Neurochemical and neurobehavioral effects of ganstigmine (CHF2819), a novel acetylcholinesterase inhibitor, in rat prefrontal cortex: an in vivo study.

Ganstigmine (CHF2819) is a novel, orally active acetylcholinesterase inhibitor that induces a stimulation of brain cholinergic transmission. In vivo studies show that, in rat prefrontal cortex, extracellular acetylcholine (ACh) concentrations are significantly increased either after local (1 and 10 microM) or oral (1.5 and 3 mg/kg) administration. Moreover, repeated oral treatment (six consecutive days; 3 mg/kg) with ganstigmine significantly increases basal extracellular concentrations of ACh in rat prefrontal cortex. Then, acute ganstigmine administration induces a significant increase in extracellular ACh concentrations (actual values) with respect to the last sample in ganstigmine-treated rats. Concentrations of serotonin (5-HT) and noradrenaline (NA) are not affected by any oral dose of ganstigmine (1.5 and 3 mg/kg) used. Moreover, levels of dopamine (DA) and metabolites are not modified either. Basal extracellular concentrations of 5-HT, NA, DA and metabolites are not affected by repeated (six consecutive days) ganstigmine treatment (3 mg/kg). Furthermore, there is no effect of the challenge dose of ganstigmine (3 mg/kg) on 5-HT, NA, DA and metabolites levels. Finally, ganstigmine reverses the scopolamine-induced deficits of habituation and non-spatial working memory in rats. Taken together, these findings suggest that ganstigmine appears to be a suitable candidate for the treatment of the cholinergic deficit in patients with Alzheimer's disease.     

Effects of chronic beta-blocker treatment on catecholamine levels in spontaneously hypertensive rats

In the present work the effects of a 55-day oral treatment with two beta-blocking agents (propranolol 40 mg/kg per day and S 2395 20 mg/kg per day) on the catecholamine (CA) content of central and peripheral structures were studied in spontaneously hypertensive rats (SHR). The concentrations of dopamine (DA), noradrenaline (NA) and adrenaline (A) in different structures dissected out from treated and control SHR were measured by a radioenzymatic method. At the peripheral level, no change in the concentration of NA (in the heart) or A (in the adrenal medulla) was observed. Propranolol increased the DA concentration in the C1 and C2 regions of the medulla oblongata and S 2395 increased the DA concentration only in the C2 region. In these two areas, the NA and A levels were unchanged. Both propranolol and S 2395 increased the DA, NA and A content in the locus coeruleus and in the anterior hypothalamus. On the contrary, there was no modification in the posterior hypothalamus. The anatomical specificity of these alterations of the CA levels suggests that they could be related to a specific action of beta-blockers on central catecholaminergic structures in SHR which might be linked to the antihypertensive effects of these drugs.     

Adrenal catecholamine concentration after chronic treatment with bromocriptine and haloperidol

Adrenal catecholamine concentration was measured by HPLC with electrochemical detection in male rats after ten days of bromocriptine and haloperidol (0.05,0.5 and 5.0 mg kg^?1) and vehicle (1.0 ml kg^?1) treatments subcutaneously. There were four rats in each group. The results indicate that bromocriptine treatment significantly increased dopamine (DA), noradrenaline (NA) and adrenaline (A) content in a dose-dependent manner. The NA/DA ratio was unchanged, but the A/NA ratio was significantly increased after treatments with two higher doses of the drug. Haloperidol treatment, on the other hand, had no significant effect on dopamine and a biphasic effect on adrenaline content. Noradrenaline concentration increased only after the lowest dose of the drug. There was no significant change in NA/DA or A/NA ratios in any group. The dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), was not detected in any adrenal gland.     

