Dependence of serotonin release in the locus coeruleus on dorsal raphe neuronal activity

The serotonergic innervation of the locus coeruleus paetly derives from the dorsal raphe nucleus (DRN). Using the push-pull superfusion technique, we investigated whether and to what extent the release of serotonin and the ex tracellular concentration of its metabolite 5-hydroxyindoleacetic acid (5-H IAA) in the locus coeruleus are influenced by the neuronal activity of the DRN. In anaesthetized rats. a push-pull cannula was inserted into the locus coeruleus, which was continuously superfused with artificial cerebrospinal fluid (aCSF). Serotonin and 5-HIAA levels in the superfusate were determin ed by HPLC combined with electrochemical detection. Electrical stimulation (5 Hz, 300 mu A, 1 ms) of the DRN for 5 min, or its chemical stimulation by microinjection of glutamate (3.5 nmol, 50 nl), led to an increased release of serotonin in the locus coeruleus and to a slight (2 mmHg) decrease in b lood pressure. Superfusion of the locus coeruleus with tetrodotoxin(1 mu M) abolished the increase in the release rate of serotonin evoked by electric al stimulation of the DRN, while the slight fall in blood pressure was not influenced. Thermic lesion (75 degrees C, 1 min) of the DRN elicited a pron ounced decline in serotonin release rate within the locus coeruleus, the ma ximum decrease being 52%. The decrease in the release of serotonin was asso ciated with a long-lasting rise in blood pressure. Microinjection of the se rotonin neurotoxin 57-dihydroxytryptamine (5 mu g, 250 nl) into the DRN led to an initial increase in the serotonin release rate that coincided with a short-lasting fall in blood pressure. Subsequently, the release of seroton in was permanently reduced and was associated with hypertension. Microinjec tion of the 5-HT1A receptor agonist (+/-)-8-hydroxy-dipropylaminotetralin ( 8-OH-DPAT; 7.5 nmol, 50 nl) into the DRN led to a longlasting reduction of the release rate of serotonin in the locus coeruleus. Microinjection of 8-O H-DPAT into the DRN also slightly lowered blood pressure (3 mmHg). Neither stimulations nor lesion of the DRN, nor microinjection of 8-OH-DPAT into th is raphe nucleus, altered the extracellular concentration of 5-HIAA. Judging from the present biochemical results it appears that the serotonerg ic afferents to the locus coeruleus originate to more than 50% from cell bo dies located in the DRN. The neuronal serotonin release in the locus coerul eus is modulated by 5-HT1A receptors lying within the DRN. Changes in blood pressure and release of serotonin elicited by stimulating or lesioning the DRN point to the importance of serotonergic neurons extending between this raphe nucleus and the locus coeruleus in central cardiovascular control.