Stimulation of α₁‐adrenoceptors in the rat medial prefrontal cortex increases the local in vivo 5‐hydroxytryptamine release: reversal by antipsychotic drugs

Abstract

Pyramidal neurons of the medial prefrontal cortex (mPFC) project to midbrain serotonergic neurons and control their activity. The stimulation of prefrontal 5-HT 2A and AMPA receptors increases pyramidal and serotonergic cell firing, and 5-hydroxytryptamine (5-HT) release in mPFC. As the mPFC contains abundant a 1 -adrenoceptors whose activation increases the excitability of pyramidal neurons, we examined the effects of their stimulation on local 5-HT release, using microdialysis. The application of the a 1 -adrenoceptor agonist cirazoline by reverse dialysis increased the prefrontal 5-HT release in a concentration-dependent manner, an effect antagonized by coperfusion of TTX, prazosin (a 1 -adrenoceptor antagonist), BAY · 3702 (5-HT 1A agonist), NBQX (AMPA/KA antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by MK-801 (NMDA antagonist). Cirazoline also enhanced the increase in 5-HT release induced by DOI (5-HT 2A/2C agonist) and AMPA. In addition, M100907 (5-HT 2A antagonist) but not SB-242084 (5-HT 2C antagonist) reversed the cirazoline-and AMPA-induced 5-HT release. These results suggest that the stimulation of prefrontal a 1 -adrenoceptors activates pyramidal afferents to ascending serotonergic neurons. The effect of cirazoline was also reversed by coperfusion of classical (chlorpromazine, haloperidol) and atypical (clozapine, olanzapine) antipsychotics, which suggests that a functional antagonism of the a 1 -adrenoceptor-mediated activation of prefrontal neurons may partly underlie their therapeutic action.

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

“…For instance, bilateral lesions of LC NA neurons with 6-OHDA in DA lesioned rats increased the firing activity of SN pars reticulata neurons (Wang et al, 2010a) and medial prefrontal cortex pyramidal neurons (Wang et al, 2010b). In addition, firing rate of serotonin neurons (Haddjeri et al, 1996;Vandermaelen and Aghajanian, 1983;Svensson et al, 1975) and serotonin synthesis and release (Adell and Artigas, 1999;Pudovkina et al, 2002Pudovkina et al, , 2003Amargos-Bosch et al, 2003;Mongeau et al, 1997;Yoshioka et al, 1992) has been shown to be modified by NA input. All of these types of neurons are known to be involved in the expression of both L-DOPA-induced dyskinesia and motor performance.…”

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…Thus, in line with previous reports (Moghaddam et al, 1997;Adams and Moghadam, 2001;Lorrain et al, 2003), MK-801 increases glutamate release onto AMPA/kainate receptors, which, in turn, elicit an enhanced glutamatergic output from mPFC neurons, including those projecting to the dorsal raphe nucleus, thereby increasing serotonergic cell firing and cortical 5-HT efflux. Although this functional interplay between the mPFC and the dorsal raphe nucleus is well documented (Hajós et al, 1998;Celada et al, 2001;Martín-Ruiz et al, 2001;Amargós-Bosch et al, 2003;Lucas et al, 2005), we presently cannot rule out the possibility of a direct effect of MK-801 on serotonergic neurons of the dorsal raphe nucleus (Callado et al, 2000;Tao and Auerbach, 2000) and its blockade downstream by NBQX acting on AMPA receptors putatively located in serotonergic terminals Effect of clozapine and haloperidol X Ló pez-Gil et al (Maione et al, 1997). With regard to glutamate, however, although presynaptic AMPA receptors have been described in striatal glutamatergic axon terminals (Patel et al, 2001;Fujiyama et al, 2004), they do not seem to be present in the cortical counterparts (Fujiyama et al, 2004).…”

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

“…Anatomical and functional studies between these two latter nuclei indicate that the discharge rate of serotonergic neurons is under the excitatory control of a1-adrenergic receptors (Baraban and Aghajanian, 1980;Bortolozzi and Artigas, 2003) and, conversely, that serotonergic cells in raphe nuclei hyperpolarize noradrenergic cells in the locus coeruleus by stimulating 5-HT 2A receptors on GABAergic interneurons (Szabo and Blier, 2001). Another non-exclusive possibility is that coupling between both neurotransmitter systems occurs in the prefrontal cortex where a1b-adrenergic and 5-HT 2A receptors are colocalized (Marek and Aghajanian, 1999;Salomon et al, 2006) and thus control noradrenergic and serotonergic mesencephalic nuclei (Gobert and Millan, 1999;Amargos-Bosch et al, 2003). Increased cortical extracellular NE and 5-HT levels would stimulate glutamatergic pyramidal cells (Sesack and Pickel, 1992), which excite ventral tegmental area (VTA) dopaminergic neurons or project directly to the nucleus accumbens (Pierce et al, 1996) and thus increase locomotor activity.…”