ABSTRACT
The potency of structurally rigid analogues of dopamine (DA) at striatal dopamine receptors was evaluated in rats using three types of assessments: (a) effectiveness in producing rotational and sniffing behaviors by intrastriatal injections (b) inhibition of [3H]-spiroperidol binding and (c) stimulation of adenylate cyclase activity. The compounds included apomorphine (APO) and its analogues, (R)-2,10,11-trihydroxyaporphine (R-THA) and (R)-2-hydroxy-10,11-methylenedioxyaporphine (MDO-APO), 2-amino-6,7-dihydroxyaminotetraline (ADTN) and its analogue, exo-2-amino-6,7-dihydroxybenzonorbornene (exo-amine). (R)-THA produced no stereotypy yet it was a potent inhibitor of [3H]-spiroperidol binding and adenylate cyclase activity. MDO-APO was quite active in inducing stereotypy and stimulating cyclase activity, but it showed low potency in displacing [3H]-spiroperidol. The exo-amine and ADTN were equally potent in enhancing rotation and sniffing intensity, however, the former was completely inactive in biochemical assessments. Except for (R)-THA, all DA analogues studied elicited dopaminomimetic behavioral activities of circling and sniffing. Relationships between the actions of these drugs in the behavioral and biochemical assessments are discussed.
Subject(s)
Corpus Striatum/physiology , Dopamine/analogs & derivatives , Adenylyl Cyclases/metabolism , Animals , Corpus Striatum/enzymology , Dopamine/pharmacology , Hydroxydopamines/pharmacology , Male , Oxidopamine , Rats , Rats, Inbred Strains , Spiperone/pharmacology , Stereotyped Behavior/drug effectsABSTRACT
Amoxapine, an antidepressant with a rapid onset of therapeutic efficacy and great utility in psychotic depression, has been reported to produce anticholinergic side effects in man similar to those observed with imipramine and amitriptyline. To establish its cholinergic disposition, amoxapine and its metabolites 7-hydroxyamoxapine and 8-hydroxyamoxapine, have been evaluated by determining their effects on quinuclidinyl benzilate (QNB) binding to membrane fractions of rat and human brain, on the carbamoylcholine-stimulated accumulation of inositol phosphates in rat cerebral cