Influence of female sex hormones on neuroleptic-induced behavioral supersensitivity

The influence of various states of female sex hormones were investigated on the development of neuroleptic-induced behavioral supersensitivity to a dopamine agonist. The chronic administration of haloperidol induced behavioral hypersensitivity in male guinea-pigs. This effect has often been reported with male animals. In female guinea-pigs, haloperidol failed to induce any behavioral changes. Oophorectomy of female guinea-pigs significantly reduced the behavioral response to apomorphine when compared to normal female animals. This behavioral hyposensitivity increased as a function of time after oophorectomy. Chronic haloperidol treatment in oophorectomized animals produced behavioral hypersensitivity. Chronic treatment of either estradiol or progesterone in oophorectomized animals caused a significant enhancement of the behavioral response. In oophorectomized animals treated chronically with estradiol plus haloperidol or progesterone plus haloperidol no greater behavioral response was observed than with treatment with estradiol or progesterone alone. These results suggest that female sex hormones are able to modify dopamine receptor sensitivity and alter the development of behavioral supersensitivity induced by neuroleptics.     

Pharmacokinetics of long-acting injectable neuroleptic drugs: clinical implications

The authors review the literature regarding the pharmacokinetics of long-acting injectable neuroleptic drugs (LINS). There are important differences between LINS and oral neurolepties that affect their pharmacokinetics. By avoiding first pass metabolism in gut and liver, LINS result in lower circulating concentrations of metabolites than are found after oral administration. In addition, LINS take more time to reach a stable steady state than their oral counterparts. The clinical significance of these pharmacokinetic properties is discussed. The authors recommend that when patients are being changed from oral neuroleptics to LINS, that this conversion be done gradually over several months.     

Increased urine volume in chronic schizophrenic patients

Polydipsia and polyuria have a long association with schizophrenia. To assess the prevalence of polydipsia and polyuria in schizophrenia, urine volume was examined in medication-free chronic schizophrenic patients, normal controls, and nonschizophrenic patients. Mean urine volume was significantly higher in the schizophrenic patients (2319 +/- SD 2052 ml/24 hours) than in the other two groups (1054 +/- SD 471 ml/24 hours for nonschizophrenic patients and 1265 +/- SD 613 ml/24 hours for normals). Seven of 35 patients with schizophrenia but 0/7 nonschizophrenics had urine volumes greater than any normal control. Polyuria was associated with a good premorbid history and a positive neuroleptic response. Among polyuric patients, those with hyponatremia may represent a different, distinct subgroup. Neuroleptic treatment was associated with a further, significant increase in urine volume. Hence, polydipsia and polyuria appear to be relatively common in schizophrenia.     

CSF dopamine turnover and positive schizophrenic symptoms after withdrawal of long-term neuroleptic treatment

Dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured in cerebrospinal fluid (CSF) of 14 schizophrenic inpatients before and 2 weeks after withdrawal of long-term neuroleptic medication. Total neuroleptic-like activity (NLA) in serum was determined at the same times. DA and its metabolites (DOPAC and HVA) were significantly reduced after neuroleptic discontinuation. NLA was substantially diminished. The decrease in DA and DOPAC was positively correlated with positive symptoms of postwithdrawal deterioration, and low prewithdrawal DOPAC level predicted severe relapse. These results are compatible with the hypothesis linking an overregulated central DA system to the positive symptoms of schizophrenia.     

Clozapine and other neuroleptic drugs antagonize the light-evoked suppression of melatonin biosynthesis in chick retina: involvement of the D4-like dopamine receptor

Summary The subtype of dopamine receptor mediating the suppressive effect of light on melatonin biosynthesis in chick retina was characterized pharmacologically. Acute exposure of animals to light during the dark phase of the light-dark cycle dramatically decreased melatonin levels and activity of serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthetic pathway). Various antagonists of dopamine receptors were tested for their ability to block this action of light on the retinal melatonin formation. Intraocular (i. oc.) pretreatment of chicks with neuroleptic drugs — blockers of the D₂-family of dopamine receptors, i.e., clotiapine, clozapine (an atypical neuroleptic with high affinity for a D₄-subtype dopamine receptor), haloperidol, spiroperidol, sulpiride, and YM-09151-2, significantly antagonized the light-evoked suppression of the nighttime NAT activity of the chick retina in a dosedependent manner. In contrast, remoxipride (a D₂-selective dopamine antagonist), raclopride and (+)-UH-232 (D₂/D₃-dopamine receptor antagonists), as well as SCH 23390, a blocker of the D₁-family of dopamine receptors, were ineffective. Clozapine, haloperidol, spiroperidol and sulpiride also potently antagonized the suppressive action of light on melatonin content of the chick retina. It is suggested that the dopamine receptor mediating the inhibitory effect of light stimulation on the nighttime melatonin biosynthesis in the retina of chick represents a D₄-like subtype.     

Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration

Rats were chronically administered either haloperidol (HAL) or fluphenazine (FLU) via depot injections for 8 months, given these same drugs in their drinking water for the next 2 months, and then withdrawn from the drugs. Throughout the experiment the animals were tested repeatedly in an enclosed tube using a computerized device which measured computer-scored movelets (CSMs) and, in the latter half of the experiment, were also scored by a human observer in the tube, as well as in an open cage, for observed oral movements (OMs). In the tube, the animals in both neuroleptic-treated groups showed initial decreases in the number of CSMs and made sluggish CSMs; these effects were generally larger in the FLU animals. After 6 months of chronic neuroleptics, the HAL-treated animals showed increased oral movements, both as reported by the human observer and in CSMs of all amplitudes, and this effect increased upon drug withdrawal. FLU-treated animals showed a more persistent depression of both OMs and CSMs of large amplitudes. However, the behavior most characteristic of both neuroleptic-treated groups was the gradual development of increases in CSMs of the smallest amplitudes measurable.A different pattern was observed in the open cage test, where both neuroleptic groups showed significant increases in vacuous OMs during drug administration which rapidly became attenuated upon drug withdrawal. These results indicate a complex syndrome of oral activity in the drugged animals which changed over time. The measure of oral activity which most clearly showed the time-course for late-onset changes in oral activity was CSMs of the smallest amplitudes.     

Some aspects of the use of liposomes to store neurotropic drugs

Anesthesiology Research Laboratory, Faculty of Surgery, I. M. Sechenov Moscow Medical Academy. (Presented by Academician of the Academy of Medical Sciences of the USSR Yu. A. Vladimirov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 11, pp. 497–499, November, 1991.     

Old and new approaches to drug treatment of schizophrenia

More than 30 years have passed since the introduction of effective antipsychotic drugs. These drugs have revolutionized both the treatment of patients with schizophrenia and the thinking about the nature of this disorder. During this time, technical improvements have widened the scope of usefulness of these agents. However, no newer drug has been more effective overall than was the first, chlorpromazine. In addition, many patients respond poorly or not at all to drug therapy; others find the side effects of present drugs unbearable. Tardive dyskinesia and tardive psychosis are developments following long-term treatment that may have serious import. Many questions about drug therapy remain unanswered. Which drug? How much? Intermittent or continual maintenance therapy? What new approaches to treatment can be considered? Atypical neuroleptics that may specifically bind to receptors in the mesolimbic system constitute the major thrust of current drug development. Interest in benzodiazepines as adjunctive agents have revived. The role of propranolol remains uncertain; it seems more to be an adjunctive treatment. Lithium and carbamazepine may be suitable adjuncts for patients who are otherwise refractory to treatment. Use of neuropeptides was greeted with initial enthusiasm, which is rapidly waning as more experience develops. New approaches to drug treatment for schizophrenia are desperately needed.     

Serenics and aggression

This paper describes the behavioural effects of a new class of psychotropic drugs, the serenics, which exert specific antiaggressive effects in animal paradigms of (offensive) agonistic behaviour. Serenics specifically inhibit offensive aggression, leaving defensive behaviour intact. Ethological profiling of serenics and reference drugs from different drug classes shows the unique profile of the serenics: antiaggressive action without impairment of sensoric or motoric functions and without sedation or muscle relaxation. This contrasts sharply with drugs from other drug classes, eg neuroleptics, psychostimulants or anxiolytics, which all have non-specific antiaggressive or even proaggressive actions. The behavioural profile of serenics is illustrated in this paper in a male aggression paradigm (resident-intruder in rats) and a female aggression paradigm (maternal aggression of lactating rats). For comparative reasons, drugs from several different classes have also been tested in these paradigms to compare the profiles of action. The use and possible future applications of specific antiaggressive drugs are discussed.     

Dopamine receptor availability in Tourette''s syndrome

A large body of evidence suggests that abnormal dopaminergic activity is present in Gilles de la Tourette Syndrome (GTS). To investigate whether dopamine dysregulation involving the D₂/D₃ receptor occurs in GTS, we performed single slice dynamic single photon emission computed tomography (SPECT) with ¹²³iodo-6-methoxybenzamide (¹²³I-IBZM) in 15 GTS patients (eight unmedicated) and six healthy volunteers. After intravenous administration of 5 mCi (185 MBq) of ¹²³I-IBZM, dynamic SPECT (5 minutes per slice) studies were performed at the level of the basal ganglia for 55 minutes. The mean activity per pixel in the basal ganglia was compared with the mean activity per pixel in the visual cortex. Unmedicated GTS patients showed no differences from control subjects. However, GTS patients taking D₂ blocking medications had significantly decreased ¹²³IIBZM binding compared with control subjects in both the right and left basal ganglia. Thus, D₂/D₃ receptor availability, as measured by ¹²³I-IBZM SPECT, is not abnormal in GTS.