A. Horita

Phencyclidine-induced stereotyped behavior in rats: Dose response effects and antagonism by neuroleptics

Abstract Phencyclidine hydrochloride produced a very characteristic and reproducible stereotyped behavioral syndrome in rats. Both the intensity and the duration of the phencyclidine-induced stereotyped behavior are elicited in a dose-dependent manner in the 2–16 mg/kg dose range. The predominant behavior elicited by low doses was repetitive lateral head swaying, while with higher doses circling and backward walking were observed in addition to the head swaying. This behavior was antagonized by the neuroleptic agents chlorpromazine, haloperidol, and pimozide, but not by α- or β-adrenergic blockers. These results indicate that the phencyclidine-induced stereotyped behavior may be mediated by central dopaminergic mechanisms.

Influence of thyrotropin releasing hormone (TRH) on drug-induced narcosis and hypothermia in rabbits.

Thyrotropin releasing homone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 μg decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 μg produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.

An update on the CNS actions of TRH and its analogs.

This brief review will discuss the recent literature on several of the central actions of TRH and its analogs. The most prominent of these actions include: (1) the arousal or analeptic effect in drug narcotized animals or in concussion models; (2) the reversal of cognitive deficits produced by various drugs or procedures, and (3) the improvement of several neurological deficits produced in animal models of spinal and/or cerebellar injury. The mediation of these TRH effects by neurotransmitters is discussed. While little has been published on the human neuropsychopharmacology of TRH, and especially of its analogs, the future holds considerable therapeutic promise for these interesting drugs.

Characterization and distribution of 3H-(eMeHis2) thyrotropin releasing hormone receptors in rat brain

Abstract The characteristics and distribution of putative thyrotropin releasing hormone (TRH) receptors were studied in rat central nervous system using the TRH analogue 3 H-(3MeHis 2 )TRH as a radiolabeled ligand. The analogue had a dissociation constant of 2.3 ± 0.2 nM and a receptor density of 34 ± 2 fm/mg protein in whole brain homogenates. An association rate constant of 1.6 × 10 −3 min −1 nM −1 and a biphasic dissociation with rate constants of 2.6 × 10 −3 min −1 and 1.3 × 10 −4 min −1 were observed. The brain was dissected into ten regions, and detectable levels of binding were found in all regions. The highest levels were found in the amygdala/piriform cortex area and the septal region, and the lowest levels were found in the cerebellar and cerebral cortex. Competition curves showed the methylated analogue to have approximately 7-fold higher affinity for the receptor than TRH. The higher affinity, along with lower nonspecific binding, accounts for the much improved sensitivity of the binding assay of the methylated analogue (70–80% specific binding) as compared to 3 H-TRH (15–20% specific binding) and enables one to work with much lower tissue amounts. Use of the tritiated analogue will greatly aid in further studies of TRH receptors.

Involvement of D1 and D2 dopamine systems in the behavioral effects of cocaine in rats

Cocaine (5-40 mg/kg, intraperitoneally) enhanced locomotion and rearing accompanied with head circling and body shaking. Although at 40 mg/kg typical stereotypy licking occasionally appeared, 40% of the rats died. At doses that did not affect physiologic locomotion and rearing, the D1-receptor antagonist SCH23390 but not D2 antagonist raclopride inhibited locomotion and rearing stimulated by cocaine (20 mg/kg). All behavioral responses of cocaine were abolished with increasing doses of raclopride and SCH23390. Sulpiride, a D2 antagonist, exerted a biphasic effect on locomotor activity (i.e., a low dose of sulpiride increased and a high dose decreased cocaine-induced locomotor activity). Sulpiride enhanced head circling, body shaking, and increases of rearing induced by cocaine. D2-receptor agonists quinpirole and bromocriptine inhibited these responses, presumably by activating the typical stereotyped behaviors such as sniffing at low doses, and licking and gnawing at high doses. The lowest dose of bromocriptine inhibited all behaviors induced by cocaine without producing typical stereotyped behaviors in itself. SK+F38393, a D1-receptor agonist, in combination with cocaine did not induce typical stereotype, which results in a synergistic effect of D1 and D2-receptor activities. The increases of locomotion and rearing, head circling, and body shaking induced by cocaine may involve the indirect activation of postsynaptic D1 and D2 receptors, presumably via dopamine release, resulting from inhibition of the presynaptic D2 receptors. These results also provide evidence that the indirect stimulation of postsynaptic D2 receptors by cocaine (20 mg/kg) is insufficient to induce stereotyped behaviors, and that the role of dopamine D1 receptors in mediating the behavioral actions of acute cocaine appears to be more important than that of D2 receptors. Our results also suggest that bromocriptine may be useful for the treatment of acute cocaine poisoning.

