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The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; DMCM) and electric foot-shock on rat conflict behavior were characterized and compared. Rats were trained to lever press under a multiple fixed-ratio schedule (FR 20) of food reinforcement in which responses during the first component were not punished, and the first response of each FR during the second component produced electric shock of an intensity sufficient to suppress responding by 10% to 15%. Intracerebroventricular injection of CRF (0.1-5.6 micrograms) caused a dose-dependent decrease in the rate of responding in both components of the schedule. However, CRF was more potent in decreasing rates of punished responding (proconflict effect). DMCM (10-100 micrograms; i.c.v.) also decreased rates of punished and nonpunished responding and was more potent during the punishment component. The suppression of punished and nonpunished responding by CRF and DMCM was mimicked by increasing the shock intensity (delta = 0.1 to 0.6 mA) during the punishment component. To determine whether CRF, DMCM and electric shock shared common mechanisms for these effects, rats were pretreated with i.c.v. injections of either a CRF antagonist (alpha helical CRF9-41, 50 micrograms), a benzodiazepine agonist (chlordiazepoxide, 10 micrograms) or a benzodiazepine antagonist (flumazenil, 10 micrograms) before the administration of equieffective doses of CRF or DMCM or an increase in shock intensity. Chlordiazepoxide attenuated the effects of all three stimuli. Flumazenil antagonized DMCM and CRF, but not shock, implicating a pharmacologic interaction between CRF and benzodiazepine systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-releasing factor (CRF) has been implicated as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), and is thought to be hypersecreted in depression. Therefore, the hypothesis that antidepressants interfere with CRF neurotransmission in the LC was tested. The acute and chronic effects of desmethylimipramine (DMI), sertraline (SER), phenelzine (PHE), mianserin (MIA), and cocaine (COC) were quantified on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by intracerebroventricular (i.c.v.)-administered CRF, and LC activation by stress in halothane-anesthetized rats. No consistent effect of the drugs on LC spontaneous discharge rate or sensory responsiveness was observed after acute administration. LC spontaneous discharge rates in rats chronically administered the drugs were similar to rates recorded in matched controls, with the exception of PHE and COC. In these rats, LC spontaneous discharge rates were lower than those of untreated rats. Interestingly, LC responses to repeated sciatic nerve stimulation (as measured by the ratio of evoked-to-tonic LC discharge rate) were enhanced in rats chronically administered SER and PHE. This is opposite to the reported effects of i.c.v.-administered CRF. This was not observed with chronic administration of DMI, MIA, or COC. The most striking effect associated with chronic administration of DMI and MIA was the attenuation of LC activation by hemodynamic stress. Because this activation requires CRF release in the LC region, and because none of the antidepressants altered LC activation by i.c.v.-administered CRF, the data suggest that chronic administration of either antidepressant, DMI or MIA, results in attenuation of stress-elicited CRF release in the LC.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-releasing factor (CRF), the hormone responsible for adrenocorticotropin release during stress, is thought to be hypersecreted in depression. Because recent studies suggest that CRF may serve as a neurotransmitter in the major noradrenergic nucleus, locus coeruleus (LC), it was hypothesized that antidepressants interfere with the putative neurotransmitter role of CRF in the LC by either: 1) decreasing release of CRF; 2) pharmacologically antagonizing CRF; or 3) functionally antagonizing CRF by producing effects on LC cells that oppose these of CRF. In order to test this hypothesis, the effects of acute and chronic administration of two antidepressants, a norepinephrine re-uptake inhibitor (desmethylimipramine, DMI) and a serotonin re-uptake inhibitor (sertraline, SER), on LC spontaneous discharge, LC sensory evoked discharge, LC activation by a stressor and LC activation by CRF, were compared in halothane-anesthetized rats. Acute i.v. administration of DMI decreased both LC spontaneous discharge and discharge evoked by repeated sciatic nerve stimulation. In contrast, acute i.v. SER administration decreased only evoked LC discharge rate. Chronic DMI administration (10.0 mg/kg/day, i.p., 21 days) resulted in tolerance to its effects on spontaneous and sensory-evoked LC discharge. However, chronic DMI administration attenuated LC activation by hemodynamic stress, which is thought to require CRF release. LC activation by intracerebroventricular CRF was not altered in the chronic DMI rats. In contrast to DMI, chronic