Distribution of dopamine-immunoreactive fibers in the rat brainstem.

We describe the distribution of axons immunoreactive for dopamine in pons and medulla oblongata of rat under normal conditions or after inhibition of monoamine oxidase or dopamine beta-hydroxylase. In the pons of non-treated animal, fairly dense plexuses of dopamine-immunoreactive varicose fibers were found in the locus coeruleus, dorsal parabrachial and dorsal raphe nuclei, central gray and reticular formation dorsal to the superior olive. In the medulla oblongata, the immunoreactive fibers were abundant in the dorsal vagal complex, lateral paragigantocellular nucleus, midline raphe nuclei and spinal trigeminal nucleus. Monoamine oxidase inhibition made it possible to increase the intensity of immunoreactivity and consequently the number of labeled fibers in these areas, indicating that dopamine is perpetually oxidized by monoamine oxidase, and consequently in low concentration under normal conditions. Sparse dopamine-immunoreactive fibers were observed in the pontine gray, motor trigeminal nucleus, inferior olive and major axon bundles such as the dorsal and ventral tegmental bundles, where numerous noradrenergic fibers have been reported. In axons of these areas, intense dopamine-immunoreactivity was seen only after inhibition of dopamine-beta-hydroxylase. It appears that dopamine is released and oxidized in response to autonomic changes such as hypoxia, hemorrhage, and cardiovascular variation in the caudal brainstem, as we have described elsewhere.

Further studies on the suppression of luteinizing hormone release due to activation of medial preoptic-anterior hypothalamic area mu-opioid receptors.

Our laboratory has previously demonstrated that specific activation of mu-opioid receptors in the medial preoptic-anterior hypothalamic area with [D-Ala2, N Me-Phe4, Gly-ol5]-enkephalin (DAGO) suppresses luteinizing hormone secretion in the ovariectomized rat [29]. In the present study, three experiments were undertaken to ascertain whether changes in the activity of norepinephrine or dopamine neurons modulate the decrease in luteinizing hormone release in response to DAGO. The first experiment utilized push-pull perfusion in conjunction with HPLC to assess in vivo norepinephrine release in the medial preoptic-anterior hypothalamic area in response to perfusion of this site with DAGO (5 micrograms/h). DAGO significantly decreased luteinizing hormone release, but perfusate norepinephrine levels did not change. In the second experiment, push-pull perfusion in the medial preoptic-anterior hypothalamic area with cerebrospinal fluid (CSF) or CSF containing DAGO was done in rats pretreated with the norepinephrine synthesis inhibitor, FLA-63. This drug pretreatment had no effect on the DAGO-induced suppression of luteinizing hormone secretion. In experiment 3, push-pull perfusion in the medial preoptic-anterior hypothalamic area with CSF followed by CSF containing DAGO was done in rats pretreated with vehicle, or a dopamine receptor antagonist, either pimozide or d-butaclamol. Neither dopamine receptor antagonist had any effect on the DAGO-induced suppression of luteinizing hormone release. Thus, these studies do not support a role for alterations in the activity of norepinephrine or dopamine neurons in mediating the suppression of luteinizing hormone release in response to activation of mu-opioid receptors in the medial preoptic-anterior hypothalamic area in the ovariectomized rat.

The role of norepinephrine in mediating luteinizing hormone release in response to blockade of kappa-opioid receptors in the medial preoptic area.

Our previous study [32] indicated that blockade of kappa-opioid receptors with nor-binaltorphimine (nor-BNI) in the medial preoptic area (MPOA) produced two different LH responses during midpregnancy in the rat: an increase in basal pulsatile LH secretion, followed in many cases by a larger and/or sustained increase in LH release. In the present study, two experiments were conducted to examine the role of norepinephrine (NE) in mediating these different LH responses. In experiment 1, the effects of NE synthesis inhibition with FLA-63 on nor-BNI induced LH secretion were examined. In 5 of 9 vehicle pretreated rats, nor-BNI perfusion in the MPOA produced only an increase in basal pulsatile LH secretion. In the remaining 4 animals blockade of MPOA kappa-receptors produced not only an increase in basal LH secretion, but also a large/sustained release of LH. Pretreatment with FLA-63 had no effect on the nor-BNI induced increase in basal pulsatile LH secretion, but completely prevented the occurrence of the large/sustained release of LH. The objective of experiment 2 was to determine whether any change in NE release occurred at the site of nor-BNI perfusion in rats showing this large/sustained increase in plasma LH levels, by measuring in vivo NE release at that site. No significant change in perfusate NE levels was observed during perfusion of the MPOA with nor-BNI alone or in combination with desipramine, a NE reuptake blocker, in rats that showed this type of LH response. These results demonstrate that while NE does not mediate the increase in basal pulsatile LH release produced by nor-BNI perfusion in the MPOA, it is essential for the large/sustained elevation in LH secretion seen in response to blockade of kappa-opioid receptors at this site. This latter type of LH secretory response is not, however, associated with an increase in NE release directly at the site of kappa-opioid receptor blockade in the MPOA in pregnant rats.

