The role of uptake and degradation in the regulation of peripheral serotonin dynamics in Gulf toadfish, Opsanus beta.

The neurotransmitter serotonin (5-hyroxytryptamine, 5-HT) is involved in a variety of peripheral processes. Arguably most notable is its role as a circulating vasoconstrictor in the plasma of vertebrates. Plasma 5-HT is maintained at constant levels under normal conditions through the processes of cellular uptake, degradation, and excretion, known collectively as clearance. However, the degree to which each individual component of clearance contributes to this whole animal response remains poorly understood. The goal of this experiment was to determine the extent to which transporter-mediated uptake and intracellular degradation contribute to 5-HT clearance in the model teleost Gulf toadfish (Opsanus beta). Fish that were treated with the 5-HT transport inhibitors fluoxetine, buproprion, and decynium-22 had 1.47-fold higher plasma 5-HT concentrations and a 40% decrease in clearance rate compared to control fish. In contrast, fish treated with the MAO inhibitor clorgyline had a 1.54-fold increase in plasma 5-HT with no change in clearance rate. The results show that transporter-mediated 5-HT uptake plays an important role in controlling circulating 5-HT and whole body 5-HT homeostasis.

Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse.

Complexin 2 is a protein modulator of neurotransmitter release that is downregulated in humans suffering from depression, animal models of depression and neurological disorders such as Huntington's disease in which depression is a major symptom. Although complexin 2 knockout (Cplx2-/-) mice are overtly normal, they show significant abnormalities in cognitive function and synaptic plasticity. Here we show that Cplx2-/- mice also have disturbances in emotional behaviours that include abnormal social interactions and depressive-like behaviour. Since neurotransmitter deficiencies are thought to underlie depression, we examined neurotransmitter levels in Cplx2-/- mice and found a significant decrease in levels of noradrenaline and the serotonin metabolite 5-hydroxyindoleacetic acid in the hippocampus. Chronic treatment with clorgyline, an irreversible inhibitor of monoamine oxidase A, restored hippocampal noradrenaline to normal levels (from 60 to 97% of vehicle-treated Cplx2+/+ mice, P<0.001), and reversed the behavioural deficits seen in Cplx2-/- mice. For example, clorgyline-treated Cplx2-/- mice spent significantly more time interacting with a novel visitor mouse compared with vehicle-treated Cplx2-/- mice in the social recognition test (34 compared with 13%, P<0.01). We were also able to reverse the selective deficit seen in mossy fibre-long-term potentiation (MF-LTP) in Cplx2-/- mice using the noradrenergic agonist isoprenaline. Pre-treatment with isoprenaline in vitro increased MF-LTP by 125% (P<0.001), thus restoring it to control levels. Our data strongly support the idea that complexin 2 is a key player in normal neurological function, and that downregulation of complexin 2 could lead to changes in neurotransmitter release sufficient to cause significant behavioural abnormalities such as depression.

Gestational exposure to nicotine and monoamine oxidase inhibitors influences cocaine-induced locomotion in adolescent rats.

RATIONALE: Many pregnant women continue to smoke, despite a strong association between maternal smoking and neurobehavioral deficits in the offspring. Although gestational nicotine (GN) treatment in rodents is used as the primary animal model of maternal smoking, tobacco smoke contains more than 4,000 constituents, including monoamine oxidase inhibitors (MAOIs). OBJECTIVES: The aim of this study was to determine whether there are interactions between the effects of gestational exposure to nicotine and MAOIs on cocaine-induced locomotor sensitization in adolescent rats. MATERIALS AND METHODS: Pregnant rats were implanted on day 4 of gestation with osmotic minipumps delivering saline, nicotine (3 mg/kg per day), the MAOIs clorgyline and deprenyl (1 and 0.25 mg/kg per day, respectively), or nicotine/clorgyline/deprenyl (GMN). Adolescent female offspring were tested for cocaine-induced locomotor sensitization. Animals were treated with saline or cocaine (5 or 15 mg/kg, intraperitoneally) daily from postnatal (P) days 32-36 and challenged with cocaine (15 mg/kg) on P51 (day 20). RESULTS: Group differences were observed in chronic but not acute effects of cocaine. Whereas gestational MAOI treatment, with or without nicotine, increased ambulatory response to cocaine on day 5, the opposite was found for vertical activity. Different adaptive responses were observed on cocaine challenge day. GNM animals exhibited enhanced locomotor activity in the cocaine-associated environment before cocaine challenge on day 20. In contrast, only GN animals exhibited significant locomotor sensitization to the cocaine challenge. CONCLUSIONS: Gestational nicotine and MAOIs both influence brain development. Such interactions may sensitize adolescents to drug abuse and should be considered in animal models of maternal smoking.

