A new animal model for schizophrenia: interactions with adrenergic mechanisms.

Amphetamine-induced stereotyped behavior in animals is proposed as a model for schizophrenia. Chronic amphetamine administration produces stereotyped behavior and a paranoid schizophreniform syndrome in man, whereas in animals a behavioral sensitization to stereotypy is evoked. We now show that phenylethylamine (PEA), an amphetamine-like stimulant concentrated in the limbic system of human brain, produces stereotypy in rats with a behavioral sensitization when chronically administered. In comparing amphetamine-induced stereotypy with PEA-induced stereotypy, we found that the alpha-adrenergic blocking agents phentolamine and phenoxybenzamine selectively antagonize PEA stereotypy, whereas the beta-adrenergic blocking agent propranolol fails to alter significantly stereotypies evoked by PEA or amphetamine administration. Catecholamine depletion by alpha-methyl-p-tyrosine administration blocks stereotypies induced by both PEA amphetamine, whereas selective norepinephrine depletion antagonizes only PEA stereotypy; the amino acid precursors of both norepinephrine and dopamine potentiate stereotypies. Therefore, PEA-elicited stereotypy, but not amphetamine-elicited stereotypy, is dependent upon norepinephrine; the significance of this for the PEA animal model of schizophrenia is discussed.

Antagonism of dopamine supersensitivity by estrogen: neurochemical studies in an animal model of tardive dyskinesia.

The withdrawal from chronic haloperidol or estradiol benzoate (EB) treatment results in a behavioral supersensitivity to dopamine agonists in ovariectomized rats. On the other hand, the administration of EB during the withdrawal from haloperidol or the continuous treatment with EB will attenuate or prevent the development of a supersensitivity to dopamine agonists. The enhanced behavioral sensitivity to dopamine agonists is correlated with an increase in 3H-dopamine binding sites in striatal membranes. The administration of EB during the withdrawal from chronic haloperidol treatment or the continuous administration of EB decreases or prevents the proliferation of dopamine binding sites in the striatum that normally orccur upon withdrawal of these two substances. These results indicate that exogenous estrogens may modulate the number of dopamine receptors in the central nervous system and, as such, may decreasse the incidence and/or relieve the symptoms of tardive dyskinesia.

Modulation of dopamine receptor sensitivity by estrogen.

Postmenopausal females have the highest incidence of tardive dyskinesia, suggesting that loss of ovarian function may predispose them to this condition. Moreover, reports have indicated that estrogens could reduce abnormal movements in tardive dyskinesia. To test the effects of estrogen in an animal model of tardive dyskinesia, ovariectomized rats were treated daily for 16 days with haloperidol (Haldol, 0.5 mg/kg) or Haldol + estradiol benzoate (EB, 10 micrograms/kg). Rats were then challenged with d-amphetamine or apomorphine 1 week following cessation of the chronic treatments. Chronic treatments with either Haldol or EB alone produced an enhanced response to both d-amphetamine and apomorphine, while the combined treatment produced a synergistic response. Rats treated chronically with Holdol, and treated daily with EB following the Haldol treatment, showed an attenuation of drug-induced stereotypy. These preliminary data indicate that estrogen can attenuate the development or mask the display of the supersensitive dopamine receptor.

Enkephalins and nigrostriatal function.

Unilateral lesions of the substantia nigra were made with 6-hydroxydopamine in rats. In this model, drugs such as naloxone, which block endogenous enkephalin receptors, potentiated agents with postsynaptic dopaminergic actions, while antagonizing agents with presynaptic dopaminergic actions. Drugs which increase brain enkephalin content (d-phenylalanine or methionine-enkephalin) antagonized postsynaptically active agents and potentiated presynaptic agents. Naloxone also reversed reserpine-induced parkinsonism in rats. Separate pre- and postsynaptic enkephalinergic neurons thus seem to modulate nigrostriatal function.

Estrogen in experimental tardive dyskinesia.

