Co-administration Of Clonidine Research Articles

Mexiletine co-injected with clonidine increases the quality and duration of cutaneous analgesia in response to skin pinpricks in the rat.

The goal of the experimental design was to assess the cutaneous analgesic effect of mexiletine by co-injection with clonidine. The effect of nociceptive block was evaluated according to the inhibition of the cutaneous trunci muscle reflex (CTMR) in response to skin pinpricks in rats. The dose-related analgesic effect of mexiletine alone or mexiletine co-administrated with clonidine was constructed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous analgesia. Compared with mexiletine (1.8μmol), adding clonidine to mexiletine (1.8μmol) solutions for skin nociceptive block potentiated and prolonged the action (p<0.01). Mexiletine (6μmol) combined with clonidine extended the duration of cutaneous analgesia when compared with mexiletine (6μmol) alone (p<0.01). Co-administration of clonidine increases the potency and extends the duration of cutaneous analgesia by mexiletine, and the minimal dose of clonidine to intensify the analgesic effect is 0.06μmol.

Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial

ABSTRACTObjectives We examined the feasibility of a high-dose, 96-h infusion of ketamine in treatment-resistant depression. Methods Ten participants were randomised to receive a 96-h ketamine infusion, titrated as tolerated to a target rate of 0.6 mg/kg/h, while 10 received a 40-min ketamine infusion (0.5 mg/kg). Both groups received clonidine, titrated to a maximum of 0.6 mg orally daily, during the infusion to mitigate side effects of ketamine. Participants were followed for 8 weeks to examine potential antidepressant effects. Results All 20 participants completed the infusion. Most participants tolerated the infusion well, with minimal psychotomimetic symptoms or blood pressure elevation despite achieving high ketamine concentrations (mean 424 ng/ml for 96-h arm, 156 ng/ml for 40-min arm). There was no rebound hypertension upon discontinuing clonidine. Rapid and sustained improvement in depressive symptoms was observed in both study groups. Higher ketamine concentration was associated with sustained antidepressant response, and was not with greater psychotomimetic side effects, in the 96-h arm. Conclusions This study provides evidence for the feasibility of prolonged ketamine infusions in treatment-resistant depression. Co-administration of clonidine appeared to mitigate ketamine’s psychotomimetic effects. Further study is required to investigate the extent to which prolonged ketamine infusions could provide both rapid and sustained improvements in treatment-resistant depression.Clinicaltrials.gov identifier NCT01179009

Clonidine intensifies memantine cutaneous analgesia in response to local skin noxious pinprick in the rat

BackgroundThe purposes of this study were to evaluate the co-administration of clonidine with memantine and to determine whether it has a peripheral action in intensifying cutaneous analgesia. MethodsCutaneous analgesia was examined through inhibition of the cutaneous trunci muscle reflex in response to the local noxious pinprick in rats. Effect of the added subcutaneous clonidine to memantine on infiltrative cutaneous analgesia was assessed and compared with the local anesthetic lidocaine. ResultsOn the 50% effective dose (ED50) basis, the rank of drug potency was memantine [4.05 (3.95–4.18)μmol]>lidocaine [5.81 (5.70–5.98)μmol] (p<0.01). Clonidine at a dose of 0.12μmol did not elicit cutaneous analgesia. Mixtures of clonidine (0.12μmol) with drug (memantine or lidocaine) at ED50 or ED95 prolonged the duration of action and enhanced the potency as infiltrative cutaneous analgesia. Clonidine enhanced the lidocaine cutaneous analgesia in which had a better effect than added to memantine. ConclusionsOur resulting data showed that memantine displayed more potent cutaneous analgesia than lidocaine. Co-administration of memantine or lidocaine with clonidine increased the potency and duration of the cutaneous analgesia. Clonidine intensified the effects of lidocaine promoting cutaneous analgesia than added to memantine.