L-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats; Insights towards selegiline's mechanism of action.

Selegiline is an inhibitor of type B monoamine oxidase (MAO) with psychostimulant effects that can decrease morphine-reinforced and non-reinforced responding. The present study was undertaken to compare the effects of MAO inhibition and treatment with L-methamphetamine, the major psychostimulant metabolite of selegiline, on these behaviors. After rats acquired a stable pattern of morphine self-administration under a progressive ratio schedule, chronic treatment was initiated with vehicle, L-methamphetamine, clorgyline (a selective inhibitor of MAO-A), or rasagiline (a selective inhibitor of MAO-B); with both MAO inhibitors administered at a dose selective for one MAO isoform and a higher dose that inhibited both isoforms. Rats were evaluated for up to four cycles of opiate dependence maintained by morphine self-administration and withdrawal during which extinction responding was recorded. Most behavioral measures (92.4%) did not differ in animals evaluated during an initial and subsequent cycles of dependence and withdrawal. All active treatments attenuated non-reinforced responding during extinction. Morphine reinforcement was also decreased by each of the three active treatments, but greater and more prolonged effects were observed following inhibition of MAO-B with rasagiline. Responding during either cue- or morphine-induced reinstatement was attenuated by either clorgyline or rasagiline administered at nonselective doses, but not by either compound administered at selective dose levels. Treatment with L-methamphetamine did not produce significant effects on cue-induced reinstatement, but decreased non-reinforced responding during morphine-induced reinstatement. These findings indicate that morphine reinforcement and different non-reinforced behaviors differ greatly in their susceptibility to modification by psychostimulant treatment or MAO inhibition.

Clorgyline. A new treatment for patients with refractory rapid-cycling disorder.

Five women with primary, major, bipolar affective disorder, characterized by rapid mood cycles and nonresponsiveness to conventional drug treatments, including lithium carbonate, were given low doses (2.5 to 10.0 mg/24 hr) of clorgyline, a selective inhibitor of monoamine oxidase type A. In four patients, clorgyline, along or in combination with lithium carbonate, prolonged the duration and lessened the severity of mood cycles. One patient experienced prolonged mania while receiving clorgyline therapy. Clorgyline-induced remissions have lasted from three to more than 12 months.

Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy.

Oxidative stress is closely associated with the pathophysiology of diabetic cardiomyopathy (DCM). The mitochondrial flavoenzyme monoamine oxidase A (MAO-A) is an important source of oxidative stress in the myocardium. We sought to determine whether MAO-A plays a major role in modulating DCM. Diabetes was induced in Wistar rats by single intraperitoneal injection of streptozotocin (STZ). To investigate the role of MAO-A in the development of pathophysiological features of DCM, hyperglycemic and age-matched control rats were treated with or without the MAO-A-specific inhibitor clorgyline (CLG) at 1 mg/kg/day for 8 weeks. Diabetes upregulated MAO-A activity; elevated markers of oxidative stress such as cardiac lipid peroxidation, superoxide dismutase activity, and UCP3 protein expression; enhanced apoptotic cell death; and increased fibrosis. All these parameters were significantly attenuated by CLG treatment. In addition, treatment with CLG substantially prevented diabetes-induced cardiac contractile dysfunction as evidenced by decreased QRS, QT, and corrected QT intervals, measured by ECG, and LV systolic and LV end-diastolic pressure measured by microtip pressure transducer. These beneficial effects of CLG were seen despite the persistent hyperglycemic and hyperlipidemic environments in STZ-induced experimental diabetes. In summary, this study provides strong evidence that MAO-A is an important source of oxidative stress in the heart and that MAO-A-derived reactive oxygen species contribute to DCM.

Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated [35S]GTP gamma S binding in rat brain regions.