Immobilization stress modifies locomotor response to catecholamine receptor agonists in rats

The effects of dopaminergic (apomorphine, nomifensine, B-HT 920) and noradrenergic (methoxamine, clonidine, salbutamol) agonists on locomotor activity were investigated in rats submitted to acute (3 h) or repeated (3 h/4 days) immobilization stress. The stress-induced functional changes were monitored by the blood level of corticosterone and the number of lymphocytes as well as the brain utilization of NA and DA. The rats subjected to acute immobilization stress displayed 30 min later an enhanced locomotor activation after apomorphine, nomifensine, or methoxamine and reduced sedative effect of clonidine, salbutamol or B-HT 920. 24 h after the repeated stress only the locomotor responses to apomorphine, nomifensine, B-HT 920 and salbutamol were modified. Spontaneous locomotor activity was not significantly changed under the influence of stressful stimuli. Increased plasma corticosterone level, strong reduction of blood lymphocytes and enhanced NA and DA utilization in the brain of rats after acute stress, together with above mentioned results, suggest that short-lasting stress evokes (30 min later) significant functional changes not only in the blood but also in the brain: enhanced CA neurons activity as well as the increased alpha 1-adrenergic and DA-post-synaptic receptors responsiveness in parallel with reduced alpha 2 - and beta-adrenergic and DA-presynaptic receptors reactivity. On the other hand, 24 h after last session of repeated stress CA brain neurons activity was not changed, however DA and beta-adrenergic responsivity was farther modified. It is postulated that the stress conditions produce in NA and/or DA brain systems a state of readiness to locomotion activating stimuli.     

Effects of subchronic methamphetamine exposure on basal dopamine and stress-induced dopamine release in the nucleus accumbens shell of rats

Rationale Subchronic administration of stimulants reduces basal dopamine (DA) concentrations and blocks stress-induced DA release in the nucleus accumbens (NA) of rats during withdrawal. However, no studies have attempted to relate early withdrawal from chronic drug exposure to stress reactivity and changes in DA transmission. Objectives The effects of subchronic low-dose methamphetamine (METH) administration on regional changes in dopamine transporter (DAT) and norepinephrine transporter (NET) immunoreactivity and function during early withdrawal were examined. The effects of subchronic METH on stress responsivity measured by DA release in the nucleus accumbens shell (NA SHELL) and core (NA CORE) during acute restraint stress were also examined. Methods Male rats received single injections of METH (2.0 mg/kg i.p.) or saline (SAL) for 10 days and then were killed 24 h after the last injection. DAT and NET protein in NA, striatum (STR), medial prefrontal cortex (mPFC), and hippocampus were assayed by Western blot analysis. Experiment 2 measured basal extracellular DA concentrations and restraint-stress-induced DA release in vivo in the NA SHELL and CORE of SAL- and METH-pretreated rats after 24-h withdrawal. Experiment 3 examined the in vivo regulation of extracellular DA in the NA SHELL and/or CORE after local administration of GBR12909 (50 μM) or nisoxetine (100 μM; NA SHELL). Results Subchronic METH increased DAT but not NET immunoreactivity in the NA compared to the STR and mPFC. METH reduced basal extracellular DA and blocked restraint-stress-induced DA release in the NA SHELL. DA uptake blockade increased extracellular DA more in the NA SHELL of METH rats, whereas NE uptake blockade increased basal DA concentrations to a similar extent in METH and SAL rats. Conclusions These results suggest that subchronic METH exposure selectively increases NA DAT and consequently reduces basal and stress-induced DA release in the NA SHELL during early withdrawal.     

Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs

Changes in dopaminergic and serotonergic levels and metabolites in cerebral cortex, corpus striatum and hippocampus were investigated during the first 6-h of withdrawal in ethanol-dependent Wistar rats. Ethanol was given by a liquid diet for 21 days. The concentration of ethanol was 7.2% (v/v) for the last 15 days of the exposure. After 2, 4 and 6 h of ethanol withdrawal, and after audiogenic stimulus (100 dB for 60 s) at 6 h of ethanol withdrawal, various brain regions were assayed for levels of dopamine (DA), DOPAC, HVA, serotonin (5-HT) and 5-HIAA. Behavioral signs of ethanol withdrawal and blood ethanol levels were also evaluated in other parallel groups of ethanol-dependent rats. Significant decreases in 5-HT levels and significant increases in HVA levels in striatum were found during the first 6 h of ethanol withdrawal and after the audiogenic seizures. In hippocampus, 5-HIAA levels were significantly reduced after 2 h of ethanol withdrawal and after the audiogenic seizures. 5-HIAA levels significantly increased after 2 h of ethanol withdrawal in cerebral cortex. Significant increases in both DA and 5-HT levels were also found in cerebral cortex after the audiogenic seizures. The results suggest that the levels of DA, 5-HT and their metabolites are altered by ethanol withdrawal. Furthermore, this may suggest that DA and 5-HT may be involved in the first 6 h of ethanol withdrawal syndrome in rats.     

