Firing Activity Of Noradrenergic Neurons Research Articles

Asenapine alters the activity of monoaminergic systems following its subacute and long-term administration: An in vivo electrophysiological characterization

Asenapine is a tetracyclic atypical antipsychotic used for treatment of schizophrenia and mania. Previous in vivo electrophysiological studies demonstrated antagonistic action of asenapine at dopamine D2, serotonin (5-HT)2A, and α2-adrenergic receptors. Here, we assessed monoamine system activities after two-day and 21-day asenapine administration at a dosage (0.1mg/kg/day) resulting in clinically relevant plasma levels. In the ventral tegmental area (VTA), asenapine increased the number of spontaneously active dopamine neurons, while firing parameters remained unchanged. Asenapine partially prevented the D2 autoreceptor-mediated inhibitory response to apomorphine after two days of administration. This effect was lost after 21 days of administration, suggesting adaptive changes leading to D2 receptor sensitization. Asenapine increased the firing activity of noradrenergic neurons in the locus coeruleus (LC) after 21, but not two days of administration. Furthermore, it potently blocked 5-HT2A receptors while α2-adrenergic receptors were unaffected by this drug regimen. Both acute and long-term asenapine administration partially blocked α2-adrenergic receptors in the CA3 region of the hippocampus, and noradrenergic tone on α1- and α2-adrenoceptors remained unchanged. In the dorsal raphe nucleus, asenapine increased the firing rate of 5-HT neurons after two, but not 21 days of administration. In addition, responsiveness of 5-HT1A autoreceptors was unaltered by asenapine. In the hippocampus, 21-day asenapine administration increased serotonergic tone by partial agonistic action on postsynaptic 5-HT1A and terminal 5-HT1B receptors. Taken together, asenapine had profound effects on both catecholamine systems, potently blocked 5-HT2A receptors, and enhanced 5-HT tone, effects that could be important in treatment of mood disorders and schizophrenia.

Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models

Among all mental disorders, major depression has the highest rate of prevalence and incidence of morbidity. Currently available antidepressant therapies have limited efficacies; consequently, research on new drugs for the treatment of mood disorders has become increasingly critical. Recent preclinical evidences that cannabinoid agonists and endocannabinoid enhancers, such as the fatty acid amide hydrolase (FAAH) inhibitors, can impact mood regulation have opened a new line of research in antidepressant drug discovery. However, the neurobiological mechanisms linking the endocannabinoid system with the pathophysiology of mood disorders and antidepressant action remain unclarified. In this review, we have presented an update on preclinical data indicating the antidepressant potential of cannabinoid agonists and endocannabinoid enhancers in comparison to standard antidepressants. Data obtained from CB(1) knockout (CB(1)-/-) and FAAH knockout (FAAH-/-) mice have also been examined within this context. We have illustrated how the various classes of antidepressants exert their therapeutic action. In particular, all antidepressants increase the neurotransmission of serotonin after long-term treatment, enhance the tonic activity of hippocampal 5-HT(1A) receptors, promote neurogenesis, and modulate (decrease or increase) the firing activity of noradrenergic neurons. Interestingly, cannabinoid agonists and endocannabinoid enhancers increase serotonin and noradrenergic neuronal firing activity, increase serotonin release in the hippocampus, as well as promote neurogenesis. Since cannabinoid-derived drugs potentiate monoaminergic neurotransmission and hippocampal neurogenesis through distinct pathways compared to classical antidepressants, they may represent an alternative drug class in the pharmacotherapy of mood and other neuropsychiatric disorders.

Firing activity of locus coeruleus noradrenergic neurons increases in a rodent model of Parkinsonism

To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD). 2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording. The firing rate of LC noradrenergic neurons increased significantly 2 and 4 weeks after 6-OHDA lesions compared to normal rats, respectively (P < 0.05). The percentage of irregularly firing neurons was obviously higher than that of normal rats during the fourth week after SNc lesion (P < 0.05). LC noradrenergic neurons are overactive and more irregular in 6-OHDA-lesioned rats. These changes suggest an implication of the LC in the pathophysiological mechanism of PD.

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 CB 1/CB 2 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 μg/kg) or CP 55940 (31.3–500 μg/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 CB 1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1 H-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 μg) or CP 55940 (20–40 μg) failed to change the spontaneous firing rate of locus coeruleus neurons. Likewise, in rat brain slice preparations perfusion with WIN 55212-2 (10 μM) or CP 55940 (10–30 μM) 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 CB 1 receptors. This stimulation appears to be indirectly induced via a receptor mechanism probably located at the peripheral level.

Effect of the selective noradrenergic reuptake inhibitor reboxetine on the firing activity of noradrenaline and serotonin neurons.

Reboxetine is a non-tricyclic antidepressant with selective noradrenergic (NA) reuptake-blocking effects. The effects of acute and sustained administration of reboxetine, on the firing activity of locus coeruleus NA neurons and dorsal raphe 5-HT neurons, were assessed using in vivo extracellular unitary recording in rats anaesthetized with chloral hydrate. Reboxetine (0.1-1.25 mg/kg, i.v.) dose-dependently decreased the firing activity of NA neurons (ED50 = 480 +/- 14 microg/kg). A 2-day treatment with reboxetine at 1.25, 2.5, 5, or 10 mg/kg per day (using osmotic minipumps implanted subcutaneously) produced significant decreases of 52%, 68%, 81%, and 83%, respectively, of NA firing activity. When the reboxetine treatment (2.5 mg/kg per day) duration was prolonged to 7 days, a 66% decrease in NA firing activity was observed which further decreased to 80% after 21 days of treatment. In contrast, 5-HT neuron firing rate remained unaltered following short- and long-term reboxetine treatments. The suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of NA neurons was unchanged in long-term reboxetine-treated rats, but its effect on the firing activity of 5-HT neurons was blunted. The enhancement of NA firing activity by the 5-HT1A agonist 8-OH-DPAT was abolished in long-term reboxetine-treated rats, whereas, the inhibitory effect of the 5-HT2 agonist DOI was attenuated by about three-fold. In conclusion, sustained NA reuptake blockade by reboxetine lead to profound alterations in the function of NA neurons and of 5-HT receptors modulating their firing activity.

The SSRI/5-HT 2A antagonist YM992 produces inverse effects compared to SSRIs on the firing activity of noradrenergic neurons

The SSRI/5-HT 2A antagonist YM992 produces inverse effects compared to SSRIs on the firing activity of noradrenergic neurons