Morris A. Lipton

Neurotensin: central nervous system effects of a hypothalamic peptide.

The central administration of neurotensin, an endogenous hypothalamic tridecapeptide, produces a marked dose-related decrease in body temperature of mice and rats at an ambient temperature of 25 degrees C. This effect is even more pronounced when mice are placed at 4 degrees C to increase the rate of decline of body temperature. Other sequelae observed after central administration of neurotensin are decreases in locomotor activity in rats and a marked dose-related enhancement in pentobarbital-induced mortality, sedation and hypothermia. This latter effect was shown to be due to a significant reduction in the metabolic degradation of the barbiturate. None of the above-mentioned effects are observed after peripheral neurotensin administration, suggesting that this peptide does not readily cross the blood-brain barrier. Neurotensin appears to be one of a growing list of neuropeptides that can affect CNS function.

Antagonism of ethanol narcosis by thyrotropin releasing hormone

Abstract Thyrotropin releasing hormone (TRH) reduced the narcosis and hypothermia produced by ethanol in mice. This action of TRH does not appear related to release of thyroid hormone or to the effects of a metabolite of TRH. The ability of TRH to reduce the actions of ethanol after intracisternal injection suggests that the mechanism of the ethanol antagonism is central in origin. The antagonism of ethanol by TRH does not appear to be related to an amphetamine-like stimulant action.

Neurotensin-induced hypothermia in the rat: Structure-activity studies

Neurotensin (NT), an endogenous brain tridecapeptide, produces hypothermia after intracerebroventricular administration in rats and mice. The hypothermie potency of a series of structural analogues of neurotensin has been studied. [d-Arg9]-NT, NT9–13 and physalemin were devoid of hypothermie activity. The most potent peptides studied in reducing body temperature of cold-exposed rats were bombesin and [d-Tyr11]-NT. [d-Arg8]-NT, [Phe11]-NT, [d-Pro7]-NT, NT-MHMe [d-Pro10]-NT and NT8–13 possessed significant hypothermie activity, though the latter two compounds were the least active. These results indicate that the C-terminal end of the neurotensin molecule is essential for hypothermie activity.

Pharmacology of orally administered Δ9‐tetrahydrocannabinol

A systematic study of the oral administration of 35 mg. of Δ9‐tetrahydrocannabinol (Δ9‐THC) in 5 different vehicles indicates that the speed and degree of absorption are greatly influenced by the vehicle. When the same vehicle was used, absorption of the drug varied significantly among individuals. The psychologic effects were characterized by a marihuana‐like “high” qualified by experienced sub;ects to be more intense than that associated with smoked marihuana or hashish. Predominant physiologic effects were congestion of the conjunctiva, tachycardia, and moderate increases in blood pressure. Hypotention with bradycardia occurred when the blood pressure control was challenged by a change in posture or blood volume. The biologic half‐life of the drug appears to be less than 48 hours. Thin‐layer chromatographic analysis indicates that the metabolites in the plasma are the 11‐OH‐Δ9‐THC, an unknown compound, the 8,11‐di‐OH‐Δ9‐THC, and a group of more polar substances located at the origin. Δ9‐THC and its metabolites are excreted extensively in the urine and feces. The maior urinary metabolites are the 8,1l‐di‐OH‐Δ9‐THC and polar substances where cannabinoid acids predominate. Appreciable amounts of Δ9‐THC are found in feces.

Catecholamines: Diminished rate of synthesis in rat brain and heart after thyroxine pretreatment

Abstract The rate at which 14 C tyrosine is incorporated into catecholamines is diminished after rats have been treated with thyroxine for ten days. This effect pertains to dopamine and norepinephrine in brain and to norepinephrine in heart. Since endogenous catecholamine levels do not change, discharge as well as synthesis is probably decreased.

Models of Neuroendocrine Regulation: Use of Monosodium Glutamate as an Investigational Tool

The administration of monosodium-L-glutamate (MSG) during the neonatal period is known to result in central nervous system lesions in the arcuate nucleus of the hypothalamus and the retina. Rodents so treated exhibit behavioral deficts and endocrinopathies including obesity, hypogonadism, hypothyroidism, pituitary atrophy, tail automutilation and diminished locomotor activity. Assessment of endocrine status revealed normal serum levels of glucagon, thyroid-stimulating hormone and luteinizing hormone, and diminished levels of thyroid hormones and growth hormone in MSG-treated rats. Prolactin levels were elevated in the glutamate-treated male rats. Within the brain hypothalamic levels of thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and somatostatin were unchanged. Measurement of neurotransmitters and neurotransmitter-related enzymes in individual hypothalamic nuclei derived from MSG-treated rats revealed normal levels of norepinephrine, serotonin and glutamic acid decarboxylase, but reduced levels of choline acetyltransferase and dopamine in the arcuate nucleus and median eminence. Histochemical methods for visualization of dopamine and acetylcholinesterase in the mediobasal hypothalamus confirmed these findings. The MSG-treated animals exhibited a normal diurnal rhythm of pineal serotonin N-acetyltransferase activity. These data indicate that the MSG-induced endocrine deficiency syndrome results at least partly from destruction of cholinergic and dopamingeric tuberoinfundibular systems in the hypothalamus.

Thyroid-imipramine clinical and chemical interaction: Evidence for a receptor deficit in depression

Abstract Normal women were given imipramine (IMP) plus placebo (P) or IMP plus triiodothyronine (T3). Depressed women were given IMP plus P or IMP plus thyroid stimulating hormone (TSH). Urine was collected and assayed for various amines and metabolites. In normal women treatments tended to diminish the excretion rates of normetanephrine (NMN), 3-methoxy-4-hydroxy phenylglycol (MHPG), and vanilmandelic acid (VMA). Treatments increased the excretion of tryptamine (TA). The addition of T3 to IMP increased the excretion of 5-hydroxy-indoleacetic acid (5-HIAA). In depressed women pretreatment excretion rates were normal for all substances save VMA, which was slightly increased, and 5-HIAA, which was greatly increased. Treatments (IMP+P or IMP+TSH) tended to increase the excretion of NMN, a finding in contrast to that which occured in normals. MHPG and VMA tended to diminish. TA increased consistently and 5-HIAA rose when TSH was added to IMP. Close attention was paid to the rate of clinical change in the patient population. IMP+ TSH patients improved faster than IMP+P patients. However, the onset of chemical changes was not affected save TSH accelerated the onset of 5-HIAA elevation. The present data and previously reported data are discussed in such manner as to suggest that in some depressed patients there may exist a deficit in aminergic receptor sensitivity. The postulated deficit appears to be compensated in the periphery but not in the brain. Even when receptor sensitivity is normal, an induced increment as produced by adjunctive hormone treatment, may contribute to recovery.

Peptides and the Central Nervous System

The brain is known to contain many peptides of diverse molecular weight and complexity. The larger ones contribute to the structure and to the enzymatic machinery essential for the metabolism of this complex organ. Smaller ones are hormones and some may be involved in the formation of long-term memory. Still others may arise as a consequence of generalized experiences such as sleep. Because the number of possible amino acid combinations is immense, it is likely that many more peptides will be discovered and that these will be found to have functions unique to the brain.

The role of hormones in depression.

Abstract Before the introduction of psychotropic drugs some 20 years ago, psychoendocrinology occupied center stage in biological psychiatry (1). The past few years have witnessed a renewal of interest, and this renaissance seems related to remarkable advances in basic neuroendocrinology. These, in turn, proceed from two convergent events: the identification of hypothalamic hypophysiotropic hormones (2); and the ability to assay with accuracy small amounts of complex molecules that possess hormonal activity (3).

Modification of pentobarbital-induced sedation by natural and synthetic peptides

Abstract The effect of intraperitoneal (i.p.) and intracisternal (i.e.) injection of various endogenous peptides and related analogues on the sedation induced by a fixed intraperitoneal dose of sodium pentobarbital in mice was examined. Several peptides were found to antagonize the effects of pentobarbital while one (neurotensin) markedly potentiated them. Certain peptides were active only after intracisternal injection, while others were effective by either route of administration. However, peptides active after intraperitoneal administration were always active after intracisternal administration. Thyrotropin-releasing hormone was the most effective antagonist and was active by both routes. Neurotensin was the most potent potentiator but was active only after central administration. Although few general structural requirements for the analeptic activity of peptides are discernable, it appears that such activity is mediated by the central nervous system.