The prelimbic cortex muscarinic M₃ receptor–nitric oxide–guanylyl cyclase pathway modulates cardiovascular responses in rats

Abstract

The prelimbic cortex (PL), a limbic structure, sends projections to areas involved in the control of cardiovascular responses. Stimulation of the PL with acetylcholine (ACh) evokes depressor and tachycardiac responses mediated by local PL muscarinic receptors. Early studies demonstrated that stimulation of muscarinic receptors induced nitric oxide (NO) synthesis and cyclic guanosine cyclic monophosphate (cGMP) formation. Hence, this study investigates which PL muscarinic receptor subtype is involved in the cardiovascular response induced by ACh and tests the hypothesis that cardiovascular responses caused by muscarinic receptor stimulation in the PL are mediated by local NO and cGMP formation. PL pretreatment with J104129 (an M3 receptor antagonist) blocked the depressor and tachycardiac response evoked by injection of ACh into the PL. Pretreatment with either pirenzepine (an M1 receptor antagonist) or AF-DX 116 (an M2 and M4 receptor antagonist) did not affect cardiovascular responses evoked by ACh. Moreover, similarly to the antagonism of PL M3 receptors, pretreatment with N(ω)-propyl-L-arginine (an inhibitor of neuronal NO synthase), carboxy-PTIO(S)-3-carboxy-4-hydroxyphenylglicine (an NO scavenger), or 1H-[1,2,4]oxadiazolol-[4,3-a]quinoxalin-1-one (a guanylate cyclase inhibitor) blocked both the depressor and the tachycardiac response evoked by ACh. The current results demonstrate that cardiovascular responses evoked by microinjection of ACh into the PL are mediated by local activation of the M3 receptor-NO-guanylate cyclase pathway.

Nitric oxide signalling and antidepressant action revisited

“…Similarly, activation of muscarinic cholinergic receptor (mAchR) subtypes 1, 2 and 3 increases the intracellular Ca 2+ following their activation by acetylcholine. In fact, studies have shown that stimulation of muscarinic receptors induces NO synthesis and cGMP formation in vitro (Bauer et al 1994) and in vivo (Fassini et al 2015). Additionally, it was shown that the activation of mAchR by carbachol has a dose-dependent relationship on nNOS activity, with low doses leading to activation of nNOS, while higher doses inhibited the enzymatic activity (Borda et al 1998).…”

Dorsal hippocampus cholinergic and nitrergic neurotransmission modulates the cardiac baroreflex function in rats

“…Moreover, the dose of 0.001 nmol of the nNOS inhibitor abrogated the reduction in the slope of bradycardic, before = −1.400 ± 0.242, 10 min = −1.546 ± 0.279 and 60 min = −1.741 ± 0.206; F (2,20) = 0.49; p = .6198 and tachycardic, before = −2.476 ± 0.274, 10 min = −2.096 ± 0.305 and 60 min = −2.347 ± 0.284; F (2,20) = 0.45; p = .6445 linear regression promoted by 1nmol of the acetylcholinesterase inhibitor (Figure ). These results imply that acetylcholine can modulate baroreflex function via the NO increase because the M1 receptor activation by acetylcholine can evoke NO rises (Fassini, Antero, Correa, Joca, & Resstel, ; Felder, ).…”

“…Right side: bradycardia linear regression before (r 2 = .65; .78; .62), 10 min (r 2 = .62; .85; .85) and 60 min (r 2 = .53; .69; .74) after the N-propyl injection into the DH. Tachycardia linear regression before (r 2 = .72; .73; .94), 10 min (r 2 = .80; .57; .76) and 60 min (r 2 = .79; .75; .79) after the doses of 0.01, 0.1 or 1 nmol of N-propyl M1 receptor activation by acetylcholine can evoke NO rises (Fassini, Antero, Correa, Joca, & Resstel, 2015;Felder, 1995).…”

Neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus contributes to the development of cocaine addiction

“…Several studies provide evidence in support of this notion. One such study reported that systemic cocaine administration resulted in elevated extracellular NO levels in the mPFC (Sammut & West, ), and another study reported that NO in turn activated mPFC neurons (Fassini et al ., ). Moreover, a recent study demonstrated that inactivation of neuronal NO synthase (nNOS) expressed in the mPFC prevents the induction of presynaptic plasticity in LDT cholinergic neurons (Kamii et al ., ).…”