Possible involvement of a gamma-hydroxybutyric acid receptor in startle disease.

Startle disease or hyperreflexia is an autosomal dominant neurological disorder, with a neonatal onset, characterized by muscular hypertonia and myoclonic jerks, exaggerated by the slightest stimulus. Low concentrations of free gamma-aminobutyric acid (GABA) have been found in the cerebrospinal fluid of two affected infants. The involvement of GABA or its receptors has been raised and the use of GABA-agonist drugs has been suggested. We report a newborn with startle disease who also had a low concentration of GABA in the cerebrospinal fluid. No clinical improvement was observed with progabide, a GABA agonist. Furthermore, a high dose (100 mg/kg) of gamma-hydroxybutyrate (GHB) did not improve muscular stiffness and failed to induce general anesthesia. GHB, currently used as an effective general anaesthetic, is a structural analogue of GABA. It is present naturally at low concentrations in the brain and is regarded as an inhibitory neurotransmitter. Two specific GHB receptors, distinct from the GABA receptors, have been identified in rat brain. Failure to induce general anesthesia with a high dose of GHB suggests that one of these receptors could be involved in startle disease.

[The mechanism of releasing and bio-behavioral significance of the hypothalamo-hypophyso-adrenal gland reaction to the environment (alarm reaction)]. / Sur le mécanisme de déclenchement et la signification bio-comportementale de la réaction hypothalamo-hypophysosurrénalienne à l'environnement (réaction d'alarme)

Laboratory experimentation has demonstrated the large increase in the rate of circulating norepinephrin (N.E.), in a parallel with an improvement in cardiovascular dynamism of suprarenalectomized rabbits under the action of injection IV of hydrocortisone. As from this ascertainment, the author attempts to make a synthesis of known experimental facts demonstrating that next to a regulation in constancy (with negative retroaction) of the C.R.F. leads to A.C.T.H. leads to cortisol system, there exists a servomechanism (control external to the system) as from the activity of the nervous systems as compared with environment. Hydrocortisone favouring passive avoidance, and extinction facilitating the activity of the cholinergic inhibiting system of action (I.S.A.). A.C.T.H. facilitates active avoidance and the catecholaminergic activating system of action (A.S.A.). Now, it has already been demonstrated in the same laboratory that stimulation of I.S.A. or inhibition of the A.S.A. freed N.E. from the peripherous nerves of a adrenalectomized animal. It, therefore, seems that the early freeing of A.C.T.H. following aggression is capable of favouring locomotive activity (flight or fight). Should the latter be efficient, there is a return to the prior behavioural and endocrinal balance. On the other hand, should they be inefficient, there arises a vicious circle (regulation with tendency, positive retroaction) because secondary secretion of glucocorticoids will maintain inhibition of action and the secondary freing of the mineralocorticoids are discussed as well as the central mechanism of illness so called "psychosomatic".

On the mechanism of activation of the hypothalamo--pituitary--adrenal reaction to changes in the environment (the 'alarm reaction').

The amount of circulating noradrenaline increases considerably in parallel with an improvement in cardiovascular haemodynamics in adrenalectomized rabbits after intravenously injected hydrocortisone. In view of this finding, that as well as a constant regulation with negative retroaction of the corticotrophic-releasing factor--adrenocorticotrophic hormone (ACTH)--cortisol system, there exists an externally controlled servomechanism from nervous system activity related to the environment. Hydrocortisone favours passive avoidance, extinction and facilitates the activity of the cholinergic inhibiting system; ACTH facilitates active avoidance and catecholaminergic activation. It has already been demonstrated that stimulation of the inhibiting system or inhibition of the activating system released noradrenaline from the peripheral nerves of an adrenalectomized animal. It therefore seems that the early release of ACTH after aggression is capable of favouring locomotor activity in 'flight or fight'. If the latter is effective, there is a return to the previous behavioural and endocrine balance. On the other hand, if 'flight or fight' should be ineffective, there arises a vicious circle with positive retroaction, because secondary secretion of glucocorticoids will maintain inhibition and considerable activity in the noradrenergic system. The significance of the alarm reaction and the secondary release of the mineralocorticoids are discussed as well as the central mechanism of allegedly psychosomatic, illness. Aggression, as well as the lesion it induces, causes a reaction from the organism subjected to aggression. This is a non-specific reaction to which Selye (1936) has drawn attention. This reaction sets the central nervous system in action, which activates the vegetative nervous system and the endocrine system through the hypothalamus and the pituitary gland. In the vegetative system and the vasomotor changes related to it, the alarm syndrome has to be understood as a way to induce flight or fight, which allows the organism to move away from the aggressor. When this behaviour is impossible or ineffective the vasomotor reaction is threatened and it is depressed or inhibited (Laborit, 1952). Resuscitation techniques involving central or peripheral inhibitors, such as lytic cocktails, neuroplegy or neuroleptanalgesia, derive from this concept. The neuro--endocrine significance of the alarm reaction is still not understood and resuscitation techniques are quite empirical in relation to it.

[Neurophysiological and biological bases of active and passive avoidance behaviors. Somatic consequences. Behavioral level. Semantic problems]. / Bases neurophysiologiques et biologiques des comportements d'évitement actifs et passifs. Conséquences somatiques. le niveau comportemental. problèms sémantiques

After a discussion concerning the semantic contents of terms such as: emotions, pulsions, motivations, as much from the physiological as from the psychological point of view as well as with regard to the role of the processes of memory and learning in their elaboration, the neurophysiological plane of fundamental behaviour patterns is approached. The role of the dorsomedian amygdala and of the lateral hypothalamus in the processes of behavioural activation as well as that of the septal area, of the hippocampus, of the lateral amygdala, of the ventro-median hypothalamus in the processes of inhibition are recalled. The action upon the environment and the reaction to the environment (conditioned or unconditioned) of this system are studied. Anxiety is considered as resulting from the inhibition of action and its endogenous or exogenous causes, as well as the mechanisms of its disappearance, are examined. The distinction between hypophyso-corticoadrenal alarm reaction and sympatho-adrenergic defence reaction is recalled. Basing himself upon the experimental work of his laboratory, the author shows that in the defence reaction it is necessary to make the distinction between the sympathetic reaction, noradrenergic, brrenergic reaction, medullo-adrenal, controlled by the system of behavioural activation. He shows the interest of such a distinction on the physio-pathological plane. Finally he approaches the biochemical level, that of the neuro-modulators and of their central role. He suggests that the effect alpha of catecholamines and the nicotinic effect of acetylcholine indeed seem to have a direct role in the control of synaptic activity, while the beta effect and the muscarinic effect could have a secondary role through the intermediary of the synthesis of cAMP and cGMP respectively. The second messengers would intervene principally in the neuronal protein synthesis and the long term memory. The work ends with a rapid summary concerning the biochemical and neurophysiological mechanisms of drugs which act upon behaviour patterns. This summary is based on the outline previously elaborated.