Idazoxan and Efaroxan Potentiate the Endurance Performances and the Antioxidant Activity of Ephedrine in Rats.

Background and objectives: The connections between the imidazoline system and multiple other neurotransmitter systems in the brain (adrenergic, dopaminergic, serotoninergic, glutamatergic, opioid) indicate the complexity of the mechanisms underlying motor activity and behavior. The aim of the present research was to investigate the effects of the combination of ephedrine (EPD) and imidazoline antagonists idazoxan (IDZ) and efaroxan (EFR) on the endurance performance in the treadmill test in rats. Materials and Methods: We used Wistar rats distributed as follows: Group 1 (Control) receiving distilled water 0.3 mL/100 g body weight; Group 2 (EPD) receiving 20 mg/kg ephedrine; Group 3 (EPD + IDZ) receiving 20 mg/kg ephedrine + 3 mg/kg idazoxan; Group 4 (EPD + EFR) receiving 20 mg/kg ephedrine + 1 mg/kg efaroxan. An additional group (C) of animals receiving 0.3 mL/100 g body weight distilled water (but not subjected) to effort was used. Endurance capacity was evaluated using a treadmill running PanLAB assay. The evaluation of the substances' influence on oxidative stress was performed by spectrophotometric determination of superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity. Results: Treatment with EPD-IDZ and EPD-EFR were correlated with a longer distance traveled on the belt and with a decrease in the necessary electric shocks to motivate the animal to continue running in the forced locomotion test. Additionally, an increase in the activity of antioxidant enzymes was found. Conclusions: Idazoxan and efaroxan potentiated the physical effort-related effects of ephedrine with regard to endurance capacity and antioxidant activity in rats.

Activation and blockade of α2-adrenoceptors in the prelimbic cortex regulate anxiety-like behaviors in hemiparkinsonian rats.

At present, whether α2-adrenoceptors in the prelimbic cortex (PrL) are involved in Parkinson's disease-related anxiety is unclear. We examined the effects of PrL α2-adrenoceptors on anxiety-like behaviors in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. Compared to the sham operation, the lesion induced anxiety-like responses as measured by the open field test and elevated plus-maze test. Intra-PrL injection of the α2-adrenoceptor agonist clonidine (1.25, 2.5 or 5 µg/rat) produced anxiolytic effects in sham-operated and lesioned rats. Furthermore, intra-PrL injection of the α2-adrenoceptor antagonist idazoxan (1, 2 or 4 µg/rat) induced anxiogenic effects in two groups of rats. The effective doses produced by clonidine and idazoxan in lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of clonidine (5 µg/rat) or idazoxan (4 µg/rat) decreased or increased dopamine (DA) and noradrenaline (NA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) and amygdala in sham-operated and lesioned rats, respectively. These results suggest that α2-adrenoceptors in the PrL are involved in the regulation of anxiety-like behaviors, which is attributable to changes in DA, NA and 5-HT levels in the mPFC and amygdala after activation and blockade of α2-adrenoceptors.

Agmatine Inhibits Behavioral Sensitization to Ethanol Through Imidazoline Receptors.

BACKGROUND: Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice. METHODS: Mice received daily single intraperitoneal injection of EtOH (2.5 g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40 µg/mouse), endogenous agmatine enhancers (l-arginine [80 µg/mouse], arcaine [50 µg/mouse], aminoguanidine [25 µg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11. RESULTS: Agmatine (20 to 40 µg/mouse) administration for 7 days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like l-arginine (80 µg/mouse) or arcaine (50 µg/mouse) and aminoguanidine (25 µg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I1 receptor agonist, moxonidine, and I2 agonist, 2-BFI, not only decreased the development and expression of locomotor sensitization but also potentiated the effect of agmatine when employed in combination. Importantly, I1 receptor antagonist, efaroxan, and I2 antagonist, idazoxan, blocked the effect of agmatine, revealing the involvement of imidazoline receptors in agmatine-mediated inhibition of EtOH sensitization. CONCLUSIONS: Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.

Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats.

Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine. The von Frey filament test was used to assess the antinociceptive effects of I2 receptor agonists, and the forced swim test was used to assess the antidepressant-like effects of these drugs. 2-BFI (3.2-10 mg/kg, intraperitoneally), phenyzoline (17.8-56 mg/kg, intraperitoneally), and CR4056 (3.2-10 mg/kg, intraperitoneally) all dose-dependently produced significant antinociceptive effects, which were attenuated by the I2R antagonist idazoxan. Only CR4056 significantly reduced the immobility time in the forced swim test in both vehicle-treated and reserpine-treated rats. These data suggest that I2R agonists may be useful to treat fibromyalgia-related pain and comorbid depression.

Stress augments the rewarding memory of cocaine via the activation of brainstem-reward circuitry.

Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a ß or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a ß or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value.

Responsiveness of α2-adrenoceptor/I1-imidazoline receptor in the rostral ventrolateral medulla to cardiovascular regulation is enhanced in conscious spontaneously hypertensive rat.

Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the α2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson's disease.

The impact of treatment with the noradrenaline (NA) re-uptake inhibitor atomoxetine and the α2-adrenoceptor (AR) antagonist idazoxan in an animal model of Parkinson's disease (PD) was assessed. Concurrent systemic treatment with atomoxetine and idazoxan, a combination which serves to enhance the extra-synaptic availability of NA, exerts anti-inflammatory and neuroprotective effects following delivery of an inflammatory stimulus, the bacterial endotoxin, lipopolysaccharide (LPS) into the substantia nigra. Lesion-induced deficits in motor function (akinesia, forelimb-use asymmetry) and striatal dopamine (DA) loss were rescued to varying degrees depending on the treatment. Treatment with atomoxetine following LPS-induced lesion to the substantia nigra, yielded a robust anti-inflammatory effect, suppressing microglial activation and expression of the pro-inflammatory cytokine TNF-α whilst increasing the expression of neurotrophic factors. Furthermore atomoxetine treatment prevented loss of tyrosine hydroxylase (TH) positive nigral dopaminergic neurons and resulted in functional improvements in motor behaviours. Atomoxetine alone was sufficient to achieve most of the observed effects. In combination with idazoxan, an additional improvement in the impairment of contralateral limb use 7 days post lesion and a reduction in amphetamine-mediated rotational asymmetry 14 days post-lesion was observed, compared to atomoxetine or idazoxan treatments alone. The results indicate that increases in central NA tone has the propensity to regulate the neuroinflammatory phenotype in vivo and may act as an endogenous neuroprotective mechanism where inflammation contributes to the progression of DA loss. In accordance with this, the clinical use of agents such as NA re-uptake inhibitors and α2-AR antagonists may prove useful in enhancing the endogenous neuroimmunomodulatory potential of NA in conditions associated with brain inflammation.

Imidazolines increase the levels of the autophagosomal marker LC3-II in macrophage-like RAW264.7 cells.

This study evaluated whether imidazolines can induce autophagy in the murine macrophage-like cell line RAW264.7. Idazoxan increased the content of LC3-II, an autophagosomal marker, in RAW264.7 cells. To determine whether this effect was due to the induction of its synthesis or inhibition of its degradation, idazoxan treatment was performed in the presence of bafilomycin A1, which blocks autophagosome-lysosome fusion, as well as Pepstatin A and E-64d, both of which block protein degradation in autolysosomes. An increased content of LC3-II was observed in the presence of bafilomycin A1 as well as the protease inhibitors. Furthermore, an increased number of autophagosomes was observed following idazoxan treatment using an autophagosome-specific dye. This indicated that idazoxan induced autophagy. Other imidazolines, such as efaroxan, clonidine, and 2-(2-benzofuranyl)-2-imidazoline, also increased the LC3-II content in RAW264.7 cells in the presence of bafilomycin A1. Taken together, these results indicate that some imidazolines, including idazoxan, can induce autophagy in RAW264.7 cells.

Noradrenergic signaling in the VTA modulates cocaine craving.

Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha1 -adrenergic and alpha2 -adrenergic receptors (α1 -ARs and α2 -ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague-Dawley rats was attenuated by intra-VTA prazosin or terazosin-two selective α1 -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α1 -AR agonist phenylephrine as well as α2 -AR antagonist RX 821002, whereas the selective ß-AR antagonist propranolol had no effects. In addition, blockade of α1 -AR in the VTA prevented α2 -AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α1 -AR and α2 -AR but not ß-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.

Activation of beta- and alpha-2-adrenoceptors in the basolateral amygdala has opposing effects on hippocampal-prefrontal long-term potentiation.

