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Biomedical subjects

R J Baldessarini

Publications and source records attributed to R J Baldessarini.

At least 19 recordsLinked to original sources
PubMed1992

Antagonism of limbic and extrapyramidal actions of intracerebrally injected dopamine by ergolines with partial D2 agonist activity in the rat.

Bromocriptine and a series of experimental ergoline D2 partial agonists (SDZ-208-911, SDZ-212-327, SDZ-208-912) were evaluated for their interactions with exogenous dopamine (DA, at ED50 = 16 micrograms) stereotaxically injected unilaterally into a limbic (superior-medial nucleus accumbens septi) or extrapyramidal (central corpus striatum) target site in rat brain. Behavioral measures to quantify responses were locomotor arousal induced by DA in accumbens and contralateral head turning with striatum. All agents, given systemically (i.p.), induced dose-dependent inhibition of behavioral responses to DA from both brain sites. In both accumbens and striatum, SDZ-212-327 was most potent and bromocriptine, least; however, bromocriptine was relatively much more potent in accumbens, and SDZ-208-912 somewhat more potent in striatum. These results add to the growing impression that agents with partial agonist actions at central DA receptors can show behaviorally inhibitory effects that may reflect paradoxical antidopaminergic actions against the full, natural agonist of DA receptors and that such effects can be regionally selective.

Animals↗
PubMed1992

Rate of recovery of D1 and D2 dopaminergic receptors in young vs. adult rat striatal tissue following alkylation with ethoxycarbonyl-ethoxy-dihydroquinoline (EEDQ).

The rate of recovery of D1 and D2 receptor binding sites in rat striatal tissue labeled with [3H]SCH-23390 or [3H]YM-09151-2 was followed daily after irreversible blockade of these receptors with the alkylating agent ethoxycarbonyl-ethoxy-dihydroquinoline (EEDQ). These rates were significantly higher in young post-weaning rats than in young adults (14% vs. 7% per day). The findings suggest that rates of synthesis of new D1 and D2 receptor proteins may be increased during a phase of neurodevelopment in the first postnatal month when the accumulation of both receptor types, especially of D1 receptors, is about maximal.

Alkylating Agents↗
PubMed1992

Stereoisomeric probes for the D1 dopamine receptor: synthesis and characterization of R-(+) and S-(-) enantiomers of 3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its 6-bromo analogue.

Substituted 1-phenyl-3-benzazepines (e.g., SKF 38393 and fenoldopam) exhibit stereoselectivity in moderately high-affinity binding to and partial agonist activation of D1 dopamine receptors. The 3-allyl (APB) and the 3-allyl-6-chloro (6-Cl-APB) analogues of SKF 38393 are reported to have higher affinity and selectivity for the D1 DA receptor and higher in vivo central neuropharmacologic activity than SKF 38393. We recently reported the corresponding 3-allyl-6-bromo analogue (6-Br-APB) also to be a high-affinity D1 agonist. We now describe the synthesis and characterization of the R-(+) and S-(-) enantiomers of both APB and 6-Br-APB and their comparison with corresponding enantiomers of SKF 38393 with respect to D1 receptor binding affinity and D1 and D2 selectivity. The R-(+) enantiomers of both novel substituted 1-phenyl-3-benzazepines bound to the D1 receptor sites in rat forebrain tissue with much higher affinity and selectivity than their S-(-) antipodes. R-(+)-3-Allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine [(R)-(+)-6-Br-APB, 18] exhibits the highest affinity of the reported 1-phenyl-3-benzazepine D1 agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Differences between antipsychotic drugs in persistence of brain levels and behavioral effects.

After a single dose of the butyrophenone neuroleptic haloperidol, behavioral effects and detectable drug levels in rat brain can last for several weeks. To determine if such persistence is a general property of neuroleptics, we compared drug levels and effects after IP administration of two butyrophenones (haloperidol and bromperidol), a high potency (fluphenazine) and a low potency (chlorpromazine) phenothiazine. Drug levels in brain tissue were measured by high pressure liquid chromatography and behavioral effects monitored as inhibition of apomorphine-induced stereotypy. Estimated near terminal elimination half-lives (t 1/2) from brain for acutely administered chlorpromazine (20 mg/kg) and fluphenazine (1 mg/kg) were 0.41 and 0.62 days, respectively, and neither drug was detectable after 4 days. Fluphenazine given daily for 5 days showed an only slightly slower elimination (t 1/2 = 1.1 days). In contrast, near-terminal elimination half-lives from brain for haloperidol and bromperidol (both at 1 mg/kg, IP) were much longer (6.6 and 5.8 days, respectively), and each was detectable for 21 days after dosing. Inhibition of apomorphine-induced stereotypy correlated highly (r = 0.95) with brain levels of haloperidol. For fluphenazine, given once or repeatedly, early inhibition was replaced within 1 week by supersensitivity to apomorphine which persisted for up to 3 weeks. These findings, indicating marked differences in clearance and recovery times after dosing with butyrophenones and phenothiazines, have clear implications for studies of the effects of neuroleptic drugs in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Increasing frequency of the diagnosis of obsessive-compulsive disorder.