Brain catecholamines during ethanol administration, effect of naloxone on brain dopamine and norepinephrine responses to withdrawal from ethanol

The variations in brain dopamine (DA) and norepinephrine (NE) levels after ethanol administration have been studied in rats. Acute ethanol administration significantly decreased brain DA and NE levels. After chronic ethanol intake no changes were observed in brain catecholamines. Ethanol withdrawal induced significant decreases in DA and NE concentrations in the brain. The administration of naloxone, antagonist of opiate receptors, blocked the effects of ethanol deprivation on brain catecholamines. These data suggest that endogenous opioids may be involved in the ethanol-withdrawal syndrome.     

Effects of adrenergic beta-receptor blocking drugs on brain catecholamine concentrations in spontaneously hypertensive rats (SHR) (author's transl)

To acquire data on the mechanism of central effects of adrenergic beta-blockers as antihypertensive agents, experiments were done on spontaneously hypertensive rats (SHR). Each group included 5 animals. Propranolol (5 mg/kg), pindolol (0.3 mg/kg), alprenolol (5 mg/kg) or bupranolol (5 mg/kg) were given subcutaneously to the respective groups, once daily for 7 days, while the control group were given no treatment. All the rats were sacrificed 12 hours after the last injection, and the concentrations of the following materials were measured: noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the brain; NA in the heart muscle; adrenaline and NA in the adrenal glands. As compared with the control group, all rats on the beta-blockers showed an increase in NA concentration in the brain. Both pindolol and alprenolol, which have an intrinsic sympathomimetic action (ISA), increased DA concentrations in the brain. Both propranolol and bupranolol, which have no ISA, either decreased DA concentrations or showed no effect. No marked change was seen in 5-HT concentration in the brain and of NA in the heart muscle. Catecholamine concentrations in the adrenal glands showed a tendency toward decrease. These results suggest that the mechanism of antihypertensive effects of beta-blockers may be due to depression of the peripheral sympathetic activity, as induced by the central inhibitory effects of beta-blockers.     

Effects of MPP+ on catecholamine levels in adrenal glands and heart of rats

The effects of MPP⁺ (2.5–20 mg/kg) on the adrenal glands and heart were investigated in rats. At various periods after s.c. drug administration the rats were decapitated and tissue catecholamine levels were determined by means of HPLC with electrochemical detection. Adrenal dopamine (DA) levels were reduced at 2–8 h after MPP⁺ administration, but this decrease was followed by an elevation after 16 h and return to the control values after one week. Three successive injections of MPP⁺ caused a statistically significant elevation in adrenal DA, one day, with a tendency to elevation four and seven days after the last injection, whereas a severe (up to 96%) decrease in heart noradrenaline (NA) was found one day after the last injection. Seven days after the last injection a 50% depletion of NA in the heart was still observed. Pretreatment with GBR 12909 (30 mg/kg, 4 h) blocked the MPP⁺ (10 mg/kg, 2 h) induced reduction of adrenal DA levels, but at the same time GBR 12909 failed to block the effects of MPP⁺ in the heart. One day after three successive daily injections of MPP⁺ (10 mg/kg each), the DA-uptake inhibitor GBR 12909 (30 mg/kg, 6 h) could still induce an increase in adrenal DA.MPP⁺ appears to lack persistent cytotoxic action in the adrenal medulla but rather to cause a transient inhibition of DA synthesis followed by a compensatory stimulation. The inhibition can be blocked by specific inhibitor of the DA-uptake mechanism, suggesting a direct effect of MPP⁺ taken up by adrenomedullary cells. The data obtained so far do not suggest any involvement of peripheral dopaminergic nerves in the action of MPP⁺ on the adrenal medulla. The long-lasting depletion of the heart NA, however, suggests a lesion of peripheral noradrenergic nerves.Part of this work was presented at 6th International Symposium on Chromaffin Cell Biology, Marburg, Germany, 18–23 August 1991 Correspondence to: M. Kujacic at the above address     

