The renin-angiotensin system and the central nervous system.

One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons in the brain merits investigation.     

Dopamine receptors in the central nervous system.

Dopamine receptors in the central nervous system can be studied by measuring the specific binding of [3H]dopamine, [3H]haloperidol, d-[3H]LSD, [3H]dihydroergocryptine or [3H]apomorphine. The receptors are stereoselectively blocked by +)-butaclamol, a neuroleptic. All neuroleptics inhibit the specific binding of [3H]haloperidol in relation to their clinical potencies. The radioligand that desorbs most slowly from the receptor is [3H]apomorphine, thus making it a reliable ligand for dopamine receptors. Dopamine agonists that compete for [3H]apomorphine binding do so at concentrations that correlate with their potency in stimulating striatal adenylate cyclase. Structure-activity analysis, using [3H]apomorphine, confirms that the active dopamine-mimetic conformation is the beta rotamer of dopamine. Prolonged exposure in vitro of caudate homogenate to high concentrations of dopamine leads to increased binding of [3H]apomorphine or [3H]haloperidol, suggesting receptor "sensitization." Chronic haloperidol treatment of rats leads to an increased number of dopamine/neuroleptic receptors in the striatum, but a decrease in the pituitary.     

Insulin and the central nervous system

Data from literature concerning the neurobiological, electrical and metabolic effects of insulin are reviewed. Emphasis is laid on insulin distribution in the CNS, on distribution and localization of the insulin brain receptors, on insulin transport through the hemato-encephalic barrier. Data concerning insulin effect on the electrical activity of various CNS neurons, particularly, on those of the feeding and satiety centres. The effects of insulin on the brain metabolism are discussed. Insulin shares many properties with the nerve growth factor and may be considered as specific neurotransmitter and neuromodulator.     

Oxygen-sensing neurons in the central nervous system.

This mini-review summarizes the present knowledge regarding central oxygen-chemosensitive sites with special emphasis on their function in regulating changes in cardiovascular and respiratory responses. These oxygen-chemosensitive sites are distributed throughout the brain stem from the thalamus to the medulla and may form an oxygen-chemosensitive network. The ultimate effect on respiratory or sympathetic activity presumably depends on the specific neural projections from each of these brain stem oxygen-sensitive regions as well as on the developmental age of the animal. Little is known regarding the cellular mechanisms involved in the chemotransduction process of the central oxygen sensors. The limited information available suggests some conservation of mechanisms used by other oxygen-sensing systems, e.g., carotid body glomus cells and pulmonary vascular smooth muscle cells. However, major gaps exist in our understanding of the specific ion channels and oxygen sensors required for transducing central hypoxia by these central oxygen-sensitive neurons. Adaptation of these central oxygen-sensitive neurons during chronic or intermittent hypoxia likely contributes to responses in both physiological conditions (ascent to high altitude, hypoxic conditioning) and clinical conditions (heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, hypoventilation syndromes). This review underscores the lack of knowledge about central oxygen chemosensors and highlights real opportunities for future research.     

Calcium channelopathies in the central nervous system.

The recent discovery that familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6 are allelic disorders caused by different mutations in CACNA1A, a calcium-channel-encoding gene, adds to a growing list of channelopathies causing paroxysmal neurologic disturbance and progressive neurodegeneration. Calcium channelopathies in the central nervous system provide a model to study the important roles that calcium channels play in neuronal function.     

Retinoic acid and development of the central nervous system.

We consider the evidence that RA, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: 1) the stimulation of axon outgrowth in particular neuronal sub-types; 2) the migration of the neural crest; and 3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA-induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryo's nervous system; the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system.     

Glutamate-like immunoreactivity in the leech central nervous system.

Using a monoclonal antibody for glutamate the distribution was determined of glutamate-like immunoreactive neurons in the leech central nervous system (CNS). Glutamate-like immunoreactive neurons (GINs) were found to be localized to the anterior portion of the leech CNS: in the first segmental ganglion and in the subesophageal ganglion. Exactly five pairs of GINs consistently reacted with the glutamate antibody. Two medial pairs of GINs were located in the subesophageal ganglion and shared several morphological characteristics with two medial pairs of GINs in the first segmental ganglion. An additional lateral pair of GINs was also located in segmental ganglion 1. A pair of glutamate-like immunoreactive neurons, which are potential homologs of the lateral pair of GINs in segmental ganglion 1, were occasionally observed in more posterior segmental ganglia along with a selective group of neuronal processes. Thus only a small, localized population of neurons in the leech CNS appears to use glutamate as their neurotransmitter.     

Chordate origins of the vertebrate central nervous system.

Fine structural, computerized three-dimensional (3D) mapping of cell connectivity in the amphioxus nervous system and comparative molecular genetic studies of amphioxus and tunicates have provided recent insights into the phylogenetic origin of the vertebrate nervous system. The results suggest that several of the genetic mechanisms for establishing and patterning the vertebrate nervous system already operated in the ancestral chordate and that the nerve cord of the proximate invertebrate ancestor of the vertebrates included a diencephalon, midbrain, hindbrain, and spinal cord. In contrast, the telencephalon, a midbrain-hindbrain boundary region with organizer properties, and the definitive neural crest appear to be vertebrate innovations.     

Corticosteroid receptors and the central nervous system

In mammalian systems, the physiological mineralocorticoid is aldosterone (aldo), and the physiological glucocorticoid cortisol (F), or corticosterone (B) in rats and mice. Receptors (MR) with high affinity for aldo, B and F are found in both epithelia and the central nervous system (CNS); receptors (GR) with lower affinity for F and B, and still lower for aldo, are found in essentially all cells. Both MR and GR bind to and activate canonical pentadecamer response elements in transfected cells and in epithelia, wherein MR aldo, B and F all act as agonists. In vivo, in epithelial cells a low K_m, NAD-dependent, 11β hydroxysteroid dehydrogenase (11βOHSD) converts B and F, but not aldo, to receptor-inactive 11-keto congeners, thus allowing aldo to occupy epithelial MR and produce sodium retention. The CNS differs markedly in terms of MR/GR in a number of ways: (i) most but not all MR in the CNS are functionally unprotected, despite the presence of a low K_m, NADP-preferring 11βOHSD, so that they operate as high-affinity GR; (ii) in such CNS ‘MR’, aldo antagonizes the effects of B, and vice versa, in contrast with epithelia; (iii) also in contrast with epithelia, activated GR in the CNS do not mimic activated MR, suggesting considerable if not total specificity at the response element level. These differences suggest that glucocorticoids have two distinct domains of action in the CNS, mediated by ‘MR’ at low B/F concentrations, and GR at higher concentrations; secondly, they suggest that the nuclear recognition and response elements mediating these effects are other than canonical pentadecamer sequences.