下丘脑异常与抑郁症

近年来的研究发现了抑郁模型动物或抑郁症病人下丘脑异常的大量证据, 诸如下丘脑体积及神经元数目的改变, 下丘脑-垂体-内分泌轴的改变, 下丘脑相关激素、受体及其基因、神经肽的改变, 下丘脑与其他脑区功能联系的改变等等。然而, 下丘脑与抑郁症关系的研究所获证据多来自动物实验、或临床间接指标(如病人外周血激素水平等), 或病人脑组织尸检, 缺乏来自病人活体下丘脑异常的直接证据。今后的研究可考虑运用影像学的手段更直接地探索抑郁症患者活体下丘脑的结构特征和功能特征, 以期发现抑郁症的生物学标记及其可靠性指标, 为抑郁症的客观诊断提供依据, 为揭示抑郁症病理机制提供线索。     

Aggressive behavior induced by electrical stimulation in the midbrain central gray of male rats

Electrical stimulation via electrodes implanted in the lateral hypothalamus may induce intraspecific aggressive behavior. Small electrolytic lesions placed via these electrodes resulted in a five– to tenfold increase in the current threshold for aggression. Degenerating fibers were stained by means of the Fink-Heimer method and could be followed caudally to the dorsal midbrain central gray and to the mammillary bodies. A few axons could be traced rostrally to the medial septum. Aggression could be induced from 10 of 112 electrodes implanted in the central gray; the other electrodes elicited either locomotion, vocalization, jump, or “alarm-like reactions.” The morphology of the induced aggression was similar to the morphology of the hypothalamically induced aggression, though it was often accompanied with motor disturbances and was less intense. Hypothalamic stimulation was combined with simultaneous central gray stimulation in rats with electrodes both in the hypothalamus and in the central gray. Hypothalamic thresholds for aggression could be lowered by this stimulation of the central gray, even when no aggressive responses were observed during central gray stimulation alone. This suggests that, although aggression is not manifest, electrical stimulation may activate neural tissue involved in aggressive behavior. It is concluded that in rats central gray and hypothalamus are part of the same neural network mediating intraspecific aggression.     

Agonistic behavior,plasma testosterone,and hypothalamic estradiol binding in male rabbits

The purpose of this study was to establish a relation between agonistic behavior, gonadal hormones, and their receptorial capacity at the central level. Male rabbits were observed in seminatural conditions and three components of their agonistic behavior were recorded: follow, attack, and chase. The three behaviors were mutually correlated and clearly differed among the four members of each group. Within the social group, one rabbit was agonistically more active than the others and his supremacy was associated with an increased level of peripheral testosterone and higher estradiol binding in the hypothalamus. On the whole, the values of the hypothalamic estradiol binding were positively correlated with the behaviors. The results show that, in the male rabbit, agonistic activity is associated with changes in testosterone concentration and in the binding at the central level of its aromatized metabolite estradiol. Aggr. Behav. 23:33–40, 1997. © 1997 Wiley-Liss, Inc.     

Intraspecific aggression in male hamsters is inhibited by intrahypothalamic vasopressin-receptor antagonist

The present study examines the effect of the arginine vasopressin (AVP) receptor antagonist, d(CH₂)₅Tyr(Me)AVP, on intraspecific aggression between pairs of male Golden hamsters in a neutral territory. Subjects drawn from a group of 24 animals were paired once each with novel partners from the group under each of three experimental conditions: 1) both members of a pair were microinjected into the anterior hypothalamus with saline (S/S), 2) one member of a pair was microinjected with AVP-receptor antagonist and its partner with saline (A/S), and 3) both members of a pair were microinjected with AVP-receptor antagonist (A/A). There were significantly (P < .01) fewer attacks during encounters between pairs of hamsters in the A/A condition compared to pairs in the A/S condition. Similarly, pairs in the A/S condition attacked significantly (P < .025) less often than pairs of hamsters in the S/S condition. These results confirm our earlier work showing that AVP-receptor antagonist reduces intraspecific aggression. In addition, saline-treated hamsters initiated significantly (P < .001) fewer attacks toward antagonist treated hamsters than would have been predicted if their opponent was not drug treated. These latter results suggest that hamsters microinjected into the anterior hypothalamus with an AVP-receptor antagonist also elicit less aggression from conspecifics.     