Intercannabinoid and cannabinoid-ethanol interactions and their effects on human performance

After intracisternal 6-hydroxydopamine (6-OHDA) in mice, brain noradrenaline (NA) and dopamine (DA) are diminished, although the reduction of NA is more pronounced. Intracisternal injection of 6-OHDA in desmethylimipramine (DMI)-pretreated animals strengthens the depletion of DA while NA is partly protected. The concentration of 5-hydroxytryptamine (5-HT) is not influenced by 6-OHDA or 6-OHDA +DMI. Chronic morphine treatment to some extent enhances reduced NA and DA levels after 6-OHDA, but the decreased central catecholamine (CA) content after 6-OHDA+DMI is not raised. Morphine analgesia is highly attenuated in 6-OHDA and 6-OHDA +DMI mice. the reduction occurs in nontolerant as well as in tolerant animals. The acute effect of morphine on body temperature is abolished with 6-OHDA, but not with 6-OHDA+DMI, whereas the interaction of central CA in morphine-induced running shows distinctly marked reduction with 6-OHDA +DMI, but not with 6-OHDA. Acute toxicity is enhanced by 6-OHDA+DMI whereas the development of tolerance against the toxicity of morphine is diminished by 6-OHDA. Lack of CA in the brain decreases sensitivity against naloxone withdrawal in acute as well as in chronic experiments.     

The influence of thiamine deficiency and ethanol on rat brain catecholamines

In rats treated with a thiamine deficient diet for 30 days the brain content of total thiamine decreased by 27-50%. Thiamine deficiency decreased the dopamine (DA) concentration of the striatum indicating a reduced synthesis of DA. In the hypothalamus the levels of the catecholamine metabolites homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) were reduced indicating a reduced DA and noradrenaline (NA) turnover. Animals on a diet containing 5% ethanol had increased concentrations of HVA and HMPG in rest brain indicating an increased DA and NA turnover. The concentration of 1-carboxysalsolinol (1-CSAL) and salsolinol (SAL) in the brain stem was increased in animals receiving ethanol. Thus, both thiamine deficiency and ethanol treatment influenced the catecholamine system in a complex region-dependent way. In the brain regions most susceptible to brain damage in thiamine deficiency, i.e., hypothalamus and brain stem, 1-CSAL and SAL increased most following thiamine deficiency combined with ethanol intake.     

The action of single and repeated doses of p-bromo-methamphetamine on the monoamine content and turnover rate in rat brain

The effect of p-bromo-methamphetamine (pBrMA) on serotonergic and catecholaminergic neurones in the rat brain was studied. Acute (15 mg/kg, s.c.) and chronic (30 × 15 mg/kg, s.c.) administration of the drug caused a long-lasting decrease in serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) content of whole brain. In contrast the catecholamine (CA) levels remained unchanged. Detailed studies of the 5-HT and CA content of brain regions showed a time-dependent decrease in 5-HT after acute injection, and a marked and persistent reduction in 5-HT and 5-HIAA after chronic treatment. In both injection regimens the content of noradrenaline (NA) was enhanced in the cortex. The turnover rate of 5-HT, dopamine (DA) and NA was reduced after acute treatment. Repeated injections caused a decrease in 5-HT turnover, while that of NA remained unchanged. However, the turnover rate of DA was enhanced. The present data appears to confirm the previous suggestion that after chronic treatment, when the rats show improvement in their learning performances, the serotonergic tone of the brain is decreased while dopaminergic tone is increased.     