Noradrenaline (NA), released by the locus coeruleus (LC), plays a key role in mediating the effects of stress on memory functions. The LC provides diffuse projections to many forebrain nuclei including the hippocampus, the prefrontal cortex (PFC), and the basolateral amygdala (BLA). These three structures are intricately interlinked. The hippocampal-prefrontal (H-PFC) pathway is involved in various cognitive functions. The first aim of this study was to examine the role of BLA in H-PFC plasticity by infusion of drugs to activate and inactivate the BLA and studying the effects on H-PFC long-term potentiation (LTP) in the rat in vivo. Activation of the BLA with glutamate impaired, while inactivation with muscimol augmented, H-PFC LTP. This study also aimed to demonstrate how directly applying noradrenaline and other noradrenergic agents in the BLA can affect H-PFC LTP. Noradrenaline at 1µg/0.2µl enhanced H-PFC LTP. Stimulating alpha-2-adrenoceptors in the BLA with clonidine enhanced LTP while blocking alpha-2 adrenoceptors with idazoxan impaired it. Propranolol, a non-selective beta antagonist, enhanced H-PFC LTP while isoprenaline, a non-selective beta agonist, decreased H-PFC LTP. These results suggest that the BLA regulates H-PFC plasticity negatively and also provide a mechanism by which noradrenaline in the BLA can affect H-PFC plasticity via alpha-2 and beta adrenoceptors.

The α2C-adrenoceptor antagonist, ORM-10921, exerts antidepressant-like effects in the Flinders Sensitive Line rat.

Depression involves deficits in monoaminergic neurotransmission. Differential roles for α2A, B and C subtypes of the α2-adrenoceptor (AR) are evident, with selective α2C-AR antagonists purported to have antidepressant and procognitive properties. However, this has not been demonstrated in a genetic animal model of depression. The role of the α2C-AR in modulating two key depression-related behaviours in the Flinders Sensitive Line (FSL) rat was studied using a dose-response analysis following subcutaneous administration with the selective α2C-AR antagonist ORM-10921 (0.03; 0.3 mg/kg), the nonselective α2-AR antagonist idazoxan (3 mg/kg), or vehicle once daily for 14 days. Behaviour in the novel object recognition test, forced swim test (FST) and locomotor activity test was assessed. To ratify the validity of the FSL model, the reference tricyclic antidepressant imipramine (15 mg/kg, intraperitoneally) was used as a comparator drug in the FST. FSL rats demonstrated significantly increased immobility and recognition memory deficits versus Flinders Resistant Line controls, with imipramine significantly reversing said immobility. Similarly, ORM-10921 at both doses but not idazoxan significantly reversed immobility in the FST as well as attenuated cognitive deficits in FSL animals. We conclude that selective α2C-AR antagonism has potential as a novel therapeutic strategy in the treatment of depression and cognitive dysfunction.

Investigation of the role of alpha-2 adrenergic receptors on prepulse inhibition of acoustic startle reflex in rats.

OBJECTIVES: Alpha-2 adrenergic receptors target several behavioral functions. These receptors may connect with the brain pathways mediating sensorimotor gating system that associate with psychoses, and the literature that investigate the relationship between alpha-2 receptors and sensorimotor gating system is very limited and some results are controversial. Thus, we aimed to investigate the role of alpha-2 receptors on prepulse inhibition (PPI) of acoustic startle reflex which is a measure of sensorimotor gating. EXPERIMENTAL DESIGN: Adult male Wistar rats were subjects. PPI was measured as the per cent inhibition of the startle reflex produced by a startling pulse stimulus. The average PPI levels were used in the further analyses. Clonidine (0.03-1 mg/kg), an agonist of alpha-2 receptors, idazoxan (10 mg/kg), an antagonist alpha-2 receptors, and saline were injected to rats intraperitoneally. PPI was evaluated at two different startle intensity levels (78 and 86 dB, respectively). PRINCIPAL OBSERVATIONS: Treatments produced some significant changes on PPI of startle reflex at all two levels of startle intensity. While clonidine (0.06, 0.25, 0.5, and 1 mg/kg) disrupted significantly PPI, idazoxan (10 mg/kg) did not produce any significant effect on PPI. However, pretreatment with idazoxan reversed significantly clonidine-induced disruption of PPI. Neither idazoxan (10 mg/kg) nor clonidine (1 mg/kg) produces any significant change on locomotor activity in naive rats. CONCLUSION: Because idazoxan and clonidine also act through imidazoline receptors, our results suggest that alpha-2 and/or imidazoline receptors are associated with PPI of acoustic startle reflex in rats. Stimulation of these receptors may cause sensorimotor gating disturbances.

