Long term treatment with desipramine increases the turnover of alpha 2-adrenoceptors in the rat brain.

The aim of this study was to quantitate the turnover of alpha 2-adrenoceptors in different regions of the rat brain and its modulation during desipramine (a cyclic antidepressant drug)-induced receptor down-regulation. The recovery of [3H]clonidine (a mixed alpha 2A/B-adrenoceptor agonist) binding after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (an alkylating agent for both alpha 2-adrenoceptor subtypes) was assessed in control and desipramine-treated (3 mg/kg, intraperitoneally, every 12 hr for 7-35 days) rats to study the process of alpha 2-adrenoceptor repopulation and to calculate receptor turnover parameters. In control rats, the turnover of brain alpha 2-adrenoceptors showed marked regional differences. The fastest receptor turnover rate was found in the hypothalamus and corpus striatum (receptor half-life, t1/2 = 2.1 days), compared with that in the brainstem (t1/2 = 2.6 days), cerebral cortex (t1/2 = 3.9 days), and hippocampus (t1/2 = 4.3 days). In the cerebral cortex and other brain regions, desipramine induced a time-dependent modulation of alpha 2-adrenoceptors, with significant decreases in the number of receptors (40-71%; p < 0.01) during the first 7-14 days of treatment and regulation to base-line values by 21-35 days. In the cerebral cortex, alpha 2-adrenoceptor turnover evaluated during desipramine-induced receptor down-regulation (phase of 7-14 days of treatment) revealed an increase in both the disappearance (degradation) (delta k = 122%; p < 0.05; t1/2 = 1.7 days) and appearance (synthesis) (delta r = 68%; p < 0.05) rates of the receptor. In other noradrenergic brain regions (hippocampus, brainstem, and hypothalamus) but not in the corpus striatum, desipramine (7-14 days) also increased alpha 2-adrenoceptor degradation (delta k = 97-144%) and shortened the half-life of the receptor, and it tended to increase the rate of synthesis (delta r = 51-83%). Similar results, but with a higher appearance rate, were obtained in the cerebral cortex during the phase of treatment (21-35 days) without apparent receptor down-regulation (delta k = 160%; p < 0.01; t1/2 = 1.5 days; delta r = 128%; p < 0.001). It is proposed that sustained stimulation of alpha 2-adrenoceptors by endogenous norepinephrine, after inhibition of neuronal uptake, increases their disappearance rate (degradation), leading to a reduction in receptor number. The increase in the appearance (synthesis) rate could be viewed as a later compensatory mechanism that would lead to restoration of brain alpha 2-adrenoceptor density.     

Repeated treatment with clenbuterol produces desensitization of rat brain beta- and alpha 2-adrenoceptors without changes of alpha 1-adrenoceptors

The effects of single and repeated administrations of the beta-agonist, clenbuterol (0.5 mg/kg i.p., twice daily for 4 or 7 days) were measured in the open-field test as responsiveness of rats to beta- (clenbuterol), alpha 2-(clonidine) and alpha 1-(phenylephrine) adrenergic stimulation. Furthermore, the effects of such treatment on beta- and beta 1-adrenoceptor binding in the rat brain cortex were studied. Repeated administration of clenbuterol failed to change the exploratory activity, in contrast to the acute sedative effect. Repeated treatment with clenbuterol resulted in a decrease in [3H]dihydroalprenolol binding to cortical beta-adrenoceptors. A single dose of clenbuterol reduced the clonidine-induced sedation and repeated treatment of clenbuterol abolished this sedation. Clenbuterol did not affect the action of phenylephrine nor did it change the binding of [3H]prazosin. These results indicate that repeated administration of a beta-agonist produces a rapid appearance of beta- and alpha 2-adrenoceptor subsensitivity, which it not followed by alpha 1-adrenoceptor changes.     

Chronic antidepressant treatment enhances agonist affinity of brain alpha 1-adrenoceptors

Binding of [3H]prazosin, a selective alpha 1-adrenoceptor antagonist, to thalamic membranes was studied following chronic treatment of rats with tricyclic antidepressants. Rosenthal analysis showed no change in the number or affinity of antagonist binding sites; however, the ability of the alpha 1-agonist phenylephrine to compete for these sites was significantly enhanced after chronic tricyclic treatment. This result is consistent with previous studies showing physiological alpha 1-supersensitivity in thalamus after chronic antidepressant administration.     

