Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain.

The present electrophysiological experiments were undertaken to investigate the effect of desipramine and d-amphetamine on noradrenergic neurotransmission in the rat central nervous system. The effectiveness of electrical stimulation of the locus coeruleus and of microiontophoretic application of norepinephrine (NE) in suppressing the firing activity of CA3 pyramidal neurons was studied in the dorsal hippocampus. Desipramine (0.5 and 5 mg/kg i.v.) and d-amphetamine (0.25 and 5 mg/kg i.v.) decreased the effectiveness of locus coeruleus stimulation and prolonged the effect of microiontophoretically applied NE on the same pyramidal neurons. Subsequent i.v. administration of idazoxan, an alpha 2-adrenoceptor antagonist, reversed the effects of desipramine and d-amphetamine on the effectiveness of locus coeruleus stimulation and decreased that of microiontophoretically applied NE. In addition, idazoxan prevented the effect of subsequent administration of desipramine (5 mg/kg i.v.) on the effectiveness of locus coeruleus stimulation. High doses of d-amphetamine (5 and 10 mg/kg i.v.) decreased the firing activity of hippocampus pyramidal neurons by 70 and 98%, respectively, whereas low doses of desipramine (0.5 mg/kg i.v.) or of d-amphetamine (0.25 mg/kg i.v.) were without effect. After lesioning of NE projections with 6-hydroxydopamine, the effect of the 5 mg/kg dose of d-amphetamine on the firing activity of hippocampus pyramidal neurons was markedly reduced, whereas the cumulative 10 mg/kg dose of d-amphetamine completely suppressed, as in control rats, the firing activity of these neurons. This effect of d-amphetamine in 6-hydroxydopamine-pretreated rats was reversed by the administration of the 5-HT1A receptor antagonist BMY 7378. These data provide evidence that acute administration of desipramine and d-amphetamine decreases the effectiveness of locus coeruleus stimulation by increasing the activation of terminal alpha 2-adrenoceptor autoreceptors. In addition, acute administration of high doses of d-amphetamine decreases the firing rate of hippocampus pyramidal neurons by increasing NE and serotonin release.     

Effects of a potential antipsychotic, BMY 14802, on firing of central serotonergic and noradrenergic neurons in rats

BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- piperazinebutanol HCl) is a novel potential antipsychotic drug which does not bind to dopamine receptors, does bind to 5-HT1A receptors, and also binds stereoselectively to sigma sites. The effects of acute systemic administration of this compound on spontaneously firing serotonergic dorsal raphe neurons and noradrenergic locus coeruleus neurons were assessed by means of extracellular single unit recordings in chloral hydrate anesthetized male Sprague-Dawley rats. (+/-)-BMY 14802 produced inhibition of firing of serotonergic dorsal raphe neurons when given intravenously (ED50 = 0.19 mg/kg) and intragastrically (effective dose = 20 mg/kg). Racemic and enantiomeric BMY 14802 mainly produced mild increases in firing (approximately 60% or less) of noradrenergic locus coeruleus neurons, with (-)-BMY 14802 slightly more potent (ED25 = 0.31 mg/kg i.v.) than (+)-BMY 14802 (ED25 = 0.55 mg/kg i.v.), and the racemate being intermediate (ED25 = 0.36 mg/kg i.v.). These electrophysiological studies demonstrate that in this rat preparation acute systemic administration of BMY 14802 produces changes in serotonergic and noradrenergic brain function.     

Serotonergic regulation of noradrenergic coerulean neurons: electrophysiological evidence for the involvement of 5-HT2 receptors

To determine the type of serotonergic receptor involved in the modulation of noradrenergic neuronal activity in the locus coeruleus, the effects of 4 systemically administered serotonergic drugs were tested on the firing rate of noradrenergic neurons in the locus coeruleus of rats under chloral hydrate anaesthesia. The serotonergic agonist, quipazine (1 mg/kg), and the selective 5-HT2 agonist, DOB (50-100 micrograms/kg), induced a pronounced decrease of the discharge frequency. This effect could be prevented or reversed by the selective 5-HT2 antagonist, ketanserin (4-8 mg/kg). Ketanserin alone and the 5-HT1 agonist, RU 24969, had no or a weak excitatory action on the neuronal activity of the locus coeruleus. We conclude that the serotonergic control of noradrenergic neurons in the locus coeruleus is mediated by post-synaptic 5-HT2 receptors because the quipazine-ketanserin effects on this unit activity persisted after depletion of serotonergic presynaptic stores.     

Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.     

Electrophysiological effects of methylphenidate on the coeruleo-cortical noradrenergic system in the rat

The effect of methylphenidate on noradrenergic neurotransmission was investigated in urethane-anesthetized rats. The spontaneous activity of locus coeruleus noradrenergic neurons was the same in rats treated for 7 days with methylphenidate as in the controls. In control rats, i.v. methylphenidate induced a reduction of locus coeruleus neuronal firing whereas in rats treated for 7 days with methylphenidate, the same dose of methylphenidate failed to induce any change in locus coeruleus activity. At this time, clonidine induced a lesser reduction of locus coeruleus neuronal firing than in the controls, indicating that their autoreceptors had become desensitized. Following electrical stimulation of the locus coeruleus, most of the spontaneously firing cortical neurons were inhibited but the percentage of such neurons was reduced and the neurons showed a decreased responsiveness after methylphenidate treatment. The responsiveness of cortical neurons to microiontophoretic applications of NA as assessed by the I.T50 method was reduced after 7 days of treatment with methylphenidate. These findings suggest that the efficacy of cortical NA neurotransmission is markedly reduced following methylphenidate treatment.     

Cholinergic control of catechol metabolism in the rat locus coeruleus as studied by in vivo voltammetry

Differential pulse voltammetry with treated carbon fibre electrodes was used to study the effect of cholinergic drugs on the metabolism of locus coeruleus (LC) noradrenergic cells in vivo. A catechol peak corresponding to DOPAC synthesized by noradrenergic cells and reflecting their metabolic activity, was recorded every two minutes in the LC of freely moving rats. Cholinergic agonists like eserine (0.5 mg/kg s.c.) and oxotremorine (0.1 and 0.4 mg/kg s.c.) increased the DOPAC peak. This effect seemed to be mediated by muscarinic receptors since it was antagonized by scopolamine (5 mg/kg i.p.). Oxotremorine in high doses (1.5 mg/kg s.c. for 3 days) induced 'delayed activation' of tyrosine hydroxylase (+273%). In these conditions LC cells were no longer responsive to a challenge dose of oxotremorine though they maintained normal responsiveness to noradrenergic drugs. The results show that cholinergic drugs can greatly influence the metabolism of LC noradrenergic neurons.     

Effects of the antidepressant compound nefazodone on central monoaminergic neuronal discharge in rats

The effects of i.v. administration of the antidepressant compound nefazodone were assessed on the firing rates of spontaneously active noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the dorsal raphe (DR), and dopaminergic neurons in the substantia nigra (SN) of chloral hydrate anesthetized male albino adult rats, utilizing extracellular single-unit recording methods. Nefazodone, tested in doses of 0.1–10.0 mg/kg, had variable effects on LC neurons, but the predominant effect was a mild excitation of firing (ED₂₅ = 1.953 mg/kg). This may in part be caused by the 5-HT₂ antagonist properties of the compound, since ritanserin also produced a mild excitation of LC neurons. By comparison, desipramine very reliably inhibited LC neurons (ED₅₀ = 0.333 mg/kg, i.v.). For DR neurons, i.v. nefazodone (0.1–3.2 mg/kg) produced variable effects, with inhibition being the most common (63% of cases tested). The ED₂₅ for inhibition was 1.230 mg/kg, and in no case was inhibition of 50% or greater observed. By comparison, clomipramine very reliably inhibited DR neurons (ED₅₀ = 0.501 mg/kg, i.v.). For SN neurons, the effects of i.v. nefazodone were also variable, with no consistent effects observed. These results indicate that acute nefazodone produces relatively weak effects on monoaminergic neuronal impulse flow in anesthetized rats, and suggest that major modifications of monoaminergic neuronal impulse flow probably do not play an important role in any neuroadaptive changes that may contribute to the clinical antidepressant actions of nefazodone.     