OBJECTIVE: This study attempted to document a hypothesized increase in the frequency of the diagnosis of obsessive-compulsive disorder at a large psychiatric teaching hospital and to investigate correlates of this trend. METHOD: The annual rates of psychiatric discharge diagnoses at the hospital from 1969 to 1990 were reviewed, and the frequency of the diagnosis of obsessive-compulsive disorder was compared with that of paranoid disorders. Correlations were also done on these diagnostic rates and the rates of reports in the literature in the same years on each of these types of disorders and their treatment. RESULTS: The frequency of the diagnosis of obsessive-compulsive disorder, but not paranoid disorders, increased markedly during the 1980s. This increase was associated strongly and selectively with increases in publications about that disorder, particularly reports on drug and behavior therapy. CONCLUSIONS: There has been a large recent increase in the rate of diagnosis of obsessive-compulsive disorder, evidently associated with advances in the study and treatment of the disorder. The observations suggest the influence of a treatment-oriented diagnostic bias in which clinicians may more readily consider and diagnose a condition for which an innovative or effective treatment is available.

Behavior Therapy↗
PubMed1992

Do central antiadrenergic actions contribute to the atypical properties of clozapine?

Full neuropharmacological understanding of the atypical antipsychotic agent clozapine remains elusive. Antidopaminergic actions of most neuroleptics probably contribute to their antipsychotic benefits, but also to neurological side-effects. Clinical evidence of abnormalities of dopamine (DA) and serotonin (5-HT) in psychotic disorders is inconsistent, but there is substantial metabolic and post-mortem evidence for hyperactivity of noradrenaline (NA). Clozapine is only weakly antidopaminergic but is a potent antagonist at brain alpha 1-adrenergic, 5-HT2-serotonergic, and muscarinic receptors. Its apparent limbic-over-extrapyramidal neurophysiological selectivity can be mimicked by combining a typical neuroleptic with a central alpha 1 antagonist. Clozapine strongly upregulates alpha 1, but not DA, receptor abundance, and may supersensitise alpha 1 but not DA receptors in rat brain. Clozapine also selectively increases activity of NA neurons and metabolic turnover in NA more than DA areas of rat brain, and also increases NA, but not DA or 5-HT, metabolites in human CSF. Potential psychotropic effects of selective central antiadrenergic agents may deserve reconsideration.

Clozapine↗
PubMed1992

Prolonged D2 antidopaminergic activity of alkylating and nonalkylating derivatives of spiperone in rat brain.

Alkyl and arylalkyl derivatives of the dopamine (DA) D2 antagonist spiperone were prepared and characterized chemically and pharmacologically. They included the N-methyl, N-phenethyl (NPS), and N-p-aminophenethyl (NAPS) derivatives, as well as the alkylating isothiocyanato (NIPS), bromacetamido, and ethylfumaramido p-substituted N-phenethylspiperones. These compounds showed high lipophilicity (log P up to 6.0 with NIPS), as well as very high in vitro D2 affinity (Ki = 35-280 pM) and D2 versus D1 selectivity (540-9000-fold) in radioreceptor assays with corpus striatum of rat brain. Of the alkylating series, NIPS showed the highest D2 affinity (57 pM) and D2 versus D1 selectivity (2040-fold) and so was selected for further evaluation. NPS, NAPS, and NIPS showed little or no affinity for 34 non-DA binding sites defined by radioligand assays for monoamine, amino acid, and peptide neurotransmitters, ion channels, peptide growth factors, and transmission mediators but did show low alpha 2 and moderate alpha 1 and 5-hydroxytryptamine (5-HT2) affinity with rat forebrain tissue in vitro; NIPS showed a marked gain in D2 versus 5-HT2 selectivity, compared with spiperone (1520- versus 26-fold). Systemic injections of NIPS induced marked decreases in rat striatal D2 binding sites 24 hr later, with little effect on D1, 5-HT2, or alpha 1 sites; NIPS and NAPS lowered apparent Bmax values at D2 receptors with little change in ligand affinity, ex vivo as well as in vitro. NPS, NAPS, and NIPS all induced dose-dependent lowering of D2 binding ex vivo (ID50 = 1-9 mumol/kg, intraperitoneally) and blocked the behavioral effects of the DA agonist apomorphine (0.9 mumol/kg) potently (ID50 = 0.3-0.5 mumol/kg) at 24 hr. Recovery from these anti-DA actions required about 1 week after equimolar (15 mumol/kg) and similarly effective doses of NPS and NAPS, as well as NIPS. Thus, highly selective and avidly bound lipophilic D2 affinity ligands with similarly avid in vitro and prolonged in vivo anti-DA activities can be derived from N-phenethylspiperones with or without an alkylating moiety present. Such affinity ligands may represent useful additions to previously used, generally less selective, D2 affinity ligands.

