Past and future of neuropsychopharmacology.

The advent of what is called the chemotherapy of mental diseases goes back to the early fifties, when a series of clinical observations led medical research to reconsider this field, that at the time was not particularly developed. The use of chlorpromazine and of reserpine in the therapy of some psychotic syndromes dates back to that time. A few years later meprobamate was introduced and proved active against anxiety. The success obtained with these drugs was followed by a flourishing of research carried out in a joint effect by pharmacologists and clinicians. This cooperation gave birth to a new discipline, the neuropsychopharmacology. In the course of time, through a progressive refining of the techniques it has been possible to acquire methods particularly suitable for the identification of the effects of the various drugs acting on the CNS. If the sixties were the decade of the synapse, during the seventies the main interest of research was focused on receptors, and the eighties can be considered the decade of post-receptor intraneuronal mechanisms. As far as the future of research is concerned, priority must be given to scientific approaches that: a) explore in a new and original chemistry; b) use advanced pharmacological techniques; c) start from scientific hypotheses based on recent discoveries and if possible suggested by scientists. Recently, special attention has been devoted to the study of inhibitors of proteolitic enzymes responsible for the degradation of enkephalins which allegedly should reinforce the endogenous mechanisms for the control of pain. Encouraging data are already available but these preliminary results should be confirmed before going into more extended investigations.(ABSTRACT TRUNCATED AT 250 WORDS)

Modifications of brain electrical activity after activation of the benzodiazepine receptor types in rats and rabbits.

The present study reports a comparative electroencephalographic (EEG) study of drugs belonging to different chemical classes which share the property to bind at benzodiazepine (BDZ) recognition sites. The EEG patterns are recorded from the neocortex of rats and rabbits as well as from dorsal hippocampus and red nucleus in rabbits after intravenous administration of diazepam (0.1-10 mg/kg), clonazepam (0.02-2.5 mg/kg), zopiclone (0.3-3 mg/kg), flunitrazepam (0.03-2.5 mg/kg), CGS 9896 (0.1-3 mg/kg), zolpidem (0.1-3 mg/kg) and Cl 218,872 (0.1-10 mg/kg). The most relevant differences are observed at the level of the neocortex. All drugs induced appearance of 7-12 Hz spindle bursts. On the contrary, the presence of 15-30 Hz waves (defined beta-like activity) mainly occurs after diazepam, clonazepam and zopiclone. Scarce beta-like activity is present after CGS 9896, zolpidem and Cl 218,872. According to the selectivity of these drugs for the various types of BDZ receptor, one can speculate that activation of BDZ2 is relevant for the appearance of the beta-like activity. Flunitrazepam, diazepam, and zolpidem increase the amplitude of the red nucleus waves. Such an effect is less marked after zopiclone and CGS 9896, whereas is almost absent after clonazepam and Cl 218,872. A reduction of the frequency is observed after flunitrazepam, diazepam, clonazepam, CGS 9896 and zolpidem, whereas it is almost absent after zopiclone and Cl 218,872. Finally, all drugs induce a reduction of the amplitude of the hippocampal theta rhythms, whereas after diazepam, flunitrazepam, zolpidem and CGS 9896 a slowing of the record also occurs.

Blockade of D-1 dopamine receptors by SCH 23390 prevents EEG and behavioral activation induced by L-dopa.

Administration of L-DOPA, a precursor of dopamine, induced EEG activation, arousal and signs of behavioral excitation in the rabbit. The effects were fully prevented by pretreatment with minute doses (0.01 mg/kg i.v.) of the selective D-1 antagonist SCH 23390. Conversely, its S-enantiomer SCH 23388, which has weak actions on D-1 receptors, displayed relatively low inhibition of L-DOPA effects. (-)-Sulpiride (12.5 mg/kg), a selective D-2 antagonist, and haloperidol (0.1-0.3 mg/kg), a neuroleptic that interacts preferentially with D-2 receptors, both inhibited behavioral effects but failed to block EEG activation. The data indicate that D-1 receptors play an essential role in mediating EEG activation induced by L-DOPA.

An EEG investigation on the role of cerebello-rubral system in the effects of diazepam and pentobarbital.

The EEG effects of diazepam and pentobarbital at the level of cerebello-rubral pathways (i.e., cerebellar cortex, interposed, fastigial and red nuclei) were studied. The drugs elicited a slowing of frequency and an enhancement of the voltage of the waves at the level of cerebellar and red nucleus leads. The effect was antagonized by picrotoxin or pentamethylenetetrazole, while ethyl - 8 - fluoro - 5,6 - dihydro - methyl-6-oxo-4H-imidazol [1,5 a][1,4]benzodiazepin-3-carboxylate (Ro 15-1788) antagonized only the effect of diazepam. The relationships between the EEG alterations and the behavioural effects of diazepam and pentobarbital, which are endowed with muscle relaxing, sedative-anesthetic and anticonvulsant activity, are discussed.

Evaluation of the analgesic activity of morphine, enkephalins and their synthetic analogues.

In the rabbit, a morphine-like analgesic activity of natural and synthetic enkephalins has been demonstrated using the method of the return of corneal anesthesia due to conjunctival instillation of procaine. FK 33824 is the most effective drug in producing analgesia when administered intracerebroventricularly, whereas morphine is much more active when injected i.v. The effect of morphine and enkephalins is readily reversed by nalorphine (10 mg/kg, i.v.) indicating an involvement of opiate receptors in the CNS.

Role of the dopaminergic system in the cataleptogenic action of bulbocapnine.

Time courses of the behavioural and biochemical effects of a cataleptogenic dose (50 mg kg-1 i.p.) of bulbocapnine have been studied in the rat. Catalepsy ensues immediately after administration of the drug and lasts 1 h. Concomitant with the onset of catalepsy there is a rise in HVA and DOPAC concentrations in whole and discrete parts of the brain (striatum, limbic system). Dopamine content does not change in whole brain but it decreases in the striatum and increases in the cortex and hippocampus. No significant effects on NA, 5-HT and 5 HIAA concentrations were observed.

Evaluation of the central effects of ergot alkaloids by means of electroencephalography.

The effects of some ergot derivatives on the electroencephalogram and behavior of laboratory animals (mice, rats, rabbits) have been surveyed. The interference of bromocriptine on the dopaminergic central systems has been studied using behavioral (interference with the effects induced by L-dopa, 5HT, TRF or neuroleptic drugs) and electrophysiological (EEG) methods. While no clear effects of bromocriptine could be evidenced in mice, EEG recordings from the dorsal hippocampus of the rabbit showed a slight disruption of epsilon-waves after administration of 2 mg/kg i.v. of the drug or more.

Effect of sexual steroid hormones and of clomiphene on the behavioral response to L-dopa in mice.

The scope of the present work was to ascertain the effects of some steroid hormones on the behavioral response of mice to L-Dopa. The drugs considered were: testosterone, mesterolone, cyproterone, estradiol, progesterone and clomiphene. The male sex steroids, having either androgen or antiandrogen properties, were able to potentiate the behavioral effect of L-Dopa in mice, while female sex steroids failed to demonstrate this activity. Clomiphene proved to be the most active in enhancing the behavioral effects of L-Dopa in mice.