Involvement of locus coeruleus noradrenergic neurons in supraspinal antinociception by alpha,beta-methylene-ATP in rats

We reported previously that intracerebroventricular (i.c.v.) administration of P2X-receptor agonists produced antinociception and the effect was attenuated by i.c.v. pretreatment with beta(2)-adrenergic receptor antagonists. The present study examined the involvement of noradrenergic neurons arising from the locus coeruleus (LC) in the supraspinal antinociception by the P2X-receptor agonist alpha,beta-methylene-ATP in rats. We found that pretreatment with DSP-4 (50 mg/kg, i.p.), which is a neurotoxin to selectively disrupt noradrenergic neurons arising from the LC, significantly attenuated the antinociception by i.c.v. administration of alpha,beta-methylene-ATP (10 nmol/rat). Microinjection of alpha,beta-methylene-ATP (0.1 and 1 nmol/side) into the bilateral LC significantly elevated the nociceptive threshold more potently than the i.c.v. administration at a dose of 10 nmol/rat. The antinociception by intra-LC injection of alpha,beta-methylene-ATP (1 nmol/side) was significantly attenuated by co-injection of pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (1 nmol/side), a non-selective P2X-receptor antagonist. These results suggest that noradrenergic neurons arising from the LC are involved in the supraspinal antinociception by alpha,beta-methylene-ATP through P2X receptors in the LC.     

Attenuation of acute and chronic effects of morphine by the imidazoline receptor ligand 2-(2-benzofuranyl)-2-imidazoline in rat locus coeruleus neurons

1 The aim of this study was to determine if 2-(2-benzofuranyl)-2-imidazoline (2-BFI) interacts with the opioid system in the rat locus coeruleus, using single-unit extracellular recordings. 2 In morphine-dependent rats, acute administration of the selective imidazoline receptor ligands 2-BFI (10 and 40 mg kg(-1), i.p. and 100 micro g, i.c.v.) or valldemossine (10 mg kg(-1), i.p.) did not modify the naloxone-induced hyperactivity of locus coeruleus neurons compared with that observed in the morphine-dependent control group. 3 After chronic administration of 2-BFI (10 mg kg(-1), i.p., three times daily, for 5 days) and morphine, naloxone-induced hyperactivity and tolerance to morphine were attenuated. This effect was not observed when a lower dose of 2-BFI (1 mg kg(-1), i.p.) or valldemossine (10 mg kg(-1), i.p.) were used. 4 Acute administration of 2-BFI (10 and 40 mg kg(-1), i.p. and 100 micro g, i.c.v.) but not valldemossine (40 mg kg(-1), i.p.) diminished the potency of morphine to inhibit locus coeruleus neuron activity in vivo (ED(50) values increased by 2.3, 2.9; and 3.1 fold respectively). Similarly, the potency of Met(5)-enkephalin to inhibit locus coeruleus neurons was decreased when 2-BFI (100 micro M) was applied to rat brain slices (EC(50) increased by 5.6; P<0.05). 5 The present data demonstrate that there is an interaction between 2-BFI and the opioid system in the locus coeruleus. This interaction leads to an attenuation of both the hyperactivity of locus coeruleus neurons during opiate withdrawal and the development of tolerance to morphine when 2-BFI is chronically administered. These results suggest that imidazoline drugs may prove to be useful agents for the management of opioid dependence and tolerance.     

Progressive attenuation of the firing activity of locus coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake inhibitors

Sustained administration of the selective serotonin (5-HT) reuptake inhibitors (SSRIs) citalopram for 2, 14, and 21 d, and paroxetine for 2 and 21 d (20 and 10 mg/kg.d, respectively, s.c. using osmotic minipumps) produced a gradual decrease in spontaneous firing activity of locus coeruleus (LC) noradrenergic neurons. In contrast, sustained desipramine administration for 2 and 21 d (10 mg/kg.d) robustly reduced LC firing activity, though only to the same extent, following these two treatment periods. The enhancement of the firing rate of LC neurons produced by the 5-HT1A agonist 8-OH-DPAT (10-50 &mgr;g/kg, i.v.) in desipramine- and citalopram-treated rats was abolished, indicating a desensitization of 5-HT1A receptors. However, the attenuation of the firing rate of LC neurons induced by the 5-HT2 agonist DOI (5-50 &mgr;g/kg, i.v.) was decreased approx. 2-fold in citalopram-treated rats but not significantly altered in desipramine-treated rats. Since 5-HT neurons exert a tonic inhibitory effect on LC neurons, it appears that enhancing 5-HT neurotransmission by sustained SSRI administration leads to a reduction of the firing rate of noradrenergic neurons. In conclusion, SSRIs attenuate the activity of noradrenergic neurons with a delay that is consistent with their beneficial effect in depression and some anxiety disorders, such as panic, generalized and social anxiety disorders. However, given the hyperadrenergic state often observed in anxiogenic conditions the latter phenomenon is believed to contribute more to the anxiolytic effect of SSRIs than to their antidepressant action.     

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission.

1-(2-Pyrimidinyl)-piperazine (1-PP) is a common metabolite of the antidepressant/anxiolytic 5-HT1A agonists, tandospirone (SM-3997), gepirone, buspirone and ipsapirone. The present electrophysiological studies were undertaken to characterize in vivo the effect of 1-PP on noradrenergic (NE) neurotransmission in rat brain. At small doses, 1-PP (ED50 = 80 micrograms/kg, i.v.) reversed the depressant effect of the alpha 2-adrenoceptor agonist, clonidine (20 micrograms/kg, i.v.) on the firing activity of NE neurones of the locus coeruleus. After long-term treatment with tandospirone (10 mg/kg/day, s.c. x 14 days), the responsiveness of these NE neurones to intravenous administration of clonidine was decreased but their mean firing frequency remained within the control range. The effect of 1-PP on the postsynaptic alpha 2-adrenoceptor of pyramidal neurones in the hippocampus was investigated: intravenous administration of 1-PP (2-8 mg/kg, i.v.) reduced the effect of microiontophoretically-applied NE on CA3 pyramidal neurones of the dorsal hippocampus, without affecting their responsiveness to GABA and 5-HT. The effect of the electrical stimulation of NE neurones of the locus coeruleus in reducing firing activity of pyramidal neurones, which is mediated by postsynaptic alpha 1-adrenoceptors, was increased by 47% after acute administration of 1-PP (4 mg/kg, i.v.), presumably as a result of blockade of terminal alpha 2-autoreceptors. The effectiveness of these stimulations remained unchanged after long-term treatment with tandospirone. Furthermore, the decrease in the effectiveness of stimulation of the locus coeruleus, obtained by increasing the frequency from 1 to 5 Hz, a phenomenon due to an increased activation of terminal alpha 2-adrenergic autoreceptors by endogenous NE, remained unaltered after long-term treatment with tandospirone. In addition to the initial depressant effect, stimulation of the locus coeruleus induces a late activation of these neurones which is mediated by a beta-adrenoceptor. The degree of activation induced by stimulation of the locus coeruleus was similar in controls and in long-term tandospirone-treated rats. It is concluded that 1-PP acts as an antagonist at somatodendritic and terminal alpha 2-adrenergic autoreceptors, as well as at postsynaptic alpha 2-adrenoceptors, in the central nervous system of the rat. However, the levels of 1-PP attained after long-term administration of tandospirone were not sufficient to modify NE neurotransmission.     

Possible involvement of the locus coeruleus in inhibition by prostanoid EP(3) receptor-selective agonists of morphine withdrawal syndrome in rats

We examined the mechanism of the inhibitory effect of prostanoid EP₃ receptor agonists on naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Rats were rendered morphine dependent by subcutaneous (s.c.) implantation of two pellets containing 75 mg morphine for 5 days. Morphine withdrawal syndrome was precipitated by i.p. injection of naloxone (3 mg/kg). Intracerebroventricular (i.c.v.) administration of (±)-15-hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorprost-13-trans-enoic acid (M&B28,767: prostanoid EP₃ receptor agonist) or sulprostone (prostanoid EP₁/EP₃ receptor agonist) significantly suppressed many withdrawal signs. Northern blotting and in situ hybridization studies revealed that i.c.v. administration of M&B28,767 (1 pg/rat) attenuated the elevation of c-fos mRNA during naloxone-precipitated withdrawal in many brain regions, including the cerebral cortex, thalamus, hypothalamus and locus coeruleus. Double in situ hybridization analysis revealed that in the locus coeruleus most of the tyrosine hydroxylase mRNA-positive neurons expressed μ-opioid receptor mRNA and more than half of these neurons were positive for prostanoid EP₃ receptor mRNA. These results indicate that the suppression by prostanoid EP₃ receptor agonists of naloxone-precipitated morphine withdrawal syndrome can be attributed to the inhibition of neuronal activity in several brain regions, including the locus coeruleus, the largest source of central noradrenergic neurons.     

