Single-unit responses of serotonergic dorsal raphe neurons to 5-HT1A agonist and antagonist drug administration in behaving cats.

Single-unit activity of serotonergic neurons in the dorsal raphe nucleus was recorded in free-moving cats in response to i.v. administration of 5-hydroxytryptamine (5-HT)1A agonist and antagonist drugs. The 5-HT1A agonist drugs 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), ipsapirone, buspirone and 5-methoxy-N,N-dimethyltryptamine produced a rapid, dose-dependent inhibition of neuronal activity. 8-OH-DPAT (ED50 = 1.5 micrograms/kg) was approximately 45 times more potent than ipsapirone, buspirone or 5-methoxy-N,N-dimethyltryptamine (ED50 range = 6.0-6.8 micrograms/kg) in producing inhibition, and all drugs were more effective when cats were inactive (e.g., drowsiness) than during periods of behavioral arousal (e.g., active waking). Administration of the 5-HT1A autoreceptor antagonist spiperone (0.25 and 1 mg/kg) produced a rapid, dose-dependent increase in the firing rate, suggesting that under physiological conditions serotonergic neurons are controlled by tonic feedback inhibition. This effect was evident during wakefulness (a period of relatively high neuronal activity), but not during sleep (a period of relatively low neuronal activity). Spiperone also blocked the inhibitory action of 8-OH-DPAT in a dose- and time-dependent manner. There was a strong positive correlation between the magnitude of spiperone-induced neuronal activation and blockade of 8-OH-DPAT-induced neuronal suppression. These effects of spiperone cannot be attributed to its dopaminergic D2 or serotonergic 5-HT2 antagonist properties, because administration of haloperidol and ritanserin produced no increase in neuronal activity and did not block the action of 8-OH-DPAT. These results confirm the marked sensitivity of serotonergic dorsal raphe nucleus neurons to selective 5-HT1A agonist compounds in unanesthetized animals and suggest that 5-HT1A somatodendritic autoreceptors exert a tonic inhibitory influence on the firing rate of these neurons during periods of behavioral activation, but not during periods of behavioral quiescence.

Single-unit responses of serotonergic neurons to vasoactive drug administration in behaving cats.

Single-unit activity of serotonergic neurons in the dorsal raphe nucleus (DRN), heart rate (HR), and arterial blood pressure were recorded in freely moving cats during spontaneous behavior and in response to systemic administration of vasoactive drugs. The activity of serotonergic neurons varied in association with behavioral arousal but was unrelated to spontaneous fluctuations in HR and blood pressure. Bolus administration of phenylephrine hydrochloride and sodium nitroprusside (15-20 micrograms/kg iv) produced a rapid transient increase (35 mmHg) and decrease (49 mmHg), respectively, in mean arterial pressure (MAP). Infusion of phenylephrine and sodium nitroprusside (100 micrograms/ml) produced sustained hypertension (avg MAP 166 mmHg) and hypotension (avg MAP 49 mmHg), respectively. The activity of serotonergic neurons was not significantly altered in response to phenylephrine or sodium nitroprusside administration. Furthermore, no significant changes in unit activity were observed after hydralazine administration (1 mg/kg iv) despite prolonged reflex activation of sympathetic outflow. Thus the activity of DRN serotonergic neurons was unrelated to transient alterations in blood pressure and baroreceptor activity. These results suggest that changes in the activity of serotonergic DRN neurons are not involved in physiological mechanisms underlying reflex alterations in sympathetic (and parasympathetic) outflow invoked by hypertension and hypotension.

Activity of cat locus coeruleus noradrenergic neurons during the defense reaction.

The single-unit activity of locus coeruleus noradrenergic (LC-NE) neurons was recorded in freely moving cats during naturally induced defense reactions. Defense reactions, consisting of arched back, piloerection, flattened ears and mydriasis, were elicited by exposing the cat either to a dog, or to a cat displaying aggressive behavior induced by electrical stimulation of the hypothalamus. LC-NE neurons were identified using previously established criteria, including suppression of firing during rapid eye movement (REM) sleep and in response to clonidine administration. Exposure to a dog evoked defense reactions and increased the tonic firing rate of LC-NE neurons (n = 8) from a baseline of approximately 0.9 spikes/s to approximately 2.5 spikes/s. Exposure to an aggressive cat evoked defense reactions that were qualitatively very similar to those produced by dog exposure, and elevated the tonic firing rate of LC-NE neurons (n = 8) from a baseline of approximately 1.0 spikes/s to approximately 2.5 spikes/s. In addition to these tonic elevations of activity, LC-NE neurons discharged in phasic bursts (as high as 10 spikes in a 500 ms period) in close association with specific threatening acts made by the dog or hypothalamically stimulated cat. The mere presence of a dog was sufficient to evoke tonic activation of LC-NE neurons, even in the absence of threatening advances by the dog, whereas exposure to a hypothalamically stimulated cat produced LC-NE neuronal activation only when the stimulated cat showed aggressive behavior. These results extend our previous work, which examined the response of LC-NE neurons to environmental and physiological stressors, into a more ethologically relevant domain, and suggest that LC-NE neuronal activation may play a role in the response to threatening or challenging situations.