Noradrenaline but not dopamine involved in NMDA receptor-mediated hyperalgesia induced by theophylline in awake rats.

Theophylline dose-dependently decreased a supraspinally integrated nociceptive threshold in awake rats. This hyperalgesia was antagonized by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801, suggesting involvement of NMDA receptors. Depletion of endogenous catecholamines with reserpine or alpha-methyl-DL-p-tyrosine and inhibition of noradrenaline synthesis with FLA 63 reduced the theophylline-induced hyperalgesia, whereas blockade of dopamine D2 receptors by pimozide, haloperidol (2 mg/kg) or (-)-sulpiride, of dopamine D1 receptors by SCH 23390, or of dopamine autoreceptors by a low dose of haloperidol (25 micrograms/kg), had no effect. By contrast, the alpha 1-adrenoceptor-blocking agent phenoxybenzamine abolished the hyperreactivity induced by theophylline, whereas the alpha 1-adrenoceptor antagonist prazosin and the beta-adrenoceptor antagonist (+/-)-propranolol were without effect. Furthermore, the alpha 2-adrenoceptor agonist clonidine (50 micrograms/kg) considerably decreased the hyperalgesia caused by theophylline. The adenosine A1/A2 receptor agonist N-ethyl-carboxamide adenosine (NECA) produced dose-dependent antinociception on the threshold for vocalization. Moreover, NECA (25 micrograms/kg) antagonized the hyperalgesia induced by different doses of theophylline, indicating that the effect is susceptible to purinergic modulation. It is suggested that theophylline-induced hyperreactivity to nociception is attributed to increased activity in NMDA and noradrenaline neurotransmission, possibly secondary to adenosine antagonism. Elevated intracellular levels of cyclic AMP might, however, also be involved in theophylline-produced hyperexcitability.

Inhibition of inositol 1,4,5-trisphosphate 5-phosphatase by micromolar concentrations of disulfiram and its analogues.

Following a preincubation period of 10 min, disulfiram and its analogues FLA 46, FLA 63, FLA 99, EWP 815 and EWP 840 inhibited the breakdown of 10 microM [3H]Ins(1,4,5)P3 by Ins(1,4,5)P3 5-phosphatase from GH3 cells, with IC50 values (in microM), for soluble/particulate enzymes respectively, of: disulfiram, 24/24; FLA 46, 23/30; FLA 63, 24/6; FLA 99, 50/48; EWP 815, 8/6; EWP 840, 11/8. The inhibition produced by FLA 99 was time-dependent in nature, although inhibition was found in the absence of a preincubation period. EWP 815 and EWP 840 were more potent inhibitors of Ins(1,4)P2 phosphatase than of Ins(1,4,5)P3 5-phosphatase. Thyrotropin-releasing hormone (TRH; 3/100 microM)-stimulated inositol phospholipid breakdown in prelabelled GH3 cells was inhibited by disulfiram (IC50 values 63/52 microM respectively), FLA 46 (89/110 microM), EWP 815 (83/71 microM) and EWP 840 (220/200 microM), without affecting basal breakdown rates. FLA 99 did not inhibit either basal or TRH-stimulated activity at any of the concentrations tested (30, 100 and 300 microM). [3H]Ins(1,4,5)P3 binding to its cerebellar receptor was not inhibited by any of the compounds over a concentration range of 3-300 microM, although an increased level of binding was seen at high concentrations. FLA 99 and EWP 840 increased the basal intracellular Ca2+ concentration in GH3 cells, but with no corresponding effect on the Ca2+ response to TRH stimulation. These compounds did not increase the cellular permeability to Trypan Blue, but did affect cell proliferation. It is concluded that disulfiram and related compounds produce dramatic effects on Ins(1,4,5)P3 metabolism in GH3 cells.

