. In addition, changes were seen in the rats under the ratio schedule of cocaine self-administration that were not seen in rats receiving yoked-cocaine infusions that included increased TOR of 5-HT in the pyriform cortex, NA in the caudate-putamen and GABA in the pyriform and motor-somatosensory cortices. Decreased 5-HT TO was seen in the motor-somatosensory cortex and dentate gyrus in the rats that had self-administered cocaine compared to the yoked-cocaine infused group. Perhaps the most interesting changes were those seen in the yoked-cocaine group that were reversed in the rats whose responding was maintained by cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)