Noradrenaline In Rat Brain Research Articles

Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.

In vivo potentiation of reboxetine and citalopram effect on extracellular noradrenaline in rat brain by α 2-adrenoceptor antagonism

The therapeutic activity of noradrenaline reuptake inhibitors (NaRIs) and serotonin reuptake inhibitors (SSRIs) as antidepressant is based on their ability to increase monoamine concentrations in the synaptic cleft. α 2-Adrenoceptors inhibit noradrenaline (NA) release, which modulates antidepressant neurochemical activity. The present study assesses the influence of the addition of the selective α 2-adrenoceptor antagonist RS79948 to the NaRI reboxetine and the SSRI citalopram on brain extracellular NA. Dual-probe microdialysis technique in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely moving rats. Acute reboxetine (3 and 5 mg/kg i.p.) promoted a dose-dependent increase of NA in LC (164 ± 15%; 243 ± 24%) and PFC (140 ± 7%; 181 ± 30%). Acute citalopram (5 mg/kg i.p.) did not change NA in LC or PFC, but at 10 mg/kg i.p. increased NA in LC (144 ± 14%) and decreased it in PFC (− 42 ± 7%). An inactive dose of RS79948 (0.1 mg/kg i.p.) in rats pretreated with reboxetine (3 mg/kg i.p.) or citalopram (5 mg/kg i.p.) induced a significant enhancement of NA in LC (reboxetine: 462 ± 137%; citalopram: 142 ± 11%) and PFC (reboxetine: 281 ± 56%; citalopram: 130 ± 16%). The results indicate that co-administration of selective α 2-adrenoceptor antagonist drugs might improve the effects of NaRI or SSRI antidepressants by enhancing extracellular NA concentrations in the brain.

Copper‐status and age alter suckling rodent brain and heart catecholamine levels

Mice and rats were compared to determine differences in dietary copper (Cu) deficiency (Cu−) started during late gestation and/or lactation on catecholamine, norepinephrine (NE) and dopamine (DA), content in brain and heart. Limiting dopamine beta-monooxygenase (DBM) results in lower NE and higher DA in Cu− tissues compared to copper adequate (Cu+) tissues. Experiments were performed with Holtzman rats and Hsd:ICR (CD-1) outbred albino mice in which dams were fed a modified AIN-76A diet and drank deionized water or Cu supplemented water. Offspring were sampled at three time points between postnatal age 3 (P3) and P31. NE concentration increased with age in both heart and brain in Cu+ rodents. Cu− pups exhibited signs consistent with Cu deficiency, lower cuproenzyme and copper content, compared to Cu+ pups. For both rat and mouse tissue NE and DA changes were amplified at later ages in Cu− mice when Cu deficiency was limited to lactation only. Although dam Cu restriction began earlier in rats than mice, embryonic day 7 (E7) compared to E17, rat brain NE and DA alterations were not impacted as severely as mouse brain. This pattern was also true for heart NE reduction in Cu− rodents. However, Cu− mouse heart DA was impacted less than Cu− rat heart DA. Both mouse and rat models illustrate limiting DBM when dietary Cu is restricted during perinatal development. Within species, changes were more severe and proportional to the length of Cu deprivation. Both models may be useful to study the impact of Cu deficiency on altered catecholamines and their role in delayed development and altered behavior. Supported by NRI USDA CSR grant 2001-00998 and by NIH grant HD 39708.

Pilocarpine treatments differentially affect alpha2-adrenoceptors which modulate the firing rate of locus coeruleus neurones and the synthesis and release of noradrenaline in rat brain.