Evidence for an increased catecholamine synthesis in rat adrenal glands following stimulation of peripheral dopamine receptors.

In studies on peripheral dopamine (DA) turnover in our department evidence has accumulated that changes in adrenal DA levels induced by varying degrees of neurogenic stimulation roughly reflect changes in the catecholamine (CA) synthesis rate. The question arises if changes in DA levels in rat adrenals induced by different DA D-2 receptor agonists and previously reported from our laboratory, also indicate changes in CA synthesis. After various periods of drug administration rats were killed by decapitation and tissue CA levels in adrenals and forebrain were determined by HPLC-EC. The potent inhibitor of DA-beta-hydroxylase FLA 63 (40 mg/kg i.p.) increased adrenal DA by 186% after 1 h and by 423% after 3 h. The DA D-2 agonist quinpirole (0.2 mg/kg s.c., 30 min) itself increased adrenal DA by 55-60% compared to control. In FLA 63 pretreated rats quinpirole increased adrenal DA levels by further 127% (FLA 63-1 h), resp. 122% (FLA 63-3 h) than did FLA 63 itself. The DA D-2 receptor antagonist domperidone (3 mg/kg s.c., 150 min) blocked the quinpirole effect both in saline and FLA 63 (3 h) pretreated rats. Adrenal DOPAC was changed in similar manner as adrenal DA in FLA 63 pretreated rats. No significant changes either in adrenal NA or A were observed after FLA 63 pretreatment. Under the present experimental conditions adrenal DA may thus mainly be looked upon as an intermediate in the synthesis of NA and A, and the elevation of DA induced by DA D-2 receptor stimulation as a consequence of increased catecholamine synthesis.

In vivo voltammetric evidence for the detection of norepinephrine release in the thalamus of freely moving rats.

The ventrobasal complex (VB) of the thalamus was monitored in awake rats for the presence of norepinephrine (NE) overflow following pharmacological manipulations and physiological stimulation. Overflow was detected using chronoamperometry with electrochemically pretreated, Nafion-coated carbon fiber microelectrodes. In vivo evaluation of the electrode responses to systemic drug administration showed that alpha-methyl-p-tyrosine (alpha-MPT) and FLA-63 caused decreases in baseline current. Increases in baseline current in the VB were observed in animals treated with pargyline, yohimbine and yohimbine injected 2 h postpargyline. The results suggest that an electrochemical signal primarily due to NE overflow can be monitored in thalamic regions. Vigorous somatosensory stimulation induced small, long-lasting (approximately 30 min), reproducible electrochemical signals in the VB which were suppressed by alpha-MPT or FLA-63. These studies provide in vivo evidence which suggests that stressful somatosensory input to the VB initiates the release of NE.

Role of the central adrenergic system in the regulation of prostaglandin biosynthesis in rat brain.

The role of endogenous catecholamines in the regulation of brain prostaglandin (PG) synthesis was studied in the rat. Male rats were injected in the brain lateral ventricle or in the ventral noradrenergic bundle with either the catecholaminergic neurotoxin 6-hydroxydopamine or vehicle. Other groups of rats were injected intraperitoneally with the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, or with the inhibitor of dopamine-beta-hydroxylase, FLA-63. All these drugs produced a significant depletion of norepinephrine (NE) content in the cortex and hypothalamus. The rats that had lower levels of NE exhibited reduced capacity to synthesize PGE2 but not thromboxane B2 and 6-keto-PGE1 alpha in the cortex and hypothalamus. However, induced production of PG, stimulated by the bacterial endotoxin lipopolysaccharide (LPS), remained unchanged, namely, a similar (2- to 2.5-fold) increase of PG synthesis was noted in control and in NE-depleted rats. We suggest that the regulation of PG synthesis under basal condition requires intact adrenergic input, whereas LPS-induced production of PG is independent of the adrenergic innervation.

The role of dopamine in regulation of thyrotropin-releasing hormone in the striatum and nucleus accumbens of the rat.