Postmenopausal women have the highest incidence of tardive dyskinesia, suggesting that loss of ovarian function may predispose to this condition. Moreover, reports have indicated that estrogens could reduce abnormal movements in tardive dyskinesia. To test the effects of estrogen in tardive dyskinesia, ovariectomized rats were treated daily for 16 days with haloperidol alone (0.5 mg per kilogram) or haloperidol plus estradiol benzoate (EB; 8 microgram per kilogram). Rats were then challenged with apomorphine (0.25 mg per kilogram) 4 and 10 days after cessation of the chronic treatments. Chronic treatment with haloperidol alone enhanced the response to apomorphine, whereas the combined treatment produced a synergistic response. Rats treated chronically with haloperidol and then treated daily with EB after the haloperidol treatment showed an attenuation of drug-induced stereotypy. These data indicate that estrogen may mask development of tardive dyskinesia.

Neuropharmacology of the extrapyramidal system.

The neuropharmacology and neuroanatomy of the extrapyramidal system are complex; however, in its most reductionistic state, this system is often described as a balance between the actions of dopamine and acetylcholine. In this paper, a thorough investigation of the neuroanatomy and neuropharmacology of the extrapyramidal system is undertaken, and an attempt is made to delineate the roles of other neurotransmitters and neuromodulators that play an important role in its functioning. To demonstrate the therapeutic complexity of extrapyramidal system movement disorders, clinical literature is briefly reviewed to show the relative efficacies of anticholinergic and prodopaminergic antiparkinsonian agents in treating neuroleptic-induced extrapyramidal side effects and to show how drugs that affect alternative neurotransmitter systems have also been used to treat these same side effects.

Lithium prevention of amphetamine-induced 'manic' excitement and of reserpine-induced 'depression' in mice: possible role of 2-phenylethylamine.

Repeated treatment of mice with lithium chloride (45 mg/kg, i.p., daily for 8 days) reduced the jumping, fighting, stereotypies, and hyperactivity induced by d-amphetamine (5 mg/kg, i.p.). Lithium also reduced the hypoactivity observed 1--3 h after reserpine (0.75 mg/kg, i.p.). In biochemical studies we found that 8-day treatment with lithium markedly reduced (to 45% of control) the recovery from brain of labelled 2-phenylethylamine (PEA) following i.p. injection of labelled L-phenylalanine, while decreasing recovery from brain of labelled PEA following its i.p. injection of 63% of control. In saline-treated mice, d-amphetamine appeared to increase PEA synthesis and to accelerate its disposition, whereas reserpine enhanced PEA synthesis and reduced disposition; all of these effects were antagonized by lithium pretreatments. Since PEA appears to be one of the most powerful behavioral stimulants among endogenous neuroamines, and because its deaminated metabolites are behavioral depressants, such antagonism of brain PEA metabolism may significantly contribute to the prophylactic action of lithium against both manic and depressive behavior.

A double-blind, randomized, placebo-controlled, multi-center study of brofaromine in the treatment of post-traumatic stress disorder.

A large multi-center, double-blind, parallel trial to assess the efficacy of brofaromine in the treatment of post traumatic stress disorder (PTSD) failed to show a significant difference between the brofaromine and placebo treatment groups. The placebo response rate in this study was higher than that in previously published double-blind, placebo-controlled studies of PTSD.

Hypophysectomy induced hypersensitivity to dopamine: antagonism by estrogen.

Hypophysectomized (HYPOX) or sham HYPOX (SHAM) and ovariectomized rats were injected with either estradiol benzoate (EB, 10 microgram/kg/day x 3) or sesame oil (0.25 ml/kg/day x 3). Twenty hours after the last dose of EB or oil all animals were injected with apomorphine and the resulting stereotypy scored. The HYPOX + oil group was more sensitive to the apomorphine than the SHAM + oil group (ED50 = 0.24 and 0.45 mg/kg, respectively). Treatment with EB resulted in a shift to the right of the dose response curves for both the HYPOX and SHAM groups. The ED50 for the HYPOX group was increased to 0.62 mg/kg, while the SHAM group increased to 0.93 mg/kg. The Bmax values for [3H]spiroperidol binding to striatal membranes were not significantly different for the HYPOX + EB, SHAM + EB, or SHAM + oil groups. However, the HYPOX + oil group was significantly increased (54%) at 7 days post-HYPOX. By 28 days post-HYPOX, the Bmax for the HYPOX animals had increased by 94% relative to SHAM animals. The HYPOX induced increase in dopamine sensitivity could be increased by chronic treatment and withdrawal of haloperidol. The haloperidol induced increase in apomorphine induced stereotypy and [3H]spiroperidol binding could be antagonized by EB treatment during the withdrawal phase of the haloperidol treatment. These data indicate that the pituitary has a modulating effect on striatal spiroperidol binding and apomorphine induced stereotypy, but that its presence is not required for estrogen to suppress the efficacy of dopamine or dopamine agonists.