We have investigated the effect of treatments with the muscarinic acetylcholine receptor agonist, pilocarpine, on the sensitivity of central alpha2-adrenoceptors that regulate the firing activity of rat locus coeruleus, the tyrosine hydroxylase activity in the rat cortex, hippocampus and hypothalamus, and the K(+)-evoked release of [3H]noradrenaline from rat cortical and hippocampal synaptosomes. Short-term (4 days), but not acute, treatment with pilocarpine caused a small but statistically significant increase in the inhibitory effect of the alpha2-adrenoceptor agonist clonidine on the firing rate of locus coeruleus neurones, with a decrease in the ED50 of 290% (P<0.001). However, no change in the effect of clonidine on the locus coeruleus was observed after longer pilocarpine (11 days) treatment. In the rat cerebral cortex, but not in hippocampus or hypothalamus, chronic (19 days) treatment with pilocarpine caused a decrease in the inhibitory effect of clonidine on tyrosine hydroxylase activity (55%, P<0.05), but did not change the stimulatory effect of the alpha2-adrenoceptor antagonist idazoxan. Moreover, treatments (4, 11 and 19 days) with pilocarpine did not alter the inhibitory effect of clonidine [10(-8)-10(-5) M] on the K(+)-evoked release of [3H]noradrenaline from rat cortical and hippocampal synaptosomes. These results indicate that administration of pilocarpine slightly potentiates some but not all the functional responses mediated by brain presynaptic alpha2-adrenoceptors. In conclusion, these results do not support the hypothesis that chronic treatments with pilocarpine lead to a suitable model of alpha2-adrenoceptor supersensitivity.

Chronic repetitive transcranial magnetic stimulation alters β-adrenergic and 5-HT 2 receptor characteristics in rat brain

Repetitive transcranial magnetic stimulation (rTMS) has been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for low- and high-frequency rTMS treatment. In animal behavioral models of depression magnetic stimulation of the brain induced similar effects to those of electroconvulsive shock (ECS). In this study the effects of repeated rTMS on rat brain noradrenaline, dopamine, serotonin and their metabolites levels, as well as on β-adrenergic and 5-HT 2 receptor characteristics were studied. After 10 days of treatment, β-adrenergic receptors were significantly up regulated in the frontal cortex, down regulated in the striatum and were unchanged in the hippocampus. 5-HT 2 receptors were down regulated in the frontal cortex and were not changed in the other brain areas. No change in benzodiazepine receptors in the frontal cortex and cerebellum were demonstrated. These findings demonstrate specific and selective alterations induced by repeated rTMS, which are distinct from those induced by other antidepressant treatments. TMS therapeutic effects in humans and behavioral and biochemical effects in animal, suggest that TMS has a unique mechanism of action which requires further investigation.

Emotional stress and characteristics of brain noradrenaline release in the rat.

We have investigated several characteristics of the rat brain noradrenaline (NA) release caused by various stressful situations. Stresses such as immobilization or electric foot shock, wherein the physical factors rather than emotional ones were greatly involved, caused more marked increases in NA release in the more extended brain regions, as compared to psychological stress and conditioned fear, which caused increases in NA release preferentially in the hypothalamus, amygdala and locus coeruleus (LC) region. When the electric shock stress and psychological stress for 1 hr daily were repeated for 5 consecutive days, increases in brain NA release induced by electric shock were rapidly reduced, but those caused by psychological stress were enhanced rather than reduced. Rats with no stressor controllability (uncontrollable) had more severe gastric lesions and more marked increases in NA release in such brain regions as the hypothalamus and amygdala after 21 hrs of training than controllable rats. Rats with no opportunity to predict electric shock exhibited more severe gastric lesions and more marked increases in hypothalamic NA release than the predictable rats. The rats not allowed to express their aggression had more severe gastric mucosal lesions and a more noticeable and persistent increases in extracellular NA content in the amygdala determined by intracerebral microdialysis than the rats allowed to express aggression by biting a wooden stick in front of them during stress exposure. In aged rats (12 months old), recovery from increases in NA release in the hypothalamus and amygdala and increases in plasma corticosterone were much later than in young (2-month-old) rats. When rats were exposed to a series of six 15-min stress interrupted by 18-min non-stress periods for 180 min, they had much greater increases in brain NA release than rats stressed continuously for 180 min. Based upon these findings, we suggest that such stresses might be harmful to our health as psychological, uncontrollable and unpredictable stresses, stress unable to express aggression, stress in elderly people, and stress with lack of suitable rest.