The effect of alpha-methyl-p-tyrosine (alpha-MT), FLA-63, amphetamine, apomorphine and quinpirole on the concentration of thyrotropin-releasing hormone (TRH) in the striatum and nucleus accumbens was studied in rats. It has been found that the TRH content was increased in both those structures after alpha-MT, an inhibitor of tyrosine hydroxylase which reduced the concentration of both dopamine (DA) and noradrenaline (NA), but not after FLA-63, an inhibitor of DA-beta-hydroxylase which decreased the NA level without affecting DA. On the other hand, the indirectly acting dopaminomimetic amphetamine, the non-selective DA receptor agonist apomorphine, and the selective D2 receptor agonist quinpirole reduced the TRH level in the striatum, but not in the nucleus accumbens. Moreover, the decrease in the striatal peptide content induced by DA-mimetics was antagonized by the selective D2-receptor antagonist sulpiride, but not by the selective D1 receptor antagonist SCH 23390. The effect of amphetamine was not modified by the selective alpha 1-adrenoceptor antagonist prazosin. These results indicate that DA and D2 receptors play a significant role in the regulation of the striatal TRH.

3,4-Dihydroxyphenylacetic acid (DOPAC) as an index of noradrenaline turnover: effects of Hydergine and vincamine.

Among the drugs commonly used in the treatment of memory disorders of the elderly, vincamine and hydergine have been shown to moderately increase the firing rate of noradrenergic locus coeruleus (LC) neurons. Since changes in electrical activity of noradrenergic neurons are generally reflected in corresponding alterations of the turnover of this transmitter, the effects of these drugs on the accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) in the presence and absence of the dopamine-beta-hydroxylase inhibitor, FLA 63, were studied in the LC as well as in two of its projection areas, the hippocampus and the cerebellum. Characterization of this procedure with the alpha 2-adrenoceptor antagonist, idazoxan, the corresponding agonist, clonidine, the alpha 1-adrenoceptor antagonist prazosine, and haloperidol, suggested that--DOPAC changes are more suitable than those of DA or DOPAC/DA ratios in reflecting changes in noradrenaline (NA) turnover, inhibiting DBH is advantageous if NA turnover is to be measured in projection areas, but not in LC, and haloperidol and prazosine, in principle, did not affect NA turnover. Vincamine and hydergine at 10 mg/kg doses, at which they were reported to increase LC firing by 50%, did not induce a change in NA turnover in any of the areas. This, together with the data obtained with haloperidol, suggests that a minimal increase in the firing rate of LC cells (+140%) is required before it could influence the turnover of NA, as measured by DOPAC changes. Thus, the stimulating effect of nootropics on the central noradrenergic system may be more sensitively detected by electrophysiological techniques than by biochemical ones.

CNS alpha 2-adrenoceptor induced mydriasis in conscious rats.

Clonidine (3-300 microgram/kg, i.p.) produced dose-dependent pupillary dilation in unanesthetized rats. At low levels of illumination (30 lux), this effect was similar to that seen in anesthetized animals but was diminished under higher ambient lighting conditions. alpha Methyldopa (60 mg/kg, i.p.) produced mydriasis that took several hours to develop and was prevented by pretreatment with a dopamine beta-hydroxylase inhibitor (FLA-63). Yohimbine antagonized pupillary dilation induced by both clonidine and methyldopa. These results demonstrate that mydriasis in the conscious rat can be an effective index of CNS alpha 2-adrenoceptor activation, particularly when measured under low lighting levels.

Prolactin (PRL) release-inhibiting properties of the alpha 2 adrenergic receptor antagonist idazoxan: comparison with yohimbine.

The effects of the alpha 2 adrenergic receptor antagonists yohimbine (YOH) and Idazoxan (ID) on secretion of PRL were compared in nonanesthetized male rats bearing permanent intraatrial cannulae for i.v. drug delivery and serial blood sampling. YOH induced a dose-related elevation of basal plasma PRL levels. ID had either no effect or a tendency to lower them and effectively inhibited stimulation of PRL secretion with morphine, 5-hydroxytryptophan (5HTP), quipazine or restraint stress. YOH at low doses did not alter the PRL secretory responses to these stimuli or enhanced them at the highest dose used (1.56 mg/kg). ID inhibited the PRL-stimulating, effect of 5HTP or morphine following inhibition of NE synthesis with FLA63 or pretreatment with clonidine. It also blocked the effect of quipazine in rats pretreated with prazosin. It is concluded that ID, in a complete contrast to YOH effectively inhibits PRL secretion. The inhibitory mechanism appears to be unrelated to its interaction with the alpha adrenergic receptors.