Effect of agmatine on locus coeruleus neuron activity: possible involvement of nitric oxide

1. To investigate whether agmatine (the proposed endogenous ligand for imidazoline receptors) controls locus coeruleus neuron activity and to elucidate its mechanism of action, we used single-unit extracellular recording techniques in anaesthetized rats. 2. Agmatine (10, 20 and 40 microg, i.c.v.) increased in a dose-related manner the firing rate of locus coeruleus neurons (maximal increase: 95 +/- 13% at 40 microg). 3. I(1)-imidazoline receptor ligands stimulate locus coeruleus neuron activity through an indirect mechanism originated in the paragigantocellularis nucleus via excitatory amino acids. However, neither electrolytic lesions of the paragigantocellularis nucleus nor pretreatment with the excitatory amino acid antagonist kynurenic acid (1 micromol, i.c.v.) modified agmatine effect (10 microg, i.c.v.). 4. After agmatine administration (20 microg, i.c.v.), dose-response curves for the effect of clonidine (0.625 - 10 microg kg(-1) i.v.) or morphine (0.3 - 4.8 mg kg(-1) i.v.) on locus coeruleus neurons were not different from those obtained in the control groups. 5. Pretreatment with the nitric oxide synthase inhibitors N(omega)-nitro-L-arginine (10 microg, i.c.v.) or N(omega)-nitro-L-arginine methyl ester (100 microg, i.c.v.) but not with the less active stereoisomer N(omega)-nitro-D-arginine methyl ester (100 microg, i.c.v.) completely blocked agmatine effect (10 and 40 microg, i.c.v.). 6. Similarly, when agmatine (20 pmoles) was applied into the locus coeruleus there was an increase that was blocked by N(omega)-nitro-L-arginine methyl ester (100 microg, i.c.v.) in the firing rate of the locus coeruleus neurons (maximal increase 53 +/- 11% and 14 +/- 10% before and after nitric oxide synthase inhibition, respectively). 7. This study demonstrates that agmatine stimulates the firing rate of locus coeruleus neurons via a nitric oxide synthase-dependent mechanism located in this nucleus.     

The CRF1 receptor antagonist,DMP695, abolishes activation of locus coeruleus noradrenergic neurones by CRF in anesthetized rats

Corticotropin-releasing factor (CRF)(1) receptors have been implicated in the excitatory influence of CRF upon noradrenergic perikarya of the locus coeruleus. This study thus characterized the influence of the novel CRF(1) receptor antagonist, DMP695 (N-(2-chloro-4,6-dimethylphenyl)-1-[1-methoxymethyl-(2-methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine mesylate), upon the electrical activity of noradrenergic perikarya in the locus coeruleus of anesthetized rats. Intracerebroventricular injection of CRF dose-dependently (0.05-4.0 microg) enhanced the firing rate of noradrenergic cell bodies and transformed their firing pattern into a burst mode. This action was dose-dependently abolished by i.v. administration of DMP695 (0.125-2.0 mg/kg i.v.), which did not itself modify the electrical activity of noradrenergic neurones. These data demonstrate antagonist properties of DMP695 at central CRF(1) receptors excitatory to ascending noradrenergic neurones, an action which may contribute to its distinctive profile of anxiolytic properties.     

Effect of buspirone on single unit activity in locus coeruleus and dorsal raphe nucleus in behaving cats

The effects of administration of the non-benzodiazepine anxiolytic buspirone on the spontaneous and sensory evoked single unit activity of serotonergic (5-HT) neurons in the dorsal raphe nucleus and noradrenergic (NE) neurons in the locus coeruleus were examined in freely moving cats. Buspirone (1.0 mg/kg i.p.) strongly suppressed both the spontaneous and evoked activity of 5-HT dorsal raphe nucleus neurons. The spontaneous activity of NE neurons in the locus coeruleus was non-significantly increased by drug administration, while the evoked response was unaffected. These effects occurred during a period of mild behavioral activation. It is suggested that the anxiolytic effects of buspirone administration are not achieved through an action of NE neurons, but may be mediated in part by actions on 5-HT neurons in the dorsal raphe.     

Systemic effect of cannabinoids on the spontaneous firing rate of locus coeruleus neurons in rats

Previous reports have described modulation of noradrenergic activity by cannabinoid receptors. The aim of the present research was to examine the effect of two synthetic cannabinoid CB1/CB2 receptor agonists, R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55940), on the spontaneous activity of locus coeruleus noradrenergic neurons by single-unit extracellular recordings in vivo and in vitro. In anaesthetized rats, intravenous administrations of WIN 55212-2 (31.3-500 microg/kg) or CP 55940 (31.3-500 microg/kg) increased the firing rate of locus coeruleus neurons in a dose-dependent manner. The stimulatory effect of WIN 55212-2 was blocked by pretreatment with the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A; 2 mg/kg). Paradoxically, local administration of WIN 55212-2 (8.3-31.3 pmol) into the locus coeruleus and intracerebroventricular injections of WIN 55212-2 (10-20 microg) or CP 55940 (20-40 microg) failed to change the spontaneous firing rate of locus coeruleus neurons. Likewise, in rat brain slice preparations perfusion with WIN 55212-2 (10 microM) or CP 55940 (10-30 microM) did not specifically affect the spontaneous firing rate of locus coeruleus cells. Therefore, we conclude that synthetic cannabinoids increase the spontaneous firing activity of noradrenergic neurons in the rat locus coeruleus through cannabinoid CB1 receptors. This stimulation appears to be indirectly induced via a receptor mechanism probably located at the peripheral level.     

Anxiolytic activity on locus coeruleus-mediated suppression of muricidal aggression

The evidence suggests that stimulation of brain noradrenergic neurons plays an inhibitory role in rat mouse-killing (muricidal) aggression. Anxiolytic benzodiazepines inhibit locus coeruleus activity and previous data showed that chlordiazepoxide was capable of antagonizing the locus coeruleus-mediated suppression of muricidal aggression. The present experiments showed that this effect is common to new anxiolytic triazolobenzodiazepines and to other non-benzodiazepine derivatives with anxiolytic activity. In this framework, 10 mg/kg of buspirone, of 1-pyrimidine-piperazine and of MJ-13805 proved to be as active as 2.5 mg/kg of alprazolam and as 5 mg/kg of chlordiazepoxide in inhibiting the locus coeruleus-mediated suppression of muricidal aggression.     

Attenuation of conflict-induced suppression by clonidine: Indication of anxiolytic activity

Clonidine was tested in a conflict-induced suppression paradigm (bar pressing for food reward suppressed by electric foot shock) in rats. This drug significantly and dose dependently (25–100 μg/kg) both increased punished responding and decreased unpunished responding. Clonidine at 200 μg/kg had no effect on punished bar pressing, although it markedly inhibited unpunished responding due to sedation. The effect of clonidine on shock-suppressed lever pressing was prevented by yohimbine 5 mg/kg and partially antagonized by phenoxybenzamine 2.5 mg/kg but was not significantly altered by phenoxybenzamine 1 mg/kg, atropine 5 mg/kg, methysergide 5 mg/kg, or naloxone 10 mg/kg. This activity of clonidine does not seem to be due to its analgesic or food intake-increasing properties. It may be a true anxiolytic effect, brought about by presynaptic stimulation of noradrenergic neurons which could result in an inhibitory influence on the locus coeruleus.     

Further evidence that noradrenaline is not involved in the anti-immobility activity of chronic desipramine in the rat

The effect of 10 mg/kg per day desipramine for 7 days on performance in the forced swimming test was studied in rats given various treatments aimed at reducing central noradrenergic transmission. 6-Hydroxydopamine-induced destruction of noradrenaline-containing neurons originating in the locus coeruleus or ascending in the ventral bundle had no effect on the anti-immobility activity of desipramine. Likewise, no changes in the effect of desipramine were seen with an intraperitoneal injection of DSP-4 (50 mg/kg) which destroyed brain noradrenergic neurons, particularly those of the dorsal bundle ascending to the forebrain. The results argue against a role of noradrenaline in the mechanism by which repeated treatment with desipramine reduces the immobility of rats in the forced swimming test.     

Trimipramine, a tricyclic antidepressant exerting atypical actions on the central noradrenergic system

Trimipramine is a tricyclic antidepressant which has only weak effects on noradrenergic systems. Its mechanism of action is not understood, but its clinical effectiveness has been proven over a period of 20 years. In the present investigation, trimipramine was shown to have no effect on noradrenaline (NA)-stimulated adenylate cyclase activity after either acute or once daily application for 28 days. There was no change in the KD or Bmax of [3H]DHA binding, demonstrating a lack of effect on beta-adrenergic receptors. However, it did exert effects on the cortical noradrenergic projection of the locus coeruleus and these effects were opposite to those described for typical antidepressants. In acute experiments, systemic injections of trimipramine potently activated locus coeruleus neurons and produced a reduction in the depressant action of noradrenaline administered iontophoretically to neurons in the cingulate cortex. After 4 weeks' treatment with a daily injection of 30 mg/kg i.p. trimipramine, cingulate cortical neurons became supersensitive to the action of iontophoretically applied noradrenaline. Although it is unknown whether these effects are related to the therapeutic efficacy of trimipramine, the results demonstrate that the down-regulation of central noradrenergic sensitivity in the rat is not a prerequisite for clinical efficacy of antidepressants in man.