Effects of sodium fluoride on locomotor behavior and a few biochemical parameters in rats

Spontaneous motor activity and motor coordination were tested in adult female rats after treating with sodium fluoride at 20 or 40 mg/kg dose level daily for 60 days, using an activity chamber and a rota-rod apparatus, respectively. Total protein concentrations were determined in skeletal muscle, liver and serum of similarly treated animals. The activities of total cholinesterase and acetylcholinesterase were determined in blood and brain regions, respectively. Sodium fluoride treatment suppressed spontaneous motor activity. But no change was observed in the motor coordination of these animals. Tissue and serum protein concentrations were decreased. Cholinesterase activity was decreased in the blood and not in brain regions. A failure of sodium fluoride to impair motor coordination indicated that neuromuscular function required for a forced task was not deteriorated in these animals, although skeletal muscles were deprived of protein and blood cholinesterase activity was suppressed. A suppression of spontaneous motor activity suggests that fluoride has, by a central action, inhibited motivation of these animals to exhibit locomotor behavior. A cholinergic mechanism through a change in the activity of acetylcholinesterase may not account for this effect, since sodium fluoride treatment did not alter the activity this enzyme in brain regions. However, an involvement of monoamines may be proposed in view of previously reported finding that excessive fluoride intake has decreased the concentrations of 5-hydroxyindoleacetic acid and increased that of norepinephrine in rat brain.

An affinity-modulating site on neuronal monoamine transport proteins.

The dissociation rates of [3H]nisoxetine, [3H]GBR 12935 and [3H]citalopram from, respectively, the rat brain noradrenaline, dopamine and 5-HT transporters were found to be markedly affected by several drugs. Sertraline strongly attenuated the rate of dissociation of [3H]nisoxetine from the noradrenaline transporter, while citalopram strongly attenuated that of [3H]citalopram from the 5-HT transporter. The effect of both drugs were stereospecific. Less potent affinity-modulating drugs were identified with regards to [3H]GBR 12935 dissociation from the dopamine transporter. All three neuronal monoamine transporters may thus have specific affinity-modulating sites which change the function of the transporters with possible implication for the reuptake of monoamines released during synaptic activity.

Acute and chronic effects of fluoxetine and haloperidol on mouse brain serotonin and norepinephrine turnover

Evidence from clinical studies suggests that the noradrenergic system may play a role in the pathophysiology of antidepressant- and neuroleptic-induced akathisia. In limited previous neurochemical research, acute treatment with selective serotonin reuptake inhibitors (SSRIs) has been reported to increase rat brain norepinephrine (NE) turnover or release We have examined the neurochemical effects of 2 hr, 4 day, and 20 day treatment with the SSRI fluoxetine, and the neuroleptic haloperidol, on regional brain monoamine metabolism. Short and long-term fluoxetine treatment produced substantial decreases (to 65–79% of control) in serotonin (5HT) turnover However no effects of fluoxetine on mouse brain NE turnover - as assessed by forebrain, hypothalamus, and hindbrain 3-methoxy-4-hydroxvphenylglycol (MHPG) levels or MHPG/NE ratios - were observed. Acute (2 hr) fluoxetine also did not alter regional NE turnover in rat brain. In contrast, haloperidol tended to increase MHPG levels and MHPG/NE ratios in the mouse brain regions studied The persistence of decreased 5HT turnover during fluoxetine treatment, the lack of an effect of fluoxetine on NE turnover, and the increased NE turnover seen after haloperidol may have important implications regarding drug responsivity and the mechanism of akathisia induction

Differential changes in rat brain noradrenaline turnover produced by continuous and intermittent restraint stress

This experiment was performed to investigate differential effects of continuous and intermittent restraint stress on noradrenaline (NA) turnover in brain regions of male Wistar rats by measuring levels of a major metabolite of NA, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4) levels, as well as by measuring levels of plasma corticosterone and organ weights of the thymus, spleen, and adrenal glands. Rats in the 15-min and 30-min intermittently stressed groups showed significantly larger increases in MHPG-SO 4 levels in most brain regions relative to those in the 90-min and 180-min continuously stressed groups, even though the total stress duration was equal or shorter. Body weight loss and loss of relative thymus weight in the 15-min intermittently stressed groups were the most marked among the five treatment groups. These findings suggest that stress-rest cyclicity is critical in determining the extent of stress-induced brain NA turnover and peripheral physiological responses.