Electrophysiological studies have led to the proposal that the neurobiological mechanism(s) underlying drug therapy of anxiety and depression involve(s) regionally specific adaptations in 5-HT(1A) receptor sensitivity. Depending on the drug utilized, a decrease in sensitivity of inhibitory somatodendritic autoreceptors, an increase in sensitivity of postsynaptic receptors, or both alterations, occur after several weeks of treatment. This hypothesis was tested using N,N-dipropyl-5-carboxamidotryptamine-stimulated guanosine-5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding assessed by autoradiography. Rats were treated for 21 days with one of four different anxiolytic/antidepressant drugs (in mg/kg): fluoxetine (10), imipramine (10), clorgyline (1), ipsapirone (2 x 20) or saline. Three brain regions rich in 5-HT(1A) receptors were examined: the dorsal raphe (somatodendritic), the dorsal hippocampus (postsynaptic) and the lateral septum (postsynaptic). Only imipramine (+17%) and fluoxetine (+54%) significantly increased agonist-stimulated binding in the dorsal hippocampus; all drugs except imipramine significantly decreased binding in the dorsal raphe (-19 to -41%). These results generally support the concept of a net enhancement of hippocampal 5-HT neurotransmission via one or more 5-HT receptor subtypes. The most consistent effect, however, was a significant decrease in stimulated [(35)S]GTPgammaS binding in the lateral septum after all four treatments (-14 to -23%), suggesting that this may be a heretofore unrecognized common outcome of antidepressant treatment deserving further study.

Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5-hydroxytryptamine uptake blocker.

The administration of 4-[2-(3-indolyl)ethyl]piperidine (LM 5008), a selective 5-hydroxytryptamine (5-HT) uptake blocker to rats pretreated with tranylcypromine (Tcp) resulted in a behavioural syndrome of locomotor hyperactivity which is indistinguishable from that following combined treatment with Tcp and L-tryptophan. A similar behavioural response was elicited by the administration of LM 5008 to rats pretreated with 5-hydroxytryptophan. The response to LM 5008 after monoamine oxidase (MAO) inhibition was abolished by pretreatment with p-chlorophenylalanine, indicating the involvement of 5-HT in producing the hyperactivity syndrome. The administration of imipramine and chlorimipramine in combination with Tcp also resulted in hyperactivity, but these drugs were much less potent than LM 5008 in producing the syndrome. In contrast to L-tryptophan, which can produce hyperactivity only after the inhibition of both type A and type B MAO, LM 5008 can elicit the syndrome after selective inhibition of MAO type A only but not after inhibition of MAO type B. The behavioural results indicate that when MAO type A is inhibited, LM 5008 treatment elicits hyperactivity by preventing the availability of 5-HT to be metabolized by MAO-B component.

The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors.

1. The binding of [3H]-idazoxan in the presence of 10(-6) M (-)-adrenaline was used to quantitate I2 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irreversible and reversible monoamine oxidase (MAO) inhibitors. 2. Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-1, i.p.), isocarboxazid (10 mg kg-1, i.p.), clorgyline (3 mg kg-1, i.p.) and tranylcypromine (10 mg kg-1, i.p.) markedly decreased (21-71%) the density of I2 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-1, i.p.) or chlordimeform (10 mg kg-1, i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-1, i.p.) did not alter the density of I2 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3. In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform displaced the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 microM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4. Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 Mclorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors.5. Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-1, i.p.), 3-methylcholanthrene (20 mg kg-1, i.p.) or 2-methylimidazole (40 mg kg-1, i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors.The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 microM)the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes.6. Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported.

Acute and chronic effects of desipramine and clorgyline on alpha(2)-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual-probe microdialysis study.

1. The effects of desipramine (3 mg kg(-1) i.p.) and clorgyline (1 mg kg(-1) i.p.) on extracellular noradrenaline (NA) in the locus coeruleus (LC) and cingulate cortex were assessed in freely-moving rats by dual-probe microdialysis. Functional activities of alpha(2)-adrenoceptors regulating NA release in the LC and cingulate cortex were determined by systemic (0.3 mg kg(-1) i.p.) or local (0.1 - 100 microM) clonidine administration. 2. Extracellular NA was increased in the LC and cingulate cortex following acute desipramine but not clorgyline treatment. Systemic clonidine decreased NA similarly in desipramine-, clorgyline-, and saline-treated animals, in both brain areas. 3. Long-term (twice daily, 14 days) but not short-term (twice daily, 7 days) desipramine, and long-term clorgyline (once daily, 21 days) treatments increased NA (3 fold) in cingulate cortex but not in the LC. Following long-term treatments, responses of NA to systemic clonidine were attenuated in the LC and cingulate cortex. 4. Clonidine perfusion by reverse dialysis into the cingulate cortex decreased local NA (-55 +/- 9%). The effect was attenuated by long-term desipramine (-31 +/- 9%) and clorgyline (-10 +/- 2%) treatments. 5. Clonidine perfusion by reverse dialysis into the LC decreased NA in the LC (-89 +/- 2%) and in cingulate cortex (-52 +/- 12%). This effect was attenuated in the LC following long-term desipramine (-72 +/- 4%) and clorgyline (-62 +/- 12%) treatments but it was not modified in the cingulate cortex (-57 +/- 10% and -68 +/- 6%, respectively). 6. These findings demonstrate that chronic desipramine or clorgyline treatments increase NA in noradrenergic terminal areas and desensitize alpha(2)-adrenoceptors modulating local NA release at somatodendritic and terminal levels. However, somatodendritic alpha(2)-adrenoceptors that control LC firing activity are not desensitized.