[Effect of cerebral noradrenaline and dopamine depletion on spontaneous and amphetamine-stimulated motor activity in rats]. / Efecto del agotamiento de la noradrenalina y dopamina cerebrales de la rata sobre la actividad locomotriz espontanea y la estimulada por anfetamina.

Selective depletion of rat brain noradrenaline and dopamine by 6-hydroxidopamine, 30-60 days after cisterna magna microinjection, reduced nocturnal spontaneous locomotor activity by 40%. This treatment also reduced by 90% the excitatory effect of amphetamine on locomotion. Disulfiram and FLA-63, selective inhibitors of dopamine-B-hydroxilase, depleted by 70% the noradrenaline content of striatum and brain cortex, without changes of dopamine concentration in the same areas. These rats showed a reduced spontaneous locomotor activity and a blockade of amphetamine stimulating activity. In conclusion, our results give support to the hypothesis of brain noradrenaline having a major role on the control of locomotor activity of rodents.

alpha-Methyldopa produces mydriasis in the rat by stimulation of CNS alpha 2-adrenoceptors.

1. The effects of i.v. administration of alpha-methyldopa (MD) on rat pupil diameter were investigated. All experiments were carried out in rats in which vagosympathetic nerve trunks were sectioned bilaterally at the cervical level. 2. In anaesthetized rats MD produced a marked dose-related increase in pupil diameter. The onset of pupillary response to MD was gradual and reached maximal levels 2-3 h after administration. 3. Pretreatment with alpha 2-adrenoceptor antagonists yohimbine (1.5 mg kg-1, i.v.) or idazoxan (0.5 mg kg-1, i.v.) blocked the pupillary response to MD. In contrast, the alpha 1-antagonists prazosin (1.0 mg kg-1, i.v.) and phenoxybenzamine (1.5 mg kg-1, i.v.) did not significantly alter the pupillary effects of MD. 4. Selective enzymatic blockade with 3-hydroxy-benzyl-hydrazine (NSD-1015; 25 mg kg-1, i.p.), a dopa-decarboxylase inhibitor, as well as bis (4-methyl-homopiperazinyl-thiocarbonyl) disulphide (FLA-63, 5.0 mg kg-1, i.p.), a dopamine-beta-hydroxylase inhibitor, prevented the mydriatic effect of MD. 5. The above findings support the hypothesis that MD produces a clonidine-like CNS mydriasis in the rat. This effect appears to be mediated primarily by the MD metabolite, alpha-methylnoradrenaline. 6. These results indicate that MD produces mydriasis in the rat by a CNS action. The mydriatic action of MD appears to be produced by its metabolite alpha-methylnoradrenaline which in turn stimulates CNS postsynaptic alpha 2-adrenoceptors.

Noradrenaline turnover after left coronary artery ligation in rat heart.

The levels and the turnover of noradrenaline were measured in the left and right ventricles following left coronary artery ligation for 2 h in untreated, adrenalectomized or hexamethonium-treated rats. Noradrenaline in the left ventricles was decreased by ligation and unaffected in the right ventricles, whether of untreated, adrenalectomized or hexamethonium-treated animals. Turnover in the left ventricles, as estimated by the decrease of noradrenaline under dopamine beta-hydroxylase inhibition with bis-(4-methyl-1-homo-piperazinyl-thiocarbonyl)-disulfide (FLA-63), was unaffected by ligation whether in untreated, adrenalectomized, or hexamethonium-treated rats. Ligation accelerated turnover in the right ventricles of untreated rats or attenuated it in adrenalectomized rats and caused no changes in hexamethonium-treated rats. These results suggest that noradrenaline turnover in ischemic myocardium is not affected by regional ischemia and that such ischemia might accelerate turnover in the non-ischemic area, probably as a result of increased activity of sympatho-adrenal reflexes.

Studies on the central action of L-threo-3,4-dihydroxyphenyl-serine (L-threo-DOPS) in FLA-63-treated mice.

In order to clarify the central action of L-threo-DOPS, the effect of benserazide on behavioral and biochemical changes by L-threo-DOPS in FLA-63-treated mice was studied. L-threo-DOPS in combination with nialamide markedly increased both the locomotor activity and the concentrations of the brain, heart and kidney norepinephrine (NE) in the FLA-63-treated mice. Benserazide at low doses did not alter either the rise of the brain NE level or the increase in locomotor activity, whereas it significantly inhibited the rise of the heart and kidney NE levels. Benserazide at a high dose significantly inhibited all of them. These results suggested that the increase in locomotor activity might be mediated via activation of the central noradrenergic neurons system by L-threo-DOPS.