Focal traumatic brain injury causes widespread reductions in rat brain norepinephrine turnover from 6 to 24 h

The effect of right sensorimotor traumatic brain injury (TBI) in male Sprague-Dawley rats on brain norepinephrine (NE) turnover was assessed by measuring the decline of endogenous NE levels following tyrosine hydroxylase inhibition produced with α-methyl-p-tyrosine. Right sensorimotor cortex contusions were produced by a pneumatically driven piston which depressed the dural surface by 2 mm at 3.2 m/s. TBI rats were compared to uninjured, anesthetized controls at 6 h and 24 h after surgery. While NE turnover was not affected at the lesion site at 6 h after TBI, it was either abolished or decreased by 33–75% bilaterally in the hypothalamus and in the cerebral cortex surrounding and rostral to the lesion site. In the cortex caudal to the lesion site, NE turnover was completely abolished. NE turnover in cerebral cortex opposite the lesion site and in the contralateral cerebellum was decreased by 51 and 43%, respectively, at 6 h. At 24 h, NE turnover was either abolished or decreased bilaterally by 45–92% in all cortical areas, in the hypothalamus, cerebellum, locus coeruleus and medulla. Thus, right sensorimotor cortex contusion causes a marked, early and widespread depression of brain NE turnover. Since amphetamine increases NE turnover, this may explain the dramatic improvement in behavioral deficits which occurs following amphatamine administration at 24 h after such lesions.

Increasedα 2-adrenoceptor mediated regulation of adult rat brain noradrenaline overflow after chronic neonatal exposure to propranolol; a microdialysis study

Direct and persistent effects of chronic neonatal administration of the β-adrenoceptor antagonist propranolol on brain noradrenergic activity were investigated by measuring tissue concentrations of noradrenaline and its metabolites and in vivo overflow of noradrenaline during adulthood. Rat pups were chronically treated with propranolol from postnatal day 1 to day 10. Determination of monoamine metabolism after the last injection showed an increase in noradrenaline metabolism in frontal cortex, limbic system and hippocampus of propranolol-exposed rats, but 47 days after this last injection it was apparent that these effects were not long-lasting. Moreover, basal noradrenaline overflow in vivo in the hippocampus of 40–55 day-old propranolol-exposed rats did not differ from that in controls. However, the regulation of noradrenaline release seemed to have been altered, since a pharmacological challenge with theα 2-adrenoceptor antagonist idazoxan induced an enhanced increase in the in vivo noradrenaline overflow in propranolol-exposed rats compared to controls. It is suggested that the neonatal β-blockade induced a supersensitivity of the presynapticα 2-adrenoceptor. The precise mechanism underlying this effect has to be elucidated.

A CRF antagonist attenuates stress-induced increases in NA turnover in extended brain regions in rats

We investigated the effects of intracerebroventricular (i.c.v.) administration of a corticotropin-releasing factor (CRF) antagonist, α-helical CRF 9–41 (ahCRF), on increases in noradrenaline (NA) turnover caused by immobilization stress in rat brain regions. Pretreatment with ahCRF (50 or 100 μg) significantly attenuated increases in levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO 4), the major metabolite of NA in rat brain, in the locus coeruleus (LC) region, and attenuated the MHPG-SO 4/NA ratio after immobilization stress for 50 min in the cerebral cortex, hippocampus, amygdala, midbrain and hypothalamus. However, stress-induced increases in plasma corticosterone levels were not decreased significantly by pretreatment with ahCRF. These results suggest that CRF, released during stress, causes increases in NA release in extended brain regions of stressed rats.