SER (10 mg/kg/day, i.p., 21 days) did not alter LC activation by either stress of CRF. However, the response of LC cells to repeated sciatic nerve stimulation was somewhat enhanced in chronic SER rats. This is an effect that is opposite that produced by CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to determine whether pharmacologically-induced alterations in the spontaneous activity of neurons in the locus coeruleus are associated with changes in blood pressure, the activity of the locus coeruleus and blood pressure were recorded simultaneously in anesthetized rats after the administration of agents known to affect both of these parameters. Spontaneous activity of the locus coeruleus was decreased by intracerebroventricular (i.c.v.) administration of both clonidine and St 91, [2,(2,6-diethyl-phenylimino)imidazolidine chloride], a charged analogue of clonidine. However, only clonidine decreased the mean blood pressure after intracerebroventricular administration suggesting that either the receptors mediating decreases in the activity of the locus coeruleus are different to those mediating hypotension, or that St 91 does not distribute to sites involved in the control of blood pressure even after intracerebroventricular administration. Intravenous administration of clonidine, but not of St 91, decreased the activity of the locus coeruleus and produced a prolonged hypotension, thus suggesting a central mechanism for these effects. Both clonidine and St 91 administered intravenously, produced a brief initial period of hypertension which was not associated with consistent changes in the spontaneous activity of the locus coeruleus. Thus, noradrenergic agonists can decrease the activity of the locus coeruleus without affecting blood pressure, and increase blood pressure without affecting the activity of the locus coeruleus. The spontaneous activity of cells in the locus coeruleus was increased by 100% after the intracerebroventricular administration of corticotropin-releasing factor (CRF; 3.0 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of hemodynamic stress produced by i.v. infusion of nitroprusside on discharge characteristics of noradrenergic locus ceruleus (LC) neurons were compared to those produced by central administration of corticotropin-releasing factor (CRF). Like CRF, both nitroprusside infusion and blood volume withdrawal increased LC spontaneous discharge. Additionally, nitroprusside disrupted the response of LC cells to repeated sciatic nerve stimulation in a manner similar to CRF. The neuronal effects of nitroprusside were prevented by prior administration of a CRF antagonist, alpha helical CRF9-41, but not by dexamethasone, which blocks CRF release into the hypophysial portal circulation. These results suggest that LC activation by hemodynamic stress is mediated by neuronal CRF release onto LC neurons. alpha Helical CRF9-41 had no effect on the magnitude or timecourse of nitroprusside-elicited hypotension, suggesting that LC activation by nitroprusside is not important for maintaining hemodynamic homeostasis. Finally, chronic administration of desmethylimipramine (DMI) attenuated the response of LC cells to nitroprusside, but not to CRF, suggesting that antidepressant therapy may inhibit stress-induced CRF release. This study supports the concept that CRF serves as a neurotransmitter in the LC in the initiation of stress responses.

Because the physiological characteristics of noradrenergic locus ceruleus (LC) neurons differ in anesthetized and unanesthetized rats, the effects of morphine on LC activity recorded in both conditions were compared. Intracerebroventricular administration of morphine inhibited spontaneous LC discharge of both anesthetized and unanesthetized rats but morphine was at least 10 times more potent in anesthetized rats. In anesthetized rats LC discharge evoked by sciatic nerve stimulation was insensitive to doses of morphine (0.03 or 0.1 microgram) that inhibited LC spontaneous activity. Only the highest dose of morphine (0.3 microgram) which inhibited completely tonic activity decreased significantly evoked discharge. In parallel experiments in unanesthetized rats, the presentation of auditory stimuli evoked a pattern of LC discharge similar to that evoked by sciatic nerve stimulation in anesthetized rats. Morphine (1.0 and 3.0 micrograms) decreased both spontaneous and evoked activity in these rats; however, spontaneous LC discharge was more sensitive to morphine, as was observed with anesthetized rats. Quantitative analyses of these effects indicated that morphine tends to alter the pattern of LC discharge to sensory stimuli such that the signal-to-noise ratio (ratio of evoked/tonic activity during stimulus presentation) is increased. Morphine effects were reversed by naltrexone (1.0 mg/kg s.c.) in anesthetized rats and 1.0 microgram i.c.v. in unanesthetized rats. The present results indicate that the degree of arousal and the availability of environmental stimuli are important determinants of opiate effects on LC activity.