Hippocampal α-adrenoceptors involve in the effect of histamine on spatial learning

Spatial learning is a model of higher human cognitive functions which is used for studying animal behavior. Histaminergic and noradrenergic systems play a modulatory role in learning and memory. The present study aimed to test the effects of α-adrenoceptor agonist/antagonist microinjection into the CA1 region of dorsal hippocampus on histamine-induced spatial learning facilitation in the water maze task. Pre-training intra-CA1 microinjection of α1- or α2-adrenergic agonist, phenylephrine (0.0025μg/rat) or clonidine (0.05μg/rat) decreased traveled distance and escape latency at the start of the training phase, suggesting a spatial learning facilitation; while the higher dose of the drugs (phenylephrine 0.005μg/rat, clonidine 0.2 and 0.5μg/rat) increased the performance level at the end of the training phase, indicating a water maze spatial acquisition impairment. However, α1-receptor antagonist, prazosin (1μg/rat) impaired spatial learning; α2-receptor antagonist, yohimbine (0.25μg/rat) facilitated spatial acquisition. Moreover, pre-training intra-CA1 microinjection of a subthreshold dose of phenylephrine (0.001μg/rat) reversed histamine response, while ineffective dose co-administration of clonidine (0.1μg/rat) potentiated histamine (0.01μg/rat) response. Subthreshold dose of prazosin or yohimbine did not alter histamine response. Bilateral infusion of histamine (0.05μg/rat) facilitated spatial learning by itself. Furthermore, the drug's injections had no effect on swimming speed on the training days of MWM. These results suggest that α-adrenergic receptors of the dorsal hippocampal CA1 regions may play an important role in histamine-induced facilitation of spatial acquisition.

Influence of Clonidine and Ketamine on m-RNA Expression in a Model of Opioid-Induced Hyperalgesia in Mice

BackgroundWe investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.Material and MethodsC57BL/6 mice received morphine injections thrice daily using increasing doses (5-20mg∙kg-1) for 3 days (sub-acute, n=6) or 14 days (chronic, n=6) and additionally either s-ketamine (5mg∙kg-1, n=6) or clonidine (0.1mg∙kg-1, n=6). Tail flick test and the assessment of the mechanical withdrawal threshold of the hindpaw was performed during and 4 days after cessation of opioid treatment. Upon completion of the behavioural testing the mRNA-concentration of the NMDA receptor (NMDAR1) and β-arrestin 2 (Arrb2) were measured by PCR.ResultsChronic opioid treatment resulted in a delay of the tail flick latency with a rapid on- and offset. Simultaneously the mice developed a static mechanical hyperalgesia with a delayed onset that that outlasted the morphine treatment. Sub-acute morphine administration resulted in a decrease of NMDAR1 and Arrb2 whereas during longer opioid treatment the expression NMDAR1 and Arrb2 mRNA increased again to baseline values. Coadministration of s-ketamine or clonidine resulted in a reversal of the mechanical hyperalgesia and inhibited the normalization of NMDAR1 mRNA expression but had no effect on the expression of Arrb2 mRNA.ConclusionIn the model of chronic morphine therapy the antinociceptive effects of morphine are represented by the thermal analgesia while the proniceptive effects are represented by the mechanical hyperalgesia. The results indicate that the regulation of the expression of NMDAR1 and Arrb2 may be associated to the development of OIH in mice.PerspectiveThe results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

Spinal administration of opioid and α2-adrenergic receptor (α2AR) agonists produces analgesia, and agonists interact synergistically when coadministered. The molecular mechanism underlying this synergy is largely unknown. Pharmacological studies have identified both the delta and the mu-opioid receptors (DOR and MOR) as candidate receptors capable of interacting synergistically with α2AR agonists. However, recent studies attribute the antinociceptive effect of DOR agonists to actions at the MOR, calling the role of DOR in opioid-adrenergic synergy into question. Other studies suggesting that DOR is implicated in morphine antinociception raise the possibility that DOR is nonetheless required for morphine synergy with α2AR agonists. This study aimed to determine whether DOR activation is sufficient and necessary to mediate opioid-adrenergic synergistic interactions in the spinal cord. The antinociceptive effects of clonidine, [D-Ala(2)]-deltorphin II (DeltII), morphine, and [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin (DAMGO) were evaluated using the substance P (SP) behavioral assay in wild type (WT) and DOR-knockout (KO) mice. Opioid-adrenergic drug interactions were evaluated after spinal coadministration of clonidine with DeltII, morphine, or DAMGO. Isobolographic analyses of dose-response curves determined whether interactions were synergistic or additive. The absence of DeltII antinociceptive efficacy in DOR-KO confirmed its selectivity in the SP assay. Although DeltII+clonidine interacted synergistically in WT mice, no interaction with clonidine was observed in DOR-KO mice. Clonidine was synergistic with morphine in both mouse strains. DAMGO did not synergize with clonidine in either strain. These findings confirm that although other opioid receptors can interact synergistically with α2AR agonists, DOR is sufficient for spinal opioid-adrenergic interactions.