Effects of repeated administration of desipramine or electroconvulsive shock on norepinephrine uptakes sites measured by [ 3H]nisoxetine autoradiography

To determine if repeated administration of desipramine (DMI) or electroconvulsive shock (ECS) regulate uptake sites for norepinephrine (NE) in rat brain, the binding of [ 3H]nisoxetine ([ 3H]NIS) was measured using quantitative autoradiography. Groups of animals were given DMI intraperitoneally, either a single injection or repeated doses of 10 mg/kg once daily for 21 days and were killed 48 h after the last injection. Another group of rats received ECS daily for 12 days (150 mA, 300 ms, 60 Hz) and was killed 24 h after the last shock. Repeated administration of DMI caused statistically significant decreases (20–40%) in the binding of [ 3H]NIS in 8 out of 17 brain regions measured; these areas included the hippocampus, thalamus and the amygdala. Acute treatment with DMI had no effect on the binding of [ 3H]NIS in any of the regions analyzed except the centrolateral nucleus of the amygdala. By contrast, except for the paraventricular nucleus of the thalamus where ECS caused a modest (20%) increase in binding, no other brain region was affected by ECS. Thus it appears that repeated administration of DMI and chronic ECS treatment have different effects on the binding of [ 3H]NIS to uptake sites for NE in rat brain.

Anxiogenic β-carboline FG 7142 produces activation of noradrenergic neurons in specific brain regions of rats

By measuring the levels of two major metabolites of rat brain noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), we investigated the effects of anxiogenic β-carboline FG 7142, an inverse agonist of benzodiazepine (BZD) receptors, on brain noradrenergic activity of rats. Thirty min after treatment with FG 7142 (15 mg/kg, IP), levels of both MHPG and DHPG in the hypothalamus, amygdala and thalamus, but not in the hippocampus and cerebral cortex, significantly increased. These increases were significantly antagonized by pretreatment with BZD receptor antagonist Ro 15-1788 (15 mg/kg, IP). Sixty min after treatment with FG 7142 at the same dose, significant increases in both metabolite levels occured in the hypothalamus, amygdala, thalamus and cerebral cortex, and increases in MHPG levels only were observed in the hippocampus. These increases were significantly blocked by pretreatment with α 2-adrenoceptor agonist clonidine (100 μg/kg, IP). The present findings suggest that FG 7142 can produce increases in brain noradrenergic activity in specific brain regions by interacting with BZD receptors, and may support the hypothesis that hyperactivity of brain noradrenergic systems may be one neural mechanism in provocation of aversive emotional changes (anxiety, fear or panic).

Methylphenidate and pemoline do not cause depletion of rat brain monoamine markers similar to that observed with methamphetamine

Methyl-phenidate (Ritalin) and pemoline (Cylert) are central nervous system stimulants which are widely prescribed for attention deficit and other psychiatric disorders. Several other related stimulants, including amphetamine and methamphetamine, have been shown to cause long lasting decreases in monoamine markers in rat brain, characteristic of axonal degeneration. To assess the neurotoxic potential of methylphenidate and pemoline, we compared the effects of multiple injections (sc, bid for up to 4 days) of methylphenidate (21 and 50 mg/kg) and pemoline (20 and 70 mg/kg) with methamphetamine (5 and 15 mg/kg) on rat brain norepinephrine, dopamine, and serotonin levels and transport sites. While decreases were observed in all brain monoamine markers measured in rats treated with methamphetamine, no changes were observed in animals treated with methylphenidate as compared to saline-treated controls. Pemoline failed to induce significant changes in the level of monoamine transport sites; however, a wide array of changes were observed in the levels of 5-hydroxyindoleacetic acid, dopamine, and norepinephrine in various brain areas after a 3-day treatment regimen with a high dose (70 mg/kg) of pemoline. The lack of changes in monoamine transport sites following the repeated administration of high doses of methylphenidate and pemoline suggests that these drugs do not affect axonal integrity. However, the pattern of changes observed in the levels of monoamines after pemoline treatment may have relevance to the self-injurious behavior seen in these animals.