Alkylating Agents↗
PubMed1979

Prenatal and early postnatal beta-adrenergic receptor-mediated increase of cyclic AMP in slices of rat brain.

The levels of cyclic AMP in slices of cerebral cortex and cerebellum from newborn rats were significantly, but transiently, increased by exposure to the beta-adrenergic agonist, isoproterenol. Isobutylmethyxanthine, an inhibitor of phosphodiesterase, enhanced this effect and permitted its detection in cerebral cortex obtained from the prenatal rat. These results are consistent with the possibilities that functional noradrenergic synapses are formed early in the ontogeny of the CNS, and that norepinephrine may exert cyclic AMP-mediated influences on brain development.

1-Methyl-3-isobutylxanthine↗
PubMed1979

Methylation hypothesis.

L-Methionine had no behavioral effects in normal humans and failed to increase concentrations of S-adenosylmethionine (methyl donor) in human or rat blood, while increasing rat liver levels more than fivefold. Methionine or S-adenosylmethionine in very high doses had almost no effect on methylation of tritiated levodopa in rodent tissues; various "methyl acceptor" molecules, including nicotinamide, guanidineacetic acid, and estradiol similarly had little effect. In rabbit lung, methionine and S-adenosylmethionine not only failed to increase production of dimethyltryptamine, but actually decreased it, possibly due to end-product inhibition by S-adenosylhomocysteine, which also strongly inhibited methylation of dopa in rat. These results fail to support several predictions of the "methylation hypothesis" concerning the pathophysiology and potential treatment of idiopathic psychotic disorders and leave the consistent clinical worsening effects of methionine in schizophrenia unexplained.

Adult↗
PubMed1979

Effects of alternative transmitter amines on cyclic AMP formation in rat brain tissue.

Aromatic amines and related compounds, some of which are taken up and released from nerve terminals, might act at brain receptors ordinarily stimulated by traditional amine neurotransmitters. Several of these compounds were evaluated for their ability to stimulate or impede synthesis of cyclic AMP in rat striatal homogenates and cortical slices. In contrast to catecholamines, most had no effect, consistent with their possible role as false transmitters.

Amines↗
PubMed1979

The "neuroleptic" antipsychotic drugs. 1. Mechanisms of action.

The antipsychotic drugs have provided effective and relatively safe treatment of schizophrenia, paranoid illnesses, and manic-depressive conditions marked by psychotic features. These agents are sometimes called "neuroleptic," as virtually all produce signs of extrapyramidal neurologic disorders in addition to their antipsychotic actions; in part, evidently, the neuroleptic effects are an artifact of the means of screening of potential new agents. These agents have a strong and selective antagonistic action on synaptic mechanisms in the brain mediated by dopamine as a neurotransmitter. This antidopamine action almost certainly contributes importantly to their parkinsonism effect (basal ganglia) and their prolactin-elevating (hypothalamic) effect; in addition, antipsychotic actions may be mediated by antidopamine effects, possibly in limbic and other forebrain centers.

Animals↗
PubMed1979

The "neuroleptic" antipsychotic drugs. 2. Neurologic side effects.

The specific neurologic side effects of the antipsychotic agents include acute dystonias, parkinsonism, motor restlessness, and late choretoathetosis. Treatment of the acute reactions is usually effected by the use of anticholinergic agents; treatment of the later dyskinesias is unsatisfactory, and these reactions are to be avoided by judicious use of antipsychotic drugs for long-term treatment.

Akathisia, Drug-Induced↗