5HT2 receptor changes in rat cortex and platelets following chronic ritanserin and clorgyline administration.

Chronic administration of clorgyline or ritanserin to adult rats for 28 days followed by a 3 day drug-free period results in a significant decrease in 5HT2 receptor number (Bmax) in rat frontal cortex from 315.23 +/- 10.72 fmol/mg protein to 249.63 +/- 13.99 fmol/mg protein and 222.55 +/- 17.17 fmol/mg protein, respectively. On rat blood platelets, ritanserin significantly increases recept number from 26.18 +/- 3.83 fmol/mg protein to 50.94 +/- 7.96 fmol bound/mg protein, whereas clorgyline has no significant effect (21.32 +/- 4.78 fmol/mg protein). Following both drug regimens, the affinity (Kd) of the respective ligands for the receptor is not significantly different from controls: the mean Kd value of the three groups for [3H]ketanserin is 1.57 +/- 0.05 nM in cortex and 0.83 +/- 0.25 nM for [125I]iodolysergic acid diethylamide (LSD) on platelets. Clorgyline increases serotonin (5HT) and noradrenaline (NA) levels in cerebellum, and decreases 5-hydroxyindole acetic acid (5HIAA) and homovanillic acid (HVA): ritanserin does not change the levels of the amines or their metabolites. The data shows that platelet and brain changes are not comparable after ritanserin administration. The receptor binding data demonstrates that curve fitting to two data points provides information which is comparable to and as statistically robust as that obtained from eight point saturation curves. Thus, if pilot studies show that the data follows a rectangular hyperbola, two point assays (optimal at 0.1 Kd and 3 Kd) can be used to obtain estimates of Bmax and Kd.

Clorgyline-induced switch from locomotion to mouthing in sensitization to the dopamine D2/D3 agonist quinpirole in rats: role of sigma and imidazoline I2 receptors.

RATIONALE: The monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. Clorgyline has a high affinity for imidazoline I(2) and sigma receptors, which could account for its effects on quinpirole sensitization. OBJECTIVES: To examine whether the effect of clorgyline on quinpirole sensitization is attributed to stimulation of either I(2) or sigma receptors. METHODS: In one experiment, rats received injections of the I(2) receptor agonist 2-BFI (0.2 mg/kg, IP) or vehicle, 90 min prior to each injection of quinpirole (0.5 mg/kg, SC, x 8, twice weekly) or saline. A similar protocol was used to examine the effects of the MAOI Ro 41-1049 (10 mg/kg, SC) on quinpirole sensitization. Unlike clorgyline, Ro 41-1049 has no affinity for sigma or I(2) sites. An initial experiment demonstrated that intermittent injections of clorgyline (1 mg/kg, SC) are as effective as a continuous clorgyline administration (1 mg/kg per day via osmotic mini-pump) on quinpirole sensitization. RESULTS: Like clorgyline, Ro 41-1049, but not 2-BFI, blocked the development of quinpirole-induced locomotor sensitization and induced instead sensitization of self-directed mouthing. CONCLUSIONS: Because Ro 41-1049 produced the same effects as clorgyline, and 2-BFI had no effects on quinpirole sensitization, it is unlikely that clorgyline exerts its effects via an action at sigma or I(2) receptors. Our results are consistent with the suggestion that clorgyline and Ro 41-1049 affect the behavioral response to quinpirole via the MAOI-displaceable quinpirole binding (MQB) site, and the hypothesis that the MQB site selects what motor output becomes sensitized to repeated injections of quinpirole.

Effect of nitecapone and clorgyline, given intracerebro-ventricularly on L-dopa metabolism in the rat brain.