Perioperative effects of various anesthetic adjuvants with TIVA guided by bispectral index

BackgroundThis prospective, randomized, double blinded, controlled study was designed to compare effects of intravenous co-administration of clonidine, magnesium, or ketamine on anesthetic consumption, intraoperative hemodynamics, postoperative analgesia and recovery indices during Bispectral Index (BIS) guided total intravenous anesthesia (TIVA).MethodsAfter ethical committee approval and written informed consent, 120 adult patients ASA I and II scheduled for open cholecystectomy were randomly assigned to one of 4 equal groups. Group CL received clonidine 3 µg/kg and maintained by 2 µg/kg/h. Group MG received magnesium sulphate 50 mg/kg and maintained by 8 mg/kg/h. Group KET received racemic ketamine 0.4 mg/kg and maintained by 0.2 mg/kg/h. Control group (CT) received the same volume of isotonic saline. Anesthesia was induced and maintained by fentanyl, propofol and rocuronium. Propofol infusion was adjusted to keep the BIS value between 45-55. Intraoperative hemodynamics, induction time, anesthetic consumption, recovery indices, and PACU discharge were recorded.ResultsInduction time, propofol requirements for induction and maintenance of anesthesia, intraoperative fentanyl and hemodynamic values were significantly lower with Groups CL and MG compared to Groups KET and CT (P < 0.05). Patients in Group MG showed significantly lower muscle relaxant consumption, delayed recovery and PACU discharge than other groups (P < 0.05). First, analgesic requirement was significantly longer and total postoperative analgesic consumption was significantly lower in the adjuvant groups versus Group CT (P < 0.05).ConclusionsClonidine, magnesium, and ketamine can be useful adjuvant agents to BIS-guided TIVA. Pharmacokinetic studies of such drug combinations were recommended to investigate their interaction.

Clonidine as adjuvant for oxybuprocaine, bupivacaine or dextrorphan has a significant peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats

The aim of the study was to evaluate co-administration of clonidine with oxybuprocaine (ester type), bupivacaine (amide type) or dextrorphan (non-ester or non-amide type) and to see whether it could have a peripheral action in enhancing local anesthesia on infiltrative cutaneous analgesia in rats. Cutaneous analgesia was evaluated by a block of the cutaneous trunci muscle reflex (CTMR) in response to local dorsal cutaneous noxious pinprick in rats. The analgesic effect of the addition of clonidine with oxybuprocaine, bupivacaine or dextrorphan by subcutaneous injection was evaluated. On an ED50 basis, the rank of drug potency was oxybuprocaine>bupivacaine>dextrorphan (P<0.01). Mixtures of clonidine (0.12μmol) with oxybuprocaine, bupivacaine or dextrorphan (ED50 or ED95) extended the duration of action and increased the potency on infiltrative cutaneous analgesia. Among these drugs, the addition of clonidine to bupivacaine (amide type) elicits the most effective cutaneous analgesia. Clonidine at the dose of 0.12 and 0.24μmol did not produce cutaneous analgesia. Oxybuprocaine showed more potent cutaneous analgesia than bupivacaine or dextrorphan in rats. Co-administration of oxybuprocaine, bupivacaine or dextrorphan with clonidine increased the potency and duration on infiltrative cutaneous analgesia. The addition of clonidine to bupivacaine (amide type) elicits more effective cutaneous analgesia than oxybuprocaine (ester type) or dextrorphan (non-ester or non-amide type).

Clonidine administered as adjuvant for bupivacaine in ilioinguinal–iliohypogastric nerve block does not prolong postoperative analgesia