Single-unit responses of serotonergic neurons to glucose and insulin administration in behaving cats.

Extracellular single-unit activity of serotonergic neurons in the dorsal raphe nucleus (DRN) was recorded in response to glucose loading and insulin administration in conscious, freely moving cats. Serotonergic neurons were identified based on their discharge characteristics, activity across states of behavioral arousal, response to systemic administration of serotonin autoreceptor agonists, and histological localization to the DRN. The spontaneous activity of serotonergic neurons varied in association with behavioral state, reaching their highest level during arousal and their lowest level during rapid-eye-movement sleep, when cells typically stopped firing. The activity of serotonergic DRN neurons was not significantly altered by a glucose load (500 mg/kg iv) that produced an approximately 3.5-fold increase in blood glucose levels. Furthermore, serotonergic DRN neuronal activity was not significantly altered after insulin administration (2-4 IU/kg iv), which lowered blood glucose approximately 50% below control levels, or after the rapid reversal of hypoglycemia by subsequent glucose administration. These results indicate that the activity of serotonergic DRN neurons is unrelated to alterations in blood glucose and is not sensitive to elevations of endogenous circulating insulin levels or to exogenous insulin administration. Furthermore, changes in the activity of serotonergic DRN neurons does not appear to be a component of glucoregulatory mechanisms invoked by either hyper- or hypoglycemia. Overall, these results do not support a role for serotonergic DRN neurons in glucoregulation in the cat.

Single-unit responses of serotonergic dorsal raphe nucleus neurons to environmental heating and pyrogen administration in freely moving cats.

Single-unit activity of serotonergic neurons in the dorsal raphe nucleus was examined in response to environmental heating and pyrogen-induced fever in freely moving cats. In the heating study, ambient temperature was rapidly raised from a baseline of 25 degrees to 43 +/- 1 degrees C and maintained at this level for 2 h. Cats displayed hyperthermia, intense panting, and signs of heat stress, however, the discharge rate of serotonergic neurons of the dorsal raphe nucleus was not significantly different from baseline at any time during heat exposure. Similarly, the activity of these neurons was not significantly altered at any time during an approximately 6-h long febrile response induced by the synthetic pyrogen muramyl dipeptide (50 micrograms/kg, i.v.). These results indicate that serotonergic unit activity in the dorsal raphe nucleus is not related to either the activation of behavioral or physiological mechanisms underlying heat defense, or to alterations in thermoregulatory mechanisms during the febrile response to exogenous pyrogen. Furthermore, because these neurons do not respond to an elevation in body temperature induced by either ambient heating or pyrogen, they do not appear to be directly temperature-sensitive. These results do not support a specific role for serotonergic neurons of the dorsal raphe nucleus in thermoregulation.

Influence of morphine during pregnancy on neuroendocrine regulation of pituitary hormone secretion.

The effects of exposure to morphine during pregnancy on postnatal neuroendocrine systems were investigated. Rats received morphine sulphate or 0.9% (w/v) NaCl twice daily on days 5-12 of pregnancy. A dose of 5 mg morphine sulphate/kg was administered for the first three injections while 10 mg/kg was used for each of the remaining 13. This treatment regimen led to a significant delay in the onset of vaginal opening in the female offspring. Mothers treated with morphine sulphate showed a marked attenuation of their prolactin response to the suckling stimulus, although they still released significant amounts of the hormone. Both male and female offspring of the opiate-treated dams showed a major reduction in the sensitivity of their hypothalamic-pituitary axis to gonadal steroids at 15 days of age. No significant differences were found in the acute thyrotrophin response to single injection of morphine sulphate of prepuberal male and female pups of morphine- and saline-treated dams. These data show that exposure to opiates during critical periods of prenatal development lead to long-lasting alterations in the neuroendocrine control systems of the animal. These alterations may then have significant consequences on the physiological maturation and adult behaviour of the animal.