A new COMT inhibitor, nitecapone (OR-462) or clorgyline, a MAO-A inhibitor, was infused into the 3rd brain ventricle (i.c.v.) of conscious male rats. None of the enzyme inhibitors given alone alter hypothalamic or striatal levels of L-dopa, dopamine or their metabolites. Most of the rats were pretreated with levodopa/carbidopa (LD/CD, 15/30 mg kg-1 intraperitoneally). Now, the action of nitecapone is localized in the hypothalamus since homovanillic acid (HVA) is decreased there, not in the striatum. The levels of 3-O-methyldopa (3-OMD) are not changed in either brain region, suggesting a lack of the peripheral leakage of nitecapone. Clorgyline (3 and 10 micrograms rat-1) elevates hypothalamic and dopamine levels. Nitecapone and clorgyline decrease prolactin (PRL) levels below those reduced by LD/CD treatment.

Interactions between relatively selective monoamine oxidase inhibitors and an inhibitor of 5-hydroxytryptamine re-uptake, clomipramine.

Features of interactions with combined antidepressants in man were evoked by clomipramine in rats pretreated with both the relatively selective monoamine oxidase (MAO) inhibitors clorgyline and deprenyl, but not when clomipramine was given to rats pretreated with deprenyl or clorgyline alone, i.e. inhibition of both MAO A and B was a likely prerequisite for clomipramine to elicit the syndrome (with the larger dose of clorgyline and deprenyl, MAO A and B inhibition exceeded 95%). The features evoked were myoclonic--forelimb flexor-extensor movements, wet dog shakes and head and body twitches; hyperthermia and ECG anomalies also developed, and locomotor activity was augmented. Myoclonic phenomena were prevented when the above pretreatment also included p-chlorophenyl-alanine, but were unaffected or even intensified when pretreatment instead included alpha-methyl-p-tyrosine; these phenomena were attenuated or abolished by pirenperone, a 5HT2 antagonist. Relevance of these findings to safer combinations of antidepressants is discussed.

Down-regulation of tryptamine receptors following chronic administration of clorgyline.

Chronic treatment with clorgyline, a type A monoamine oxidase (MAO) inhibitor (1 mg/kg/day for 11 days), reduced the number (Bmax) but not the affinity (Kd) of [3H]tryptamine binding sites in rat frontal/parietal cortical membranes. Binding was reduced for at least 36 days following the last injection. The reduction in [3H]tryptamine binding was dose-related and appeared to be maximal following a daily dose of 3 mg/kg. Chronic treatment with deprenyl, a type B MAO inhibitor (1 mg/kg/day for 11 days), did not affect [3H]tryptamine binding. Acute clorgyline administration (11 mg/kg) also had no effect. These data suggest that [3H]tryptamine binds to neurotransmitter receptors for tryptamine since mere chemical recognition sites would not be expected to be modulated by chronic drug treatment. Also, since [3H]tryptamine binding was down-regulated by a type A, but not a type B, MAO inhibitor, tryptamine may be selectively metabolized by type A MAO in vivo.

Monoamine oxidase inhibitor sensitive site implicated in sensitization to quinpirole.

Clorgyline (1.0 mg/kg/day) administered via osmotic minipumps blocked the development of locomotor sensitization to the dopamine receptor agonist quinpirole (0.5 mg/kg every 3 days for 8 injections). In male rats already well sensitized to quinpirole, the continuous infusion of clorgyline (1.0 mg/kg/day for 28 days) produced a progressive decline in locomotor activity, despite a continued regimen of quinpirole injections (0.5 mg/kg every 3 days). It is suggested that the development, as well as the maintenance, of locomotor sensitization to quinpirole is modulated by the activation of an monoamine oxidase inhibitor-sensitive site. This site may be a dopamine D2 receptor-linked monoamine oxidase inhibitor-displaceable quinpirole binding site, the enzyme monoamine oxidase-A, or other clorgyline binding sites.

Behavioural response to SKF 38393 and quinpirole following chronic antidepressant treatment.