Prevention of neutrophil extravasation by α2-adrenoceptor-mediated endothelial stabilization.

Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α-mediated decrease in expression of the adherens junctional molecules, VE-cadherin, ß-catenin, and plakoglobin, and reduced the ICAM-1-mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans.

Selective Blockade of α2-Adrenoceptor Subtypes Modulates Contractility of Rat Myocardium.

The study examined the dose-dependent effects of selective antagonists of α2A/D-, α2B-, and α2C- adrenoceptors applied in concentrations of 10-9-10-5 M on atrial and ventricular contractility of rat myocardium in vitro. Selective blockade of each α2-adrenoceptor subtype affected the contractile force of the atrial and ventricular strips. Various concentrations of α2A/D- and α2C-adrenoceptor antagonists produced positive inotropic effect on ventricular strips and negative effect on atrial strips. α2B-Adrenoceptor blocker in the majority of the tested concentrations produced a positive inotropic effect in both atria and ventricles.

Spinal cord stimulation modulates supraspinal centers of the descending antinociceptive system in rats with unilateral spinal nerve injury.

BACKGROUND: The descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine ß-hydroxylase (DßH)] in the spinal dorsal horn. RESULTS: Intrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DßH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DßH in the spinal dorsal horn. CONCLUSIONS: The serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.

Effects of idazoxan on alcohol pharmacokinetics and intoxication: a preliminary human laboratory study.

BACKGROUND: Preliminary basic and human studies suggest that the α2 -adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence. The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral mechanisms of idazoxan may alter alcohol's effects. METHODS: This was a preliminary double-blind, single-dose, placebo-controlled, crossover, randomized human laboratory study. Ten social drinkers were dosed, in 2 different alcohol challenge studies (ACS), with a single oral dose of idazoxan (40 mg) or placebo, followed by a fixed alcohol dose 60 minutes later. Participants returned after a 1-week washout, and they were crossed over to the opposite medication condition. RESULTS: There were no significant differences in adverse events between idazoxan and placebo. Moreover, during the ACS paradigm, 40 mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (p < 0.01) and time to peak (p < 0.05) compared to placebo. A PK/pharmacodynamic model aligned the biobehavioral effects, demonstrating that the co-administration of 40 mg idazoxan with alcohol decreased alcohol-related stimulation (p < 0.05) and increased alcohol-related sedation (p < 0.05). CONCLUSIONS: This study supports the safety and tolerability of 40 mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients.

Pharmacological profile of encounter-induced hyperactivity in isolation-reared mice.

We have recently found that isolation-reared mice show hyperactivity during an encounter with an intruder. However, it is not known whether encounter-induced hyperactivity may model some aspects of psychiatric disorders. The present study examined the pharmacological profile of encounter-induced hyperactivity in isolation-reared mice. Encounter-induced hyperactivity was reduced by acute administration of various antidepressants including the tricyclic antidepressant desipramine (10 mg/kg), the selective serotonin (5-HT) reuptake inhibitors fluvoxamine (10 mg/kg) and paroxetine (10 mg/kg), the 5-HT/noradrenaline reuptake inhibitors venlafaxine (10 mg/kg) and duloxetine (10 mg/kg), the antipsychotic drug risperidone (0.01 mg/kg), the 5-HT2 antagonist ritanserin (1 mg/kg), and the glucocorticoid receptor antagonist RU-43044 (30 mg/kg). The α2 adrenoceptor agonist clonidine (0.03 mg/kg) and the 5-HT4 receptor agonist BIMU8 (30 mg/kg) also reduced encounter-induced hyperactivity. The effect of desipramine was blocked by the α2 adrenoceptor antagonist idazoxan (0.3 mg/kg). The effect of fluvoxamine was blocked by the 5-HT4 receptor antagonist GR125487 (3 mg/kg), but not the 5-HT1A receptor antagonist WAY100635 (1 mg/kg), the 5-HT3 receptor antagonist azasetron (3 mg/kg), or the 5-HT6 receptor antagonist SB399885 (3 mg/kg). The effect of venlafaxine was blocked by the simultaneous administration of idazoxan (0.3 mg/kg) and GR125487 (3 mg/kg), but not by either compound alone. These findings suggest that encounter-induced hyperactivity in isolation-reared mice is a robust model for testing the pharmacological profile of antidepressants, although the range of antidepressants tested is limited and some non-antidepressants are also effective. The present study also shows a key role of α2 and 5-HT4 receptors in the antidepressant effect in this model.