Dopamine-induced up-regulation of alpha 2-adrenoceptors in crude synaptic membranes of rat brain

After cerebral cortical membranes were incubated with 0.1-100 microM of dopamine (DA) in 50 mM Tris-HCl buffer (pH 7.7) at 37 degrees C for 30 min, [3H] clonidine binding to alpha 2-receptors was increased in a concentration-dependent manner without changing [3H] WB4101 and [3H] DHA binding to alpha 1- and beta-receptors, respectively. Scatchard analysis of [3H] clonidine binding to cortical membranes showed that DA increased the Bmax in both high- and low-affinity components. The increasing effect of DA on [3H] clonidine was dependent on incubation time and temperature, and it was antagonized by pimozide and cis-flupenthixol. The addition of GTP produced a reduction in DA-induced elevation in [3H] clonidine binding, while that of cyclic AMP did not affect the effect of DA. DA and Mn2+, though both of them increased [3H] clonidine binding, appeared to act at a different site in the membrane. Furthermore, the DA-induced increase in [3H] clonidine was found uniformly in membranes prepared from 7 other regions of the rat brain. These results suggested that DA regulates specifically alpha 2-receptor density by stimulating D1-receptors and/or via other mechanism(s).     

The cholinesterase inhibitor soman increases inositol trisphosphate in rat brain

Studies were conducted to determine the effect of the cholinesterase inhibitor soman on the amount of inositol trisphosphate in the neocortex, striatum, cerebellum, and medulla-pons regions of rat brain in vivo. The studies indicate that treatment with soman increases inositol trisphosphate in the neocortex and striatum, but not in the cerebellum or medulla-pons region. In the neocortex the most pronounced increases were observed in animals with severe poisoning symptoms, however inositol trisphosphate was also found to be elevated in animals with only mild poisoning symptoms.     

Effects of muscarinic receptor agonists and antagonists on alpha 2-adrenoceptors in rat brain

The specific binding of [3H]clonidine to alpha 2-adrenoceptors on neural membranes isolated from six brain areas was determined with rats treated for various periods of time with the muscarinic agonists, oxotremorine or pilocarpine, or with the muscarinic antagonists atropine, atropine methyl nitrate, scopolamine and scopolamine methyl bromide. Administration of pilocarpine, 10 mg/kg, twice daily i.p. for 1 and 14 days increased markedly the number of alpha 2-adrenoceptors on neural membranes from all six brain areas. In contrast, oxotremorine, 0.3 mg/kg, twice daily i.p., for 7 days decreased the number of alpha 2-adrenoceptors on membranes from all brain areas except the brainstem and caudate nucleus. Both atropine and scopolamine increased the density of alpha 2-adrenoceptors in specific brain areas. Neither atropine methyl nitrate nor scopolamine methyl bromide had an appreciable effect upon the specific binding of [3H]clonidine to neural membranes from most brain areas.     

Effect of long-term rolipram administration on the sensitivity of alpha 2-adrenoceptors in rat brain

The effects of single and chronic doses of rolipram on the sensitivity of alpha 2-adrenoceptors have been compared with the phosphodiesterase inhibitors, isobutylmethylxanthine (IBMX) and ICI 63,197, and the antidepressant, desipramine. While pretreatment with a single dose of rolipram, ICI 63,197 or IBMX administered either 1 or 24 h prior to clonidine (0.1 mg/kg) enhanced clonidine-induced hypothermia and hypoactivity, chronic dosing (twice daily for 14 days) with desipramine (10 mg/kg) or rolipram (5 mg/kg) antagonized these behavioural effects. In contrast, chronic dosing with IBMX or ICI 63,197 failed to antagonize clonidine-induced hypothermia and hypoactivity. In binding studies neither ICI 63,197, IBMX, rolipram nor desipramine induced changes in the binding of 3H-labelled clonidine to rat cerebral cortical membranes following chronic administration. The failure of ICI 63,107 and IBMX to antagonize clonidine-induced hypothermia and hypoactivity suggests that the antidepressant effect of rolipram is independent of its phosphodiesterase inhibitor property.     

Desensitization of alpha(2)-adrenoceptors which regulate noradrenaline synthesis and release after chronic treatment with clorgyline in the rat brain

We wanted to determine whether oxygen radicals open the mitochondrial ATP-dependent potassium channels (K(ATP)) during an ischemic period to reduce cell death and oxidant stress. Chick embryonic cardiomyocytes were used. Cell viability was quantified with propidium iodide (5 microM), and free radicals was measured using 2',7'-dichlorofluorescein diacetate. Preconditioning was produced by 10 min of simulated ischemia followed by 10 min of reoxygenation. Acetylcholine (1 mM), infused for 10 min instead of preconditioning, reduced cell death similarly (24 +/- 5%, n = 7 and 18 +/- 2%, n = 7, respectively, vs. controls, 49 +/- 6%, n = 8). In control series, 60 min of simulated ischemia and 3 h of reoxygenation generated free radicals more than 300% above the baseline (ischemia: 3.63 +/- 0.58, reoxygenation: 3.66 +/- 0.47, n = 8). Preconditioning and acetylcholine markedly attenuated the oxidant stress during simulated ischemia (1.18 +/- 0.41, n = 6 and 1.34 +/- 0.60, n = 7 vs. controls 3.63 +/- 0.58, n = 8) and re-oxygenation (1.23 +/- 0.36, n = 6 and 1.50 +/- 0.59, n = 7 vs. controls 3.66 +/- 0.47, n = 8). The protection of acetylcholine was abolished with pretreatment with the antioxidant thiol reductant 2-mercaptopropionyl glycine and posttreatment with 5-hydroxydecanoate, a selective mitochondrial K(ATP) channel antagonist (37 +/- 7%, n = 7). These results demonstrate that oxygen radicals open mitochondrial K(ATP) channels, which mediates the acetylcholine-induced preconditioning effect, and that stimulation of this signaling pathway attenuates oxidant stress.     

Comparison of alpha 1-adrenoceptors between rat brain and spleen.

Scatchard analyses of 3H-prazosin binding in rat brain membranes showed biphasic curves, which identified the presence of alpha 1High- and alpha 1Low-affinity sites. The alpha 1High-affinity site was completely inhibited by 0.1 microM phenoxybenzamine. On the other hand, 3H-prazosin binding in rat spleen membranes resulted in linear curves that were identical to the binding curve for the alpha 1High-affinity site in the brain. The displacement potencies of alpha 1-adrenergic antagonists were characterized by 3H-prazosin binding to alpha 1High-affinity sites in the rat spleen and brain and alpha 1Low-affinity sites in the brain in the presence of 0.1 microM of phenoxybenzamine. The affinities of WB-4101, phenoxybenzamine, phentolamine, chlorpromazine, labetalol and nifedipine for brain alpha 1High-affinity sites were significantly higher than those in the spleen. The affinities of most ligands for alpha 1Low-affinity sites were significantly lower than those for both alpha 1High-affinity sites in the brain and spleen, but chlorethylclonidine was significantly selective for alpha 1Low-affinity sites, and bunazosin, dibenamine and 5HT had the same affinities for the alpha 1Low- and both alpha 1High-affinity sites. These results show that two alpha 1-adrenoceptor subtypes, alpha 1High- and alpha 1Low-affinity, are present in the rat brain and that a different alpha 1High-subtype, exists in the rat spleen.     

A study of the sensitivity of rat brain alpha2-adrenoceptors during chronic antidepressant treatments