Effects of CI-926 (3-[4-[4-(3-Methylphenyl)-l-Piperazinyl] Butyl]-2,-4-Imidazolidinedione), an Antihypertensive Agent, on Rat Brain Catecholamine and Serotonin Turnover

The effects of the antihypertensive drug CI-926 on rat brain norepinephrine (NE), dopamine (DA), and serotonin (5-HT) turnover and its in vitro affinity for several receptors were investigated. CI-926 (3-30 mg/kg intraperitoneally, i.p.) caused a dose-dependent increase in the rate of brain stem NE synthesis and increased the decline in NE after inhibition of its synthesis by alpha-methyl-p-tyrosine. These findings indicated that CI-926 increased brain NE turnover, probably as a compensatory response to central adrenoceptor blockade based on its nanomolar affinity for alpha 1-adrenoceptors and micromolar affinity for alpha 2-adrenoceptors. CI-926 also increased the rate of DA synthesis and DA metabolite levels; this indicates an increase in DA turnover. The latter effect of CI-926 is attributed to a compensatory response to DA-2 receptor blockade because no affinity for DA-1 relative to DA-2 receptors was found and the effect was antagonized by the DA agonist pergolide. CI-926 decreased brain 5-HT turnover, as indicated by reduced concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid and a reduced rate of 5-HT synthesis, effects characteristic of centrally acting 5-HT agonists. Based on its affinity for 5-HT-1A receptors versus 5-HT-1B and 5-HT-2, the decrease in 5-HT synthesis and release is interpreted as evidence of 5-HT-1A receptor activation. These findings indicate that besides peripheral alpha 1-adrenergic blockade, an interference of CI-926 with central adrenergic and serotoninergic neurotransmission may contribute in part to an explanation of its antihypertensive properties.

Stressor predictability and rat brain noradrenaline metabolism

This study examined the effects of stressor predictability on regional rat brain noradrenaline (NA) turnover, by measuring levels of a principal metabolite of NA (3-methoxy-4-hydroxyphenylenhyleneglycol sulfate, MHPG-SO 4). Male Wistar rats were exposed to one of three shock conditions for 19 hr: nonshock, signalled, and unsignalled shocks. Rats in the shock conditions received shock (1.2 mA intensity, 2 sec duration) on a 2.5 min variable time (VT) either preceded by a 12-sec, 10-W light signal (signal-shock interval of 10 sec) or not preceded by this signal. The tail electrodes for these rats were in series, so that the shock received by all rats was of exactly the same number and duration. After 19 hr in a VT-2.5 min shock session, the rats exposed to unsignalled shock (unpredictable group) showed significantly greater increases in MHPG-SO 4 levels in the hypothalamus, amygdala, midbrain, cerebral cortex, thalamus and locus coeruleus, as well as in plasma corticosterone levels. Rats exposed to signalled shock (predictable group) showed significant increases in MHPG-SO 4 levels in the first four of these regions, as compared to the nonshocked rats. Moreover, the unpredictably shocked rats exhibited greater elevations in MHPG-SO 4 levels in the hypothalamus, amygdala, and thalamus, as well as in plasma corticosterone levels, when compared to the predictably shocked rats. These results are consistent with previous reports showing that unsignalled shock induced extensive somatic effects in comparison to signalled shock. The present study suggests that the presence of a signal attenuates the extent of NA release in some brain regions resulting from irregular inescapable shock stress.

Nicotine-induced regional changes in brain noradrenaline and dopamine turnover in rats.

Using high performance liquid chromatography with electrochemical detection, the levels of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) were determined in various brain regions of the rat 1 h after nicotine administration. Nicotine (1 mg/kg, s.c.) produced an increase in MHPG concentrations in the occipital cortex, hippocampus, striatum, hypothalamus, thalamus, midbrain, pons/medulla and cerebellum. This alkaloid at the same dose also caused an increase in DOPAC concentrations in the hypothalamus, thalamus and pons/medulla. The nicotine-induced increase in MHPG and DOPAC concentrations in the brain regions was inhibited by pretreatment with mecamylamine (5 mg/kg, i.p.) but not by hexamethonium (10 mg/kg, i.p.). Nicotine (1 mg/kg, s.c.) produced an increase in DOPA concentrations under DOPA decarboxylase inhibition with NSD-1015 (200 mg/kg, i.p.) in the hypothalamus, thalamus and pons/medulla. These results indicate that nicotine can increase the turnover of noradrenaline and dopamine in various brain regions of the rat and this effect is mediated via activation of central nicotinic receptors.

O-093 - Effects of uncontrollability versus loss of shock control labi1ity on rat brain noradrenaline turnover.

O-093 - Effects of uncontrollability versus loss of shock control labi1ity on rat brain noradrenaline turnover.