Phenomenology and neurobiology of cocaine withdrawal: are they related?

1. The presence of mood disturbances and platelet 3H-imipramine binding, a putative peripheral serotonergic marker, were evaluated in a group of 27 cocaine users three days after drug withdrawal. 2. Parameters of cocaine use and the linkage between cocaine withdrawal and "post-cocaine depression" were also investigated. In a subgroup of 10 patients, both psychopathological and biological measurements were repeated after 5 or 6 weeks. 3. Interpretation of the data by Pearson's analysis showed a statistically significant and positive correlation between Hamilton Rating Scale for Depression (HAM-D) scores and period of use. A trend towards a negative correlation, which however did not reach the statistical significance, was found between 3H-Imipramine binding and period of cocaine use, number of days of abstinence and HAM-D scores 4. When compared with normal volunteers at baseline, patients had significantly lower Bmax and Kd values which returned towards normal values after 5 or 6 weeks of cocaine withdrawal. 5. These results indicate the presence of a decreased platelet imipramine binding during cocaine withdrawal which may be due to the effect of the drug or alternatively, a result of concomitant depression which may be primary or secondary in origin. The decreased imipramine binding is a reversible phenomenon, since it increases with the time, in parallel with the improvement of depressive symptoms.

Regional selectivity of neuroleptic drugs: an argument for site specificity.

Differences among neuroleptic drugs in their abilities to produce extrapyramidal side-effects have alternatively been ascribed to their inherent anticholinergic effect or their preferential action with particular brain areas. Animal behavioral studies in rats, with the intralimbic or intrastriatal injection of dopamine demonstrate that atypical neuroleptics, i.e., clozapine, thioridazine, show a greater relative preference for blocking dopamine's limbic actions. Studies using the rat model of tardive dyskinesia (neuroleptic-induced behavioral hypersensitivity), suggest that the atypical neuroleptics are again unique. Receptor ligand studies in rat brain and human brain, using 3H-spiroperidol, show that haloperidol produces a preferential blockade of striatal receptor sites, whereas clozapine and thioridazine are most active at limbic sites. Biochemical data in animals and clinical data in man are reviewed to further support the concept of site specificity.

Treatment approaches in Gilles de la Tourette syndrome.

The neurological disorder Gilles de la Tourette syndrome is most often treated with the receptor blocker haloperidol, which also produces multiple side-effects, including the risk for tardive dyskinesia. In placebo control double-blind studies, two other neuroleptic drugs, fluphenazine and trifluoperazine, were found to be as efficaceous as haloperidol, but with fewer side-effects. In other studies, clonidine was shown to be equally efficaceous with haloperidol, but did not produce adverse central nervous system side-effects. To treat the extrapyramidal side-effects accompanying the treatment of Tourette syndrome with neuroleptic agents, amantadine and benztropine were compared in a crossover study. It was demonstrated that amantadine is a superior agent in treating the side effects of haloperidol treatment in Tourette syndrome. The use of lithium was without significant action upon lessening the tics of Tourette syndrome.

Plasma dopamine and norepinephrine correlations with psychomotor retardation, anxiety, and depression in non-psychotic depressed patients: a pilot study.

The relationship of plasma catecholamine levels to severity of depression and psychomotor retardation was examined in 12 male inpatients who met criteria for major depressive episode. Psychomotor retardation was measured with the Psychomotor Retardation Rating Scale (PRRS), and depression was assessed with the Hamilton Rating Scale for Depression (HRSD). Blood samples for biochemical measurements were obtained from drug-free patients at approximately 09:00 h. Plasma dopamine (DA) levels correlated significantly with the HRSD total score and the anxiety subscale score. Plasma norepinephrine (NE) levels demonstrated a trend toward a negative correlation with the HRSD total score. Neither plasma DA nor NE levels showed a significant correlation with either the global PRRS score or the cognitive or motor subscale score. HRSD scores failed to correlate with the PRRS scores.