Summary Two experimental approaches were used to study the effect of chronic antidepressant treatments on the functioning of central alpha₂-adrenoceptors. In one, the effect of antidepressant treatment on the ability of a low dose of clonidine (25 g/kg) to lower rat brain 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO₄) levels was studied. In the other, potential treatment-induced alterations in rat frontal cortex ³H-clonidine binding were determined. The same cortical tissue was also studied in parallel for ³H-dihydroalprenolol binding.Of the tricyclics imipramine, amitriptyline and nortriptyline, only chronic imipramine (10 mg/kg b.i.d. for 14 days) attenuated the clonidine-induced reduction in brain MHPG-SO₄ levels. Repeated electroconvulsive shock therapy (100 mA for 1 s once daily for 10 days), but not chronically administered pargyline, also antagonized the neurochemical response to clonidine.The following long-term antidepressant treatments were investigated for their effect on rat frontal cortex ³H-clonidine and ³H-dihydroalprenolol binding: desipramine, imipramine, nortriptyline, amitriptyline, mianserin, iprindole, nisoxetine, pargyline and electroconvulsive shock therapy. Only chronic pargyline (25 mg/kg once daily for 14 days) altered cortical ³H-clonidine binding. Scatchard analysis revealed that the drug-induced decrease was due to a reduction in the number of recognition sites with no change in affinity. With the exceptions of mianserin and nisoxetine, all other seven forms of antidepressant treatment decreased cortical ³H-dihydroprenolol binding, Scatchard analysis revealing a diminution in the number of recognition sites.The results of this, and previous studies, indicate that under the dosage regimens employed only some forms of long-term antidepressant treatments induce a down-regulation in the functioning of rat brain presynaptic alpha₂-adrenoceptors, as assessed by the clonidine-MHPG-SO₄ model. No correlation was found between treatment-induced alterations in the characteristics of cortical ³H-clonidine recognition sites and the effect of identical treatment on the clonidine-induced reduction in rat brain MHPG-SO₄ levels.To unequivocally assume that drug-induced changes in central ³H-clonidine recognition sites reflect alterations in the functioning of central presynaptic alpha₂-adrenoceptors may be open to question.     

Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by alpha2-adrenoceptors.

1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.     

Characteristics of the binding of the antihypertensive agent moxonidine to alpha 2-adrenoceptors in rat brain membranes

The characteristics of the alpha 2-adrenoceptor binding property of moxonidine (4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrim idinamine, BDF 5895), a newly developed centrally acting antihypertensive agent, was investigated in receptor binding assays using [3H]-rauwolscine bound to rat cortex membranes. The results are as follows: 1. [3H]-Rauwolscine binds in a saturable manner to rat cerebral cortex membranes with a Bmax of 320 +/- 50 fmol/mg of protein and KD of 1.7 +/- 0.5 nmol/l. 2. The alpha 2-adrenoceptor antagonist yohimbine competes with a Ki value of 8.0 nmol/l and slope factor close to unity. (--)-Norepinephrine competes with an overall Ki-value of 50 nmol/l and slope factor of 0.61. Mg2+ concentrations of 10 mmol/l in the presence of 0.1 mmol/l 3'-guanylimidodiphosphate (Gpp(NH)p) (Mg2+/Gpp(NH)p) do not affect the yohimbine inhibition curve, but increase the (--)-norepinephrine Ki value to 2.8 mumol and the slope factor to unity. 3. Moxonidine competes with [3H]-rauwolscine binding with an overall Ki value of 460 nmol/l and slope factor of 0.72. Moxonidine binding inhibition was potentiated by Mg2+, but shifted to lower potency by Mg2+/Gpp(NH)p and 150 mmol/l NaCl. 4. Binding inhibition curves for (--)-norepinephrine and moxonidine fitted better to a 2-site model and could be interpreted in terms of high affinity site (with Ki value KH) and low affinity site (with Ki value KL). The effect of Mg2+/Gpp(NH)p and NaCl was to convert the high affinity sites to low affinity sites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute and long-term regulation of brain alpha 2-adrenoceptors after manipulation of noradrenergic transmission in the rat

The specific binding of [3H]clonidine (KD and Bmax) to rat brain membranes was used as a biochemical index to directly evaluate alpha 2-adrenoceptor changes after manipulation of synaptic noradrenaline (NA) pools or stimulation or blockade of the receptor. Acute (2 h) and prolonged (7 days) inhibition of NA synthesis with alpha-methyl-p-tyrosine (150 mg/kg) or acute (2 h) and chronic (14 days) treatment with reserpine (0.1-0.5 mg/kg) reduced the NA content by 15-90%, which also resulted in marked reductions (35-55%) of the KD values for [3H]clonidine in all brain regions studied. In contrast to alpha-methyl-p-tyrosine, chronic reserpine treatment did not alter the Bmax values for [3H]clonidine or [3H]UK 14304 in any brain region. In the hypothalamus and cerebral cortex, acute (2 h) and chronic (7-14 days) treatment with the monoamine oxidase (MAO) inhibitors clorgyline (1 mg/kg) or tranylcypromine (5 mg/kg) increased the content of NA by 6-100%, which led to marked reductions (20-50%) of Bmax without altering the KD values for [3H]clonidine. Similarly, prolonged (21 days) inhibition of NA neuronal uptake with cocaine or protriptyline (10 mg/kg) also resulted in decreases in Bmax (20-25%) with no alterations in KD in the hypothalamus. In various brain regions, chronic (14 days) but not short-term (1 day) treatment with clonidine (0.1 mg/kg) or yohimbine (10 mg/kg) resulted in decreases (30-40%) and increases (15-20%), respectively, in Bmax without altering the KD values for [3H]clonidine. The results indicate that drugs which deplete endogenous NA up-regulate alpha 2-adrenoceptors (increased affinity of [3H]clonidine binding sites) while drugs which increase the intraneuronal and/or synaptic NA pools down-regulate the receptors (decreased number of [3H]clonidine binding sites). These adaptive receptor changes appear to be dependent on NA availability.     