Neurochemical mechanisms underlying amygdaloid modulation of aggressive behavior in the cat

Studies designed to determine the respective roles of substance P, excitatory amino acids, and enkephalins in amygdaloid modulation of defensive rage behavior in the cat are presented. The basic design of these studies involved three stages. In stage I, cannula electrodes for stimulation and drug infusion were implanted into medial hypothalamic or midbrain periaqueductal gray (PAG) sites from which defensive rage behavior could be elicited. Then, a stimulating electrode was implanted into a site within the medial, basal, or central nuclear complex from which modulation of the defensive rage response could be obtained. Amygdaloid modulation of defensive rage was determined in the following manner: it employed the paradigm of dual stimulation in which comparisons were made of response latencies between alternate trials of dual (i. e., amygdala = medial hypothalamus [or PAG]) and single stimulation of the hypothalamus or PAG alone. Thus, stage I established the baseline level ofmodulation (i. e., facilitation or suppression of defensive rage) in the predrug stimulation period. In stage II, a selective or nonselective receptor antagonist for a given transmitter system was administered either peripherally or intracerebrally at the defensive rage site, after which time the same dual stimulation paradigm was then repeated over the ensuing 180 min postinjection period in order to determine the effects of drug delivery upon amygdaloid modulation of defensive rage. Stage III of the study took place at the completion of the pharmacological testing phase. The retrograde axonal tracer, Fluoro-Gold, was microinjected into the defensive rage site within the medial hypothalamus or PAG, and following a 6-14 day survival period, animals were sacrificed and brains were processed for histological and immunocytochemical analyses for the neurotransmitters noted above. This procedure thus permitted identification of cells within the amygdala which were labeled retrogradely and which were also immunostained positively for substance P, excitatory amino acids, or enkephalin. For studies involving substance P, defensive rage was elicited from the medial hypothalamus and for studies examining the roles of excitatory amino acids and enkephalin, defensive rage was elicited from the PAG. In the first study, facilitation of hypothalamically elicited defensive rage was obtained with dual stimulation of the medial nucleus of the amygdala. In separate experiments, the selective NK₁ non-peptide antagonist, CP 96,345, was administered both peripherally as well as intracerebrally into the hypothalamic defensive rage sites in doses of 0.5-4.0 mg/kg (i. p.) and 0.5-2.5 nmol (i. c.). Following drug delivery, the facilitatory effects of medial amygdaloid stimulation were blocked in a dose- and time-dependent manner in which the effects were noted as early as 5 min postinjection. The maximum drug dose (4.0 mg/kg) employed for peripheral administration resulted in a 42% reduction in the facilitatory effects of the medical amygdala (P < 0.002). This drug, when microinjected directly into medial hypothalamic defensive rage sites at the maximum dose level of 2.5 nmol, resulted in an 84% reduction of the suppressive effects of amygdaloid stimulation (P < 0.5) at 5 min postinjection. In the next study, an N-methyl-D-aspartate (NMDA) antagonist, DL-α-amino-7-phosphonoheptanoic acid (AP-7), was administered either peripherally (0.1-1.0 mg/kg) or intracerebrally (0.2 and 2.0 nmol) into PAG defensive rage sites. Facilitation of defensive rage behavior, which was observed following dual stimulation of the basal amygdala and PAG, was significantly reduced by either route of drug administration in a dose- and time-dependent manner. At the maximum dose level of peripheral administration, AP-7 reduced amygdaloid facilitation of defensive rage by 63% (P < 0.001) for 60 min, postinjection. A smaller (i. e., 19%) but still significant (P < 0.05) reduction in facilitation was obtained following intracerebral administration of the drug. In a third study, the non-selective opioid receptor antagonist, naloxone (27.5 nmol), infused directly into PAG defensive rage sites, totally blocked the suppressive effects of central amygdaloid stimulation for a period of 30 min (P < 0.05) in a dose- and time-dependent manner. The anatomical phase of this study revealed the following relationships: 1) that large numbers of neurons projecting to the medial hypothalamus from the medial amygdala immunoreact positively for substance P; 2) that neurons projecting to the PAG from the basal complex of amygdala immunoreact positively for glutamate and aspartate; and 3) that neurons located within the central nucleus of the amygdala which project to the PAG immunoreact positively for met-enkephalin. Collectively, these observations provide new evidence which characterizes the likely neurotransmitters linked with specific amygdaloid pathways subserving the modulation of defensive rage behavior in the cat.     

Directional interaction of midbrain and hypothalamus in the control of carbachol-induced aggression

Microinjection of carbachol into the ventromedial part of the anterior hypothalamus or the ventrolateral part of the mesencephalic central gray elicits affective aggression in the cat. Pretreatment with atropine in the same site blocks carbachol-induced aggression. Prior administration of atropine into the midbrain blocks aggression induced by carbachol injections into the hypothalamus, but atropine injected into the hypothalamus does not prevent affective aggression elicited by carbachol administered into the midbrain. The results demonstrate a directional interaction between midbrain and hypothalamus, and provide suggestive evidence for a hierarchal organization of these limbic structures in the control of cholinergically-mediated affective aggression.