Coadministration of clonidine with local anesthetics is associated with improvement of the quality of peripheral nerve block and significant prolongation of postoperative analgesia. Better analgesia has been reported with clonidine in ilioinguinal nerve block compared with caudal use. The object of this study was to determine whether adding of 1 microg.kg(-1) clonidine to bupivacaine 0.25% in ilioinguinal-iliohypogastric nerve block prolongs postoperative analgesia in children. Ninety-eight children ASA I-II aged between 1 and 12 years, scheduled for elective outpatient herniorrhaphy or orchidopexy were randomly allocated to receive an ilioinguinal-iliohypogastric nerve block either with 0.3 ml.kg(-1) bupivacaine 0.25% plus 1 microg.kg(-1) clonidine or only bupivacaine. Postoperative analgesic needs, time to the first analgesic supplementation and sedation score were assessed in hospital for 6 h postoperatively and at home by telephone call. Demographic data were similar in both groups. There was no statistical difference in the rate of rescue analgesia between the two groups during the first six postoperative hours (20.4% group clonidine vs 30.6% group no clonidine) (P = 0.17). A slight decrease in systolic blood pressure during surgery was reported in the clonidine group. There was no difference in the scores of sedation between the two groups. At home, 10 patients in the clonidine group and nine patients in the nonclonidine group received analgesic medication. There was no difference between the two groups regarding the number of patients receiving analgesic rescue during the first 24 h (log rank = 0.39). Parental satisfaction was high in both groups. Our study failed to demonstrate any advantage in addition of 1 microg.kg(-1) clonidine to 0.25% bupivacaine for ilioinguinal-iliohypogastric nerve block compared with bupivacaine 0.25% alone.

Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice II: interactions with apomorphine.

Adult mice were administered either the noradrenaline (NA) neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or distilled water (control), 10-12 days before motor activity testing, and 6 h before testing all the mice were administered reserpine (10 mg/kg), the monoamine-depleting agent. The interactive effects of (I) clonidine, the alpha(2)-adrenoceptor agonist, with the dopamine (DA) agonist, apomorphine, and the alpha(2)-antagonist, yohimbine, and (II) with either yohimbine or the alpha(1)-antagonist, prazosin, upon motor behaviour in activity test chambers were studied in reserpinized DSP4-treated and control mice. It was shown that apomorphine (3 mg/kg) increased locomotor and total activity in both reserpinized DSP4-treated and control mice but the effect was attenuated in the DSP4 mice. Co-administration of clonidine (3 mg/kg) with apomorphine potentiated the effects of apomorphine on motor activity and this effect was enhanced markedly by DSP4 pretreatment. Yohimbine (10 mg/kg) antagonized the motor activity-stimulating effects of apomorphine in both DSP4-treated and control mice. Co-administration of clonidine with apomorphine, following yohimbine, restored motor activity levels to those obtained in the absence of yohimbine and this effect upon locomotor activity was enhanced by DSP4 pretreatment. The effects of clonidine on motor activity were enhanced by NA-denervation. Prazzosin (3 mg/kg) enhanced the locomotor activity of both reserpinized DSP4-treated and control mice after the initial 30-min period but was not affected by DSP4 treatment. Analysis of post-decapitation convulsions (PDCs) indicated loss of the reflex by DSP4 pretreatment. Reserpine pretreatment abolished the initial, exploratory phase (30 min) of motor activity. These results demonstrate interactions between NA and DA systems that may bear eventual relevance to neurologic disorders such as parkinsonism.

Complex stimulus properties of LSD: a drug discrimination study with alpha 2-adrenoceptor agonists and antagonists.

The influence of several alpha 2-adrenergic agents on the discriminative stimulus (DS) properties of lysergic acid diethylamide (LSD) was studied in rats trained to discriminate 0.08 mg/kg (186 nmol/kg) of LSD from saline in a two-lever operant paradigm. Only yohimbine fully mimicked LSD with an ED50 of 2.05 mg/kg (5.24 mumol/kg). Yohimbine's 5-HT1A agonist properties may be responsible for this substitution. Other alpha 2-adrenoceptor antagonists, idazoxan with an agonist/antagonist profile at 5-HT1A receptors and RS 26026-197, a highly selective alpha 2-adrenoceptor antagonist, failed to produce substitution. Clonidine, an alpha 2-adrenoceptor agonist, did not substitute for LSD but the response rate was dose-dependently reduced. None of the alpha 2-adrenergic agents used for pretreatment before LSD inhibited the response to the LSD training dose. Coadministration of clonidine with LSD produced a leftward shift of the dose-response relationship of LSD without a significant change in the slope of the dose-response line. Simultaneous administration of alpha 2-adrenergic agents with LSD shifted the dose-response curve to the left only when the adrenergic agent also possessed at least moderate affinity for the 5-HT1A receptor. In addition, radioligand competition experiments were performed that showed LSD to have relatively high affinity (Ki = 37 nM) for [3H]clonidine-labeled sites in rat cortex with lower affinity for [3H]yohimbine labeled sites. While previous studies have suggested that the nature of the LSD cue may be essentially expressed by 5-HT2 receptor activation, the present data show that this cue can be modulated by effects of LSD at 5-HT1A and at other monoamine neurotransmitter receptors.

Postoperative Analgesia After Co-administration of Clonidine and Morphine by the Intrathecal Route in Patients Undergoing Hip Replacement

Postoperative analgesia after intrathecal co-administration of clonidine hydrochloride (75 micro gram) and morphine sulfate (0.5 mg) was compared with analgesia produced after either intrathecal morphine (0.5 mg) or 0.9% sodium chloride in 90 patients undergoing total hip replacement under bupivacaine spinal anesthesia. Patient-controlled morphine requirements were significantly reduced (P < 0.001) postoperation by both clonidine/morphine (median 5 mg/24 h) and morphine (median 7 mg/24 h) compared with control (saline) (median 28 mg/24 h). However, no significant additional reduction in postoperative analgesic requirements was shown with the clonidine/morphine combination compared with morphine alone. Visual analog pain scores, although good in all groups at all times, were significantly poorer in the control group at 2 h (P < 0.04) and 4 h (P < 0.001) after operation compared with both treatment groups, and significantly poorer than the clonidine/morphine group at 6 h (P < 0.002) and 24 h (P < 0.009) postoperation. Mean arterial blood pressure was significantly lower in the clonidine/morphine group than in the two other groups (P < 0.001) between 2 and 5 h after operation. The incidence of emesis was similar in the clonidine/morphine and morphine groups and was significantly more than in the control group. (Anesth Analg 1995;80:86-91)

Postoperative Analgesia After Co-administration of Clonidine and Morphine by the Intrathecal Route in Patients Undergoing Hip Replacement

Postoperative analgesia after intrathecal co-administration of clonidine hydrochloride (75 micrograms) and morphine sulfate (0.5 mg) was compared with analgesia produced after either intrathecal morphine (0.5 mg) or 0.9% sodium chloride in 90 patients undergoing total hip replacement under bupivacaine spinal anesthesia. Patient-controlled morphine requirements were significantly reduced (P < 0.001) postoperation by both clonidine/morphine (median 5 mg/24 h) and morphine (median 7 mg/24 h) compared with control (saline) (median 28 mg/24 h). However, no significant additional reduction in postoperative analgesic requirements was shown with the clonidine/morphine combination compared with morphine alone. Visual analog pain scores, although good in all groups at all times, were significantly poorer in the control group at 2 h (P < 0.04) and 4 h (P < 0.001) after operation compared with both treatment groups, and significantly poorer than the clonidine/morphine group at 6 h (P < 0.002) and 24 h (P < 0.009) postoperation. Mean arterial blood pressure was significantly lower in the clonidine/morphine group than in the two other groups (P < 0.001) between 2 and 5 h after operation. The incidence of emesis was similar in the clonidine/morphine and morphine groups and was significantly more than in the control group.

Intrathecal coadministration of clonidine with serotonin receptor agonists produces supra-additive visceral antinociception in the rat

The intrathecal (i.t.) coadministration of sub-antinociceptive doses of clonidine, an α 2-adrenoceptor agonist, with DOI or RU-24969 (5-HT 2 or 5-HT 1B receptor agonists, respectively) produced dose-dependent supra-additive antinociceptive effects in a model of visceral pain. The enhanced attenuation of responses to noxious colorectal distension produced by the coadministration of these drugs is evidenced by significant leftward shifts in the dose-response curves as compared to those of each drug alone and by isobolographic analysis. The supra-additive antinociceptive effects produced following the i.t. coadministration of clonidine with RU-24969 were antagonized by i.t. pretreatment with phentolamine; the coadministration of phentolamine with methysergide produced no greater antagonism of effects. The supra-additive antinociceptive effects produced by i.t. coadministration of clonidine with DOI were antagonized by i.t. pretreatment with methysergide; the coadministration of methysergide with yohimbine produced no greater antagonism of effects. These data suggest that receptors acted upon by descending bulbospinal neurons interact to modulate the rostrad transmission of visceral nociceptive transmission.

The cardiovascular actions of clonidine and neuropeptide-Y in the ventrolateral medulla of the rat.

1. The cardiovascular responses to neuropeptide-Y (NPY) (25 and 50 pmol) and clonidine (10 and 20 nmol) were examined following microinjection into the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Mean arterial pressure (MAP) and heart rate (HR) were measured in anaesthetized rats, pre- and post-injection. 2. The alpha 2-adrenoceptor agonist clonidine (10 and 20 nmol) reduced MAP and HR significantly when microinjected into the CVLM and RVLM. 3. NPY (25 and 50 pmol) microinjected into the CVLM decreased MAP and HR. However, in the RVLM neither dose had a significant cardiovascular effect. 4. The possibility of a functional interaction between the adrenergic system and NPY was examined by co-administration of clonidine and NPY in doses that gave submaximal blood pressure responses. In the CVLM this produced hypotension and bradycardia which was similar in magnitude to the sum of their individual responses, indicating that in this area their actions appear to be independent. 5. In the RVLM, where NPY has no significant cardiovascular effects, co-administration with clonidine, did not alter the response to clonidine. 6. It appears that in the areas investigated, there is no functional interaction between NPY and clonidine.

Interaction between the cardiovascular effects of Clonidine and the κ-opioid agonist U-50,488H in the anterior hypothalamic area of the rat brain

In thiobutabarbitone-anaesthetized rats, microinjection of clonidine (1-40 nmol) into the anterior hypothalamic area (AHy) produced dose-dependent reductions in mean arterial blood pressure and heart rate. Microinjection of the kappa-opioid agonist U-50,488H (3 and 10 nmol) did not modify these parameters. Simultaneous co-administration of clonidine (4 nmol) and U-50,488H (10 nmol) into the AHy resulted in significant potentiation of the clonidine-induced hypotension and marked attenuation of the bradycardia. A lower dose of U-50,488H (3 nmol) co-administered with clonidine (4 nmol) did not influence the cardiovascular responses to clonidine. These findings suggest that AHy neurons involved in the cardiovascular responses to clonidine may be modulated by kappa-opioid receptor stimulation.

Further evidence for, and nature of, the facilitatory GABAergic influence on central noradrenergic transmission.

In order to explore the nature of the facilitatory GABAergic control of cerebral noradrenergic neurons, we have studied the effect of a variety of GABA mimetics (given systemically or injected locally into brain areas containing noradrenergic cell bodies or terminals) on several indices of noradrenaline turnover in the rat brain. Systemic administration of both direct and indirect acting GABA mimetics enhanced; 1) the pargyline induced accumulation of normetanephrine in the hypothalamus; 2) total DOPEG levels in a number of brain regions innervated by noradrenergic neurons; 3) both DOPAC and MOPEG levels in noradrenergic cell body areas (A1, A2 and A6). These effects are probably mediated by GABAA receptors as specific GABAA or mixed GABAA/GABAB agonists but not the GABAB agonist baclofen enhanced noradrenaline turnover. Interruption of noradrenergic impulse flow (by local injection of tetrodotoxin or by hemitransection) blocked the ability of progabide to increase DOPEG concentrations in the hypothalamus and cerebral cortex. Similarly, the co-administration of clonidine with progabide antagonized the progabide-induced increase in hypothalamic total DOPEG levels. Co-administration of yohimbine with progabide provoked an additive effect on hypothalamic DOPEG levels at moderate but not at high doses of yohimbine. Thus, the acceleration of noradrenaline turnover induced by GABA mimetics appears to depend on ongoing activity in noradrenergic neurons and occurs via an increase in neuronal discharges. Local injection of muscimol into the nucleus accumbens or hypothalamus failed to affect DOPEG levels in these structures; similarly, local injection of muscimol into the locus coeruleus failed to modify DOPEG levels in corresponding noradrenergic projection areas. These data indicate that the GABAergic influence is not exerted via GABA receptors located on noradrenergic cell bodies or nerve endings. Furthermore, since systemically administered progabide still increased hypothalamic DOPEG levels after ibotenate-induced destruction of the hypothalamic neuronal cell bodies, a presynaptic modulation of noradrenergic neurons by local GABAergic interneurons is excluded. Chemical destruction of serotoninergic pathways or enhancement of 5-HT transmission by quipazine failed to alter the ability of progabide to increase cerebral DOPEG levels. Moreover, scopolamine or naloxone also failed to affect the progabide-induced increase in cerebral DOPEG levels.(ABSTRACT TRUNCATED AT 400 WORDS)