Antagonist properties of 1-(2-pyrimidinyl)piperazine at presynaptic alpha 2-adrenoceptors in the rat brain

The effect of 1-(2-pyrimidinyl)piperazine (PmP), the main metabolite of buspirone, was tested on K(+)-evoked [3H]noradrenaline and [3H]serotonin release from superfused synaptosomes obtained from rat cerebral cortex. PmP had no effects per se, but antagonized the effect of noradrenaline, producing a parallel shift to the right of the noradrenaline inhibition curves. From these data pA2 (apparent affinity) values of 6.8 and 7.3 were calculated for PmP on presynaptic alpha 2-adrenoceptors located on noradrenergic and serotonergic nerve terminals, respectively.     

Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain

RATIONALE: Oxazepam has been demonstrated to slow reaction times and increase the rate of omission errors in attentional experiments. This suggests that action monitoring might also be impaired. OBJECTIVES: The present study used the event-related brain potential (ERP) technique to investigate this hypothesis. The P3b component to targets was taken as an indicator of the target evaluation process, and the response-locked error-related negativity (ERN) served as an indicator of action monitoring. We hypothesized that the amplitudes of ERN and P3b would be reduced as an effect of oxazepam. METHODS: A simple "oddball" reaction time experiment was conducted in a double-blind crossover study of 30 mg oxazepam versus placebo. In order to investigate variations in attentional allocation, separate experimental runs were undertaken with target frequencies of 50% and 80%. RESULTS: ERN and P3b amplitudes were lower in the 80% target condition than in the 50% condition. Oxazepam did not affect behavioral parameters but was associated with an ERN of lower amplitude than the placebo condition. ERN amplitude variations between target conditions remained unchanged. CONCLUSIONS: Although the intake of 30 mg oxazepam did not impair behavioral performance, measures of the electrophysiological recordings show that action monitoring processes were altered. We argue that this may be related to the anxiolytic properties of the drug and may constitute an important causal factor for behavioral impairments after the intake of oxazepam.     

Chronic corticosterone treatment increases the endocannabinoid 2-arachidonylglycerol in the rat amygdala

This research was designed to examine the effect of three weeks of administration of corticosterone (20 mg/kg) on endocannabinoid content and cannabinoid CB1 receptor binding in the amygdala. It was found that the endocannabinoid 2-arachidonylglycerol was significantly increased in the amygdala following chronic corticosterone treatment. However, there was no change in either the maximal binding (Bmax) or binding affinity (KD) of [3H]-CP 55,940 to the CB1 receptor in the amygdala. Given the role of amygdalar endocannabinoids in the regulation of emotionality, this suggests that the ability of glucocorticoids to influence affective behavior may involve interactions with regulation of endocannabinoid content.     

Alpha 1- and alpha 2-adrenoceptors in rat cerebral cortex: effects of neonatal treatment with 6-hydroxydopamine