Alcohol intake and ethanol intoxication in the rat: Effect of a 6-OHDA-induced lesion of the ascending noradrenaline pathways

The ascending noradrenaline (NA) pathways were lesioned by injecting 6-hydroxydopamine (6-OHDA) 16 μg/ 4 μl bilaterally into the posterior mesencephalon in male Long Evans rats. Another group of rats was pretreated with protriptyline (25 mg/kg), a NA uptake blocking agent, 15 min before they received the intracerebral injections of 6-OHDA. The controls received the vehicle only. Spectrofluorimetric determination of the catecholamine concentrations in various parts of the brain revealed a marked degeneration of the ascending NA systems in the group receiving 6-OHDA. Unexpectedly, the DA systems were also affected by the 6-OHDA treatments. Three weeks after the operation the 6-OHDA group showed a transient increase in ethanol intake. In the tilting-plane test, ethanol (2 g/kg, i.p.) impaired the performance of the 6-OHDA-treated rats significantly more than that of the controls. In contrast, the hypothermic effect of ethanol (4 g/kg, i.p.) was significantly smaller in the lesioned rats. Furthermore, the catecholamine levels in various parts of the brain could be significantly correlated with both the extent of ethanol intoxication and the hypothermia. However, the duration of ethanol-induced narcosis (4 g/kg, i.p.) was not affected by the present treatments. These results give further support for the view that the central NA neurons are important in the control of ethanol intake, and that they are also involved in the expression of the acute effects of ethanol administration.     

Effects of chronic amphetamine intoxication on the accumulation in the rat brain of labelled catecholamines synthesized from circulating tyrosine-14C and dopa-3H

Summary Accumulation of labelled noradrenaline (NA) and dopamine (DA) and endogenous levels of NA and DA in brain and heart were measured after infusion of tyrosine-¹⁴C and dopa-³H in rats. After a single dose of 20 mg/kg i.p. of dl-amphetamine sulphate a 50–65% decrease in the NA accumulation in the brain and heart was observed. The accumulation of DA was not changed. In rats treated chronically with amphetamine sulphate, 16–32 mg/kg i.p. twice daily for 4 weeks, both the brain and heart NA and brain DA levels were depleted by 40–70% at 20–24 h after amphetamine withdrawal. The accumulation of labelled NA and DA in these animals was not different from that of saline treated controls. When amphetamine sulphate, 20 mg/kg i.p., was given to chronically amphetamine treated rats there was a 45–60% decrease in the accumulation of labelled NA; labelled DA remained unchanged. It is concluded that the decrease in NA accumulation under acute and chronic amphetamine intoxication is most likely due to a preferential release of newly synthesized NA.The skilful technical assistance of Mrs Inger Jansson is gratefully acknowledged. A sample of 3-methoxytyrosine was generously supplied by AB Hässle, Mölndal, Sweden. The study was supported by the Swedish Medical Research Council (Project B71-14X-1017-07 and B71-27P-2627-03) and the Tri-Centennial Fund of the Bank of Sweden (Project Nr. 150).     

Increased brain serotonergic and noradrenergic activity after repeated systemic administration of the beta-2 adrenoceptor agonist salbutamol,a putative antidepressant drug

Subchronic (5 mg/kg SC, twice daily for 14 days) but not acute administration of the beta-2-adrenoceptor agonist salbutamol to rats caused a significant increase in the accumulation of 5-hydroxytryptophan in the limbic forebrain, the corpus striatum and the cerebral cortex when measured during 30 min after inhibition of l-amino acid decarboxylase by NSD 1015 (100 mg/kg IP). Simultaneously assayed tryptophan concentrations in the same brain regions were not affected. These results indicate an increase in the in vivo rate of tryptophan hydroxylation in the brain, produced by subchronic salbutamol administration.The effect of salbutamol treatment on brain catecholamine (CA) utilization was estimated by studying the disappearance of CA in the brain after inhibition of tyrosine hydroxylase by alpha-methyltyrosine methyl ester (H 44/68) 250 mg/kg IP, 3.5 h before sacrifice. Subchronically but not acutely administered salbutamol caused both a significant increase in endogenous noradrenaline (NA) levels and an increased NA utilization. Dopamine levels and turnover were, however, not altered by either acute or subchronic treatment.The activation, probably centrally elicited, of brain NA and 5-hydroxytryptamine systems by the subchronic salbutamol regimen supports the concept of beta-adrenoceptor mediated regulation of brain monoamine systems, and could contribute to the clinically reported antidepressant activity of beta-2-adrenoceptor agonists.     