α2-adrenoceptor binding in Flinders-sensitive line compared with Flinders-resistant line and Sprague-Dawley rats.

OBJECTIVES: Disturbances in the noradrenergic system, including alterations in the densities of α2-adrenoceptors, are posited to be involved in the pathophysiology of depression. In this study, we investigate the binding of α2-adrenoceptors in regions relevant to depression in an animal model of depression. METHODS: Using in vitro autoradiography techniques and the selective α2-ligand, [3H]RX 821002, we investigated the density of α2-adrenoceptors in female Flinders-sensitive line (FSL) rats, a validated model of depression, and in two traditional control groups - female Flinders-resistant line (FRL) and Sprague-Dawley (SD) rats. RESULTS: The α2-adrenoceptor density was increased in most regions of the FSL rat brain when compared with SD rats (10% across regions). Moreover, the α2-adrenoceptor density was further increased in the FRL rats compared with both FSL (10% across regions) and SD rats (24% across regions). CONCLUSIONS: The increase in α2-adrenoceptor binding in cortical regions in the FSL strain compared with the SD control strain is in accord with α2-adrenoceptor post-mortem binding data in suicide victims with untreated major depression. However, the differences in binding observed in the two control groups were unexpected and suggest the need for further studies in a larger cohort of animals of both sexes.

IMMOBILIZING THE VULNERABLE APENNINE CHAMOIS (RUPICAPRA PYRENAICA ORNATA) WITH A LOW-DOSE XYLAZINE-KETAMINE COMBINATION, REVERSED WITH IDAZOXAN OR ATIPAMEZOLE.

Little information is available on chemical capture of the vulnerable subspecies within the genus Rupicapra. Low-dosage combinations of xylazine and ketamine were tested for immobilization of captive and free-ranging Apennine chamois, Rupicapra pyrenaica ornata (85 and 66 immobilizations, respectively) in a retrospective analysis. Of the six dosage groups, all of them providing an acceptable level of immobilization, the optimal trade-off between safety and efficacy was found following administration of a mean dosage of 0.24±0.03 mg/kg xylazine and 1.07±0.15 mg/kg ketamine, resulting in 7.50±3.31 min induction time, deep sedation with no or limited reaction to handling in 96% of the chamois, minimal deviation of physiologic parameters from previously reported physiologic values for anesthetized or physically restrained chamois, and no mortality. Intravenous injection of idazoxan (0.05±0.01 mg/kg) or atipamezole (0.38±0.37 mg/kg) resulted in faster reversal than intravenous injection of tolazoline (1.05±0.15 mg/kg) in 1.3 vs. 4.1 min. When free-ranging chamois were darted with similar xylazine and ketamine dosages, induction time was 8.49±5.48 min, 88% of the animals were deeply sedated, and a single animal died from respiratory arrest (1.5% mortality). Intramuscular atipamezole provided smoother reversal than intravenous idazoxan. The results of this study suggest that xylazine/ketamine combinations, at remarkably lower dosage than previously published in Caprinae, may be safely and effectively used in chemical capture protocols of Apennine chamois, to facilitate conservation-oriented relocation and research.

Peculiar Effects of Selective Blockade of α2-Adrenoceptor Subtypes on Cardiac Chronotropy in Newborn Rats.

We studied the effects of selective blockade of various subtypes of α2-adrenoceptors on cardiac chronotropy in newborn rats. This period in rats is characterized by the absence of adrenergic regulation of heart function. Blockade of α2A/D- and α2B-adrenoceptors in 1-weekold rats provoked tachycardia. In contrast, blockade of α2C-adrenoceptors in newborn rats had no effect on heart rate.