Neonatal 6-hydroxydopamine treatment was used to destroy the noradrenergic nerve terminals in rat cerebral cortex and thus give some insight into the in vivo regulation of alpha-adrenoceptor subtypes, which in turn provides information concerning the anatomical localization of alpha 1- and alpha 2-adrenoceptors. Treatment of rats in the neonatal period with 6-OHDA causes an irreversible decrease in noradrenaline levels of the cerebral cortex compared to controls. Differences in [3H]clonidine and [3H]prazosin binding in the cerebral cortex occurred which varied depending upon the time elapsed between denervation and the binding assay. In rats aged 7-14 days there was a 20% decrease in the number of alpha 2-adrenoceptors and a slight increase in alpha 1-adrenoceptors. In older rats (45-50 day old) both types of alpha adrenoceptors were increased. Results of this study indicate that alpha 2-adrenoceptors located on presynaptic noradrenergic terminals represent only a small proportion of the total alpha 2-adrenoceptors in rat cerebral cortex. Increases in the binding capacity after 67-OHDA treatment indicate an up-regulation phenomenon affecting alpha 1-adrenoceptors and alpha 2-adrenoceptors located on structures other than noradrenergic nerve endings.     

Chronic reboxetine desensitizes terminal but not somatodendritic alpha2-adrenoceptors controlling noradrenaline release in the rat dorsal hippocampus.

The slow onset of antidepressant drugs' effects is thought to reflect the time required for the development of adaptive changes such as desensitization of presynaptic autoreceptors controlling the release of neurotransmitters. Using in vivo microdialysis in conscious rats, we studied the effect of a continuous infusion of the selective noradrenaline (NA) reuptake inhibitor reboxetine on extracellular concentrations of NA. Doses of 10 mg/kg/day reboxetine through subcutaneous osmotic pumps for 2 days increased extracellular NA by 272% in the dorsal hippocampus (DH) of rats. NA rose significantly more in rats given reboxetine for 7 (469%) and 14 (437%) days. Intraperitoneal injection of 30 microg/kg clonidine, an alpha2-adrenoceptor agonist, reduced the release of NA to 49% of basal levels in rats given vehicle or reboxetine for 2 days, but this effect was markedly less in rats given reboxetine for 7 and 14 days. Likewise, the effect of intrahippocampal infusion of clonidine (0.05 and 0.2 microM) on extracellular NA was significantly attenuated in rats given reboxetine for 7 and 14 days, whereas the injection of 0.6 nmol clonidine into the locus coeruleus caused similar reductions of extracellular NA in the DH and prefrontal cortex (PFC) of rats infused with vehicle (DH -64%; PFC -42%) and reboxetine (DH -45%; PFC -28%) for 14 days. The results indicate that chronic treatment markedly enhances the effect of reboxetine on extracellular NA in the DH and suggest that this effect may be due to the desensitization of hippocampal alpha2-adrenoceptors.     

Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat

We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg(-1)) showed significant alpha1-adrenoceptor antagonist potency, but methiothepin did not show alpha2-adrenoceptor antagonist potency. MDMA (1 and 5 mg kg(-1)) produced pressor responses which were significantly reduced by the alpha(1)-adrenoceptor antagonist prazosin (0.1 mg kg(-1)), yohimbine (1 mg kg(-1)) or methiothepin (0.1 mg kg(-1)), but not by the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1)). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg(-1)) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg(-1)) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg(-1)) was significantly reduced by methoxyidazoxan (0.1 mg kg(-1)), and by the noradrenaline re-uptake blocker cocaine 10 mg kg(-1) but not 1 mg kg(-1). However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg(-1)) in anaesthetized rats involves alpha2- and possibly alpha1-adrenoceptors and 5-HT2 receptors, the pressor component at 1 min is largely alpha1-adrenoceptor mediated, and the sustained depressor response involves alpha2-adrenoceptors.     

Platelet alpha 2-adrenoceptors in heroin addicts during withdrawal and after treatment with clonidine

The density of platelet alpha 2-adrenoceptors, quantitated by means of the binding of [3H]clonidine and [3H]yohimbine, and the aggregation response induced by adrenaline were investigated in thirty-two heroin addicts during spontaneous withdrawal. The number of binding sites for [3H]clonidine, but not for [3H]yohimbine, was significantly increased during withdrawal and the increase followed a time course related to the severity of the abstinence syndrome. There was a positive and significant correlation between the severity of withdrawal and the density of platelet alpha 2-adrenoceptors. Concomitantly, the adrenaline-induced platelet aggregation was potentiated. Treatment with clonidine led to significant decreases in receptor densities as well as in functional responses. These results suggest that only alpha 2-adrenoceptors in the agonist state (i.e. number of binding sites for [3H]clonidine) are modulated during the development of the heroin withdrawal syndrome.