Influence of age on effects induced by intermittent ethanol treatment on the ethanol drinking pattern and related neurochemical changes in the rat

Male rats were treated with one ethanol (2.0 g/kg i.p.) or saline injections once a week for 50 weeks. During this treatment period the rats had in addition access to ethanol (10% in drinking fluid) as a choice against water for 24 h prior to the injection. During the following evaluation period, animals had a continuous choice between ethanol and water and the concentration of the ethanol solution increased every 3rd week from 5 to 10, 15 and 25%, with 10% as a reference tested between the other concentrations. The animals were killed after an abstinence of 4 weeks, whereupon the concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) were determined in the frontal cortex. In the remaining cerebral cortex, activity of monoamine oxidase, reuptake of NA and stimulated inositol phospholipid (PI) breakdown was also determined. Muscarinic binding sites were determined in the striatum. During treatment, saline injected rats had a constant voluntary 24 h ethanol intake. There was a decrease in the corresponding intake in the animals given the ethanol injections. The diminishing of the intake was more marked in rats starting treatment at an age of 19.4 weeks when compared to rats starting at an age of 5.4 weeks. In the evaluation period the ethanol intake was fairly constant for all groups. However, the regressions between intake of the reference concentration when plotted against the different tested concentrations were most marked in the group where ethanol injections started at an early age. In the total material there were significant F-values when concentrations of NA, 5-HIAA, 5-HT/5-HIAA in the cortex and muscarinic binding sites in the striatum were tested. Age could not be excluded as a contributing factor, but for muscarinic binding sites in the striatum, concentrations of DA and 5-HIAA in the cortex, and potassium stimulated PI breakdown in the cortex significant regressions with voluntary ethanol intake as dependent variable could be established. Since these intakes are stable, a causal relation with dependence may be involved.     

Antiestrogen-induced alterations of hypothalamic dopamine and norepinephrine levels in the female rat

The influence of antiestrogen (tamoxifen) administration in vivo on the steady state concentration of dopamine (DA) and norepinephrine (NE) in the hypothalamus-median eminence area of mature female rats was investigated. Rats were treated with tamoxifen at 3 different dose levels (0.1, 1.0 and 10.0 mg/kg, s.c.) daily for 7 or 21 days. Control groups were injected with vehicle only (10% ethanol; 1.0 ml/kg). In a separate experiment, mature female rats were ovariectomized or sham operated and killed either 7 or 21 days after operation. Dopamine and NE were estimated by high pressure liquid chromatography with electro-chemical detection. Seven days of tamoxifen treatment at 3 different dose levels did not alter DA and NE concentrations compared to the control. The chronic (21 days) tamoxifen treatment in the smallest dose (0.1 mg) significantly increased the DA concentration. The concentration of NE was reduced only at the 1.0 mg/kg dose. There was no significant difference in the NE concentration 7 or 21 days after ovariectomy or sham operation, but the DA concentration was significantly increased 21 days after ovariectomy. The uterine weights were reduced significantly after 21 days of treatment with tamoxifen in the two larger doses, but were increased with the smallest dose of tamoxifen. Uterine weight after ovariectomy both after 7 and 21 days was significantly reduced. These results suggest that chronic low-dose antiestrogen treatment may affect the hypothalamic-median eminence DA and NE concentrations. The data also suggests that antiestrogenic action (uterine growth inhibition) of tamoxifen is not related to the alterations of DA and NE in the hypothalamus-median eminence.     

Catecholamine synthesis, storage and release in adrenal medulla and whole brain during acute and chronic methadone administration.

Methadone was administered daily to rats and the adrenals were analyzed for catecholamines (CA), tyrosine hydroxylase (TH) activity and dopamine β-hydroxylase (DBH) activity. Four hr after 2.5 mg/kg, CA and DBH were depleted significantly but recovered to normal by 24 hr. After 6 days of treatment, adrenal catecholamines were elevated above controls; 24 hr after increasing the dose to 10 mg/kg, CA and DBH again declined, and TH was elevated. Chronic administration of 10 or 25 mg/kg led to restoration or elevation of adrenal CA and marked increases in TH and DBH. While methadone increased the rate of formation of new adrenal storage vesicles, it also inhibited CA uptake into the vesicles, an effect which was also observed with methadone in vitro. Similarly, methadone in vitro inhibited amine uptake into crude whole brain synaptosomes, but the effect was not observed after acute or chronic administration in vivo. These data suggest that methadone, like morphine, stimulates the sympatho-adrenal axis, but that unlike morphine, methadone exerts a direct effect on adrenal storage vesicles.     

The role of alpha1- and alpha2-adrenoreceptors on venlafaxine-induced elevation of extracellular serotonin, noradrenaline and dopamine levels in the rat prefrontal cortex and hippocampus

The role of adrenergic alpha1- and alpha2-adrenoreceptors in augmentation of venlafaxine-induced elevation of extracellular serotonin (5-HT),noradrenaline (NA) and dopamine (DA) levels in the rat prefrontal cortex (PFC) and hippocampus (HIPP) was studied by in vivo microdialysis in anaesthetized rats. The alpha1-adrenoreceptor antagonist prazosin given alone (0.3 mg/kg, s.c.) induced only a moderate reduction of hippocampal 5-HT and NA levels. The alpha2-adrenoreceptor antagonist idazoxan (1.5 mg/kg, s.c.) causes moderate increases in the levels of 5-HT and DA in the PFC. The mixed 5-HT and NA reuptake inhibitor venlafaxine (10 mg/kg, i.p.) increased the efflux of 5-HT, NA and DA almost equally, to approximately 200% of the control levels in the PFC. The levels of 5-HT increased to 310%, an effect approximately twice the effect on NA in the HIPP. Venlafaxine also produced a moderate increase in DA levels in the PFC but had no effect in the HIPP. Pre-treatment with prazosin caused a significant attenuation of the venlafaxine induced 5-HT effect in the PFC, and a moderate increase in DA levels in the HIPP. Prazosin had no significant effect on the venlafaxine-induced increase of the NA levels in PFC or HIPP. A combined treatment of venlafaxine with idazoxan increased the venlafaxine NA and DA effects in PFC by a factor of two and resulted in a very robust five-fold augmentation of NA and DA concentrations in the HIPP. In summary, idazoxan was found to produce a potent enhancement of the venlafaxine effect to increase extracellular NA and DA levels in the PFC and, in particular, in the HIPP. Idazoxan had no effect on venlafaxine-induced elevation of extracellular 5-HT levels in either PFC or HIPP and prazosin induced a decrease of 5-HT in the PFC. The present data suggest that blockade of alpha2-adrenoreceptors may play an important role in augmentation of the effects of mixed monoamine reuptake inhibitors.     

Effects of morphine on the rat adrenal medulla.

Morphine was administered twice daily to rats and the adrenals were analyzed for catecholamines(CA), tyrosine hydroxylase (TH) activity and dopamine β-hydroxylase (DBH) activity. Twenty-four hr after dosage with 10 mg/kg. CA were reduced and TH and DBH were slightly elevated. After 1 week of treatment, all three were elevated. Subsequent dose increments resulted in acute decreases in CA and DBH and increases in TH. followed by dose-dependent increases in CA, DBH and TH to a maximum of two to three times control levels after 2 weeks at 100 mg/kg. Withdrawal led to a decline to control levels within 10 days. Shifts in the subcellular distribution of DBH suggested that morphine administration increased the rate of vesicle synthesis, and measurements of the uptakes of [¹⁴C]epinephrine and [³H]metaraminol into isolated storage vesicles indicated an increased proportion of “immature” vesicles. Prolonged administration of large doses of morphine led to the formation of vesicles with an apparently defective amine uptake mechanism; these vesicles also displayed abnormally low fragility and a reduced rate of spontaneous CA efflux. These data suggest that: (1) tolerance to morphine-induced sympathoadrenal discharge does not develop and that the recovery from the acute CA depletion results from increased CA synthesis and storage: and (2) morphine produces a persistent change in the properties of adrenal medullary storage vesicles.