The effects of chronic administration of antidepressant drugs (21-22 days s.c. via osmotic mini-pumps) on the behavioural responses of male Sprague-Dawley rats to (-)-quinpirole hydrochloride (0.05 mg kg-1 s.c., 5 min) and (+/-)-SKF 38393 hydrochloride (10 mg kg-1 s.c., 5 min) were investigated. Desipramine hydrochloride (10 mg kg-1 per day), phenelzine sulphate (10 mg kg-1 per day) and clorgyline hydrochloride (1 mg kg-1 per day) attenuated the suppression of locomotor activity induced by quinpirole, a dopamine D2-like receptor agonist, while clomipramine hydrochloride (10 mg kg-1 per day) was without effect. Yawning elicited by quinpirole was absent in phenelzine- and clorgyline-treated rats, but unaffected in rats treated chronically with desipramine and clomipramine. SKF 38393, a dopamine D1-like receptor agonist, significantly increased locomotor activity and time spent grooming in control animals. There were no significant effects of antidepressants on the behavioural responses to SKF 38393.

Antidepressant-induced modulation of GABAA receptors and beta-adrenoceptors but not GABAB receptors in the frontal cortex of olfactory bulbectomised rats.

The effects of prolonged administration of antidepressant drugs, belonging to three different classes, on high-affinity GABAA receptor, GABAB receptor and beta-adrenoceptor binding parameters were determined in the frontal cortex of olfactory bulbectomised rats. Clorgyline (1 mg/kg/day), paroxetine (10 mg/kg/day) or desipramine (10 mg/kg/day) were administered for 21 days via subcutaneous osmotic minipumps implanted in the scapular region 7 days after bulbectomy. Cortical GABAA receptor densities, defined with [3H]gamma-aminobutyric acid ([3H]GABA), were significantly increased following bulbectomy. This effect on Bmax values was reversed by all three antidepressant drugs. GABAB receptor densities decreased slightly after bulbectomy. Chronic antidepressant administration had no effect on GABAB receptor binding parameters. Olfactory bulbectomy did not induce any changes in cortical beta-adrenoceptor binding parameters determined with [3H]CGP-12177 ((-)-4-(3-t- butylamino-2-hydroxypropxy)- [5,7-3H]benzimidazol-2-one). However, prolonged administration of all three antidepressant drugs induced a downregulation of beta-adrenoceptors. The results of the present study confirm the involvement of cortical GABAA rather than GABAB receptors in the olfactory bulbectomy animal model of human depression. Moreover, the data further support the hypothesis that a decrease in function of the GABAA receptor complex could play a role in the therapeutic effects of antidepressant treatments.

Chronic inhibition of monoamine oxidase type A increases noradrenaline release in rat frontal cortex.

Chronic but not acute treatment of rats with MAO inhibitors, as with other antidepressant drugs, has been shown to down-regulate the number of cerebro-cortical beta-adrenoceptors. In order to establish whether this effect is associated with an increase in cortical noradrenaline release, rats were treated for 1, 3 or 21 days with clorgyline (2 mg/kg i.p. single injection; 1 mg/kg i.p. repeated injections), and the frontal cortex was then perfused by microdialysis in the awake animal. Control animals were injected with saline. The concentration of noradrenaline in the microdialysate increased only slightly after 1 or 3 days of clorgyline treatment but increased fourfold over control levels after 21 days treatment. Yohimbine (20 mumol/l) added to the perfusing solution caused a similar degree of enhancement in microdialysate noradrenaline concentration in all groups of rats. Tetrodotoxin (10 mumol/l) reduced noradrenaline concentration to low levels in all groups of animals, but noradrenaline was still detectable in the microdialysate in rats treated with clorgyline for 21 days. Concentrations of the deaminated metabolites dihydroxyphenylacetic acid, dihydroxyphenylglycol and methoxy-hydroxyphenylglycol were lowest after the 21 day clorgyline treatment. Determination of enzyme activity ex vivo showed that MAO-A was inhibited more than 95% by all clorgyline treatments with less than 10% inhibition of MAO-B. The results indicate that cerebrocortical noradrenaline release increases gradually during chronic MAO inhibition. This may be the result of more complete inhibition of the enzyme with time, not detectable by the ex vivo assay, but shown by the progressive reduction in metabolite levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Modification of cerebral cortical noradrenaline release by chronic inhibition of MAO-A.

Chronic treatment of rats with clorgyline (1 mg/kg i.p. daily for 21 days) caused a highly significant increase in the concentration of noradrenaline in microdialysate from the frontal cortex of the awake animal. Acute (one injection, 2 mg/kg) or subacute (1 mg/kg daily for 3 days) treatment did not lead to a significant increase in microdialysate noradrenaline. Concentrations of deaminated metabolites (DPHG, MHPG, DOPAC) in the microdialysate decreased with time of treatment, reaching a minimum after 21 days.