Central beta- and alpha-adrenolytic activities of adimolol.

The central adrenergic blocking activity of adimolol (ADL) was studied in rats and mice in the tests which can differentiate beta-, alpha 1-, and alpha 2-adrenolytic effects. Clenbuterol- and salbutamol-induced sedation in rats (open field test) and clenbuterol-induced hyperthermia (at high ambient temperature) were antagonized by low doses of ADL (0.1-1.0 mg/kg ip). ADL (10 mg/kg ip) attenuated the clonidine-induced aggression in mice, and its higher doses (20 and 40 mg/kg ip) depressed the hind limb flexor reflex of the spinal rat and counteracted the stimulatory action of clonidine. ADL at doses from 2.5 to 40 mg/kg ip affected neither the clonidine-induced sedation in rats and mice (locomotor activity, open field test), nor the hyperthermia (at high temperature). The hypothermia (at a room temperature of 21 degrees C) induced by clonidine was partially antagonized. The Ki values for ADL displacement of 3H-dihydroalprenolol and 3H-prazosin binding in the rat cerebral cortex were 1.2 nM and 951 nM respectively. These results indicate that ADL is a potent antagonist of central beta-adrenoceptors and has a weaker alpha 1-adrenolytic action. The central alpha 2-antagonistic effect is either very weak or absent.

Serotonergic influence on the growth hormone response to clonidine in rat.

Administration of the alpha 2-adrenoceptor agonist clonidine induces growth hormone (GH) release in rat and man. In the present study it is shown that the GH response to clonidine is weaker in rats exposed to depletion of both noradrenaline and serotonin (by means of reserpine or the combined treatment of FLA-63 and PCPA) than in animals exposed to noradrenaline depletion (by means of FLA-63) only. The possibility that an impaired serotonergic neurotransmission contributes to the blunted GH responses to clonidine observed in patients suffering from endogenous depression is discussed.

In vivo voltammetric monitoring of catecholamine metabolism in the A1 and A2 regions of the rat medulla oblongata.

Catecholaminergic metabolism was estimated in A1 and A2 noradrenergic nuclei of the rat medulla oblongata using differential normal pulse voltammetry combined with electrochemically treated carbon fiber microelectrodes. In both areas an oxidation peak appearing at +50 mV was recorded. Electrochemical data and pharmacological experiments indicated that 3,4-dihydroxyphenylacetic acid (DOPAC) synthesized by noradrenergic neurons was the major contributor to this signal. Indeed, alpha-methyl-p-tyrosine, by inhibiting tyrosine hydroxylase, and pargyline, by inhibiting monoamine oxidase, both totally suppressed the peak appearing at +50 mV in A1 and A2 areas. Conversely, FLA-63, an inhibitor of dopamine-beta-hydroxylase, increased it. Moreover, a local and unilateral injection of catecholaminergic neurotoxin (6-hydroxydopamine) in the vicinity of A1 induced a 60% decrease in the peak height. This effect was prevented by pretreatment with desipramine, an inhibitor of noradrenaline reuptake, which is known to protect noradrenergic neurons against the action of 6-hydroxydopamine. Finally, specific drugs acting on alpha-2-noradrenergic receptors (clonidine and piperoxane) modulated the peak height recorded from both structures. Thus, as previously shown in the locus ceruleus, the variations in the extracellular DOPAC levels reflect the metabolic activity of A1 and A2 noradrenergic neurons.

Alpha 2-receptor control over release of noradrenaline in rat thalamus.

Rat brain thalamic tissue was examined for the presence of alpha 2-receptor control over noradrenaline (NA) utilization. Systemically administered clonidine (0.1 mg/kg i.p.) decreased NA turnover, yohimbine (10 mg/kg i.p.) increased NA turnover, and prazosin (0.5 mg/kg i.p.) had no effect. In vitro, yohimbine increased K+-stimulated overflow of endogenous NA in a dose-dependent fashion. It appears that locus coeruleus neurons which project to thalamus exhibit the same type of alpha 2-receptor control as those terminating in other forebrain regions.