Low-level microwave irradiation and central cholinergic systems

Our previous research showed that 45 min of exposure to low-level, pulsed microwaves (2450-MHz, 2-microseconds pulses, 500 pps, whole-body average specific absorption rate 0.6 W/kg) decreased sodium-dependent high-affinity choline uptake in the frontal cortex and hippocampus of the rat. The effects of microwaves on central cholinergic systems were further investigated in this study. Increases in choline uptake activity in the frontal cortex, hippocampus, and hypothalamus were observed after 20 min of acute microwave exposure, and tolerance to the effect of microwaves developed in the hypothalamus, but not in the frontal cortex and hippocampus, of rats subjected to ten daily 20-min exposure sessions. Furthermore, the effects of acute microwave irradiation on central choline uptake could be blocked by pretreating the animals before exposure with the narcotic antagonist naltrexone. In another series of experiments, rats were exposed to microwaves in ten daily sessions of either 20 or 45 min, and muscarinic cholinergic receptors in different regions of the brain were studied by 3H-QNB binding assay. Decreases in concentration of receptors occurred in the frontal cortex and hippocampus of rats subjected to ten 20-min microwave exposure sessions, whereas increase in receptor concentration occurred in the hippocampus of animals exposed to ten 45-min sessions. This study also investigated the effects of microwave exposure on learning in the radial-arm maze. Rats were trained in the maze to obtain food reinforcements immediately after 20 or 45 min of microwave exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related decreases in dopamine receptors in the caudate nucleus and putamen of the rhesus monkey (Macaca mulatta)

Specific binding of the dopamine receptor ligand 3H-spiroperidol to cell membranes prepared from the caudate nuclei and putamens of 29 rhesus monkeys (M. mulatta), ranging in age from 2 to 22 years, was investigated. Receptor concentration (Bmax) decreased in the caudate nucleus and putamen with age at mean rates of 2.1 and 1.7% per year, respectively, whereas binding affinity (Kd) did not change significantly with age. The rate of decline in Bmax appeared to be more rapid before adulthood and in old age than during young adulthood and middle age. These data are compared with the results from similar studies of other animal species including human, rabbit, rat, and mouse. The rate of decline in striatal dopamine receptors is closely related to the rate of aging and maximal life span of the species. It may reflect both maturational and senescent processes modifying the behavior of animals as they age.

Effects of ethanol on turnover and function of striatal dopamine

Acute oral administration of ethanol increased the rate of depletion of dopamine in the striata of rats injected with α-methyl-p-tyrosine. This effect was eliminated by pretreatment with atropine or by lesioning of the striato-nigral tract. Ethanol also attenuated the inhibitory effect of apomorphine on turnover of striatal dopamine. Unilateral injection of ethanol into the neostriatum of rats followed by intraperitoneal injection of either apomorphine or amphetamine elicited marked ipsilateral head-to-tail body turning. This turning was blocked by pretreatment with haloperidol. Chronic intubation of ethanol to rats enhanced contralateral body turning elicited by unilateral intrastriatal injection of dopamine. Injection of 6-hydroxydopamine into the substantia nigra led to denervation supersensitivity of dopaminergic functions in the neostriatum. This effect was not seen in rats that were given ethanol postinjection of 6-hydroxydopamine. These results suggested that ethanol has an inhibitory effect on the nigrostriatal dopaminergic system.

A study of 5-hydroxytryptamine formation from L-tryptophan in the brain and other tissues☆

Abstract Three methods have been developed to study, in the rat, the synthesis of 5-hydroxytryptamine (5-HT) from the amino acid precursor L-tryptophan (Try): the first involves perfusion of the small intestine in situ with a Tyrodes solution containing Try; the second involves i.p. injections of the amino acid into unoperated and into partially or totally eviscerated rats; the third consists in infusing Try into the brain via the internal carotid artery. All these procedures showed synthesis of 5-HT in the brain as measured by fluorometric techniques. The results showed that the brain formed 5-HT from Try and that the brain did not depend on the stomach, intestine, spleen, kidneys, or liver for 5-hydroxytryptophan.

Effects of thyrotropin-releasing hormone (TRH) microinjected into various brain areas of conscious and pentobarbital-pretreated rabbits

Abstract Thyrotropin releasing hormone (TRH) was administered intracerebrally into various brain regions of conscious and pentobarbitalnarcotized rabbits. In conscious animals tachypnea was observed after TRH administration into all brain regions investigated. Behavioral excitation was most pronounced after TRH administration into the cerebral cortex, caudate nucleus and hypothalamus. Hyperthermia was produced only after hypothalamic injections of TRH. In pentobarbital-narcotized rabbits TRH exerted analeptic activity (shortening of narcosis) regardless of the brain area injected, although some quantitative differences were observed. These results indicate that the analeptic effect of TRH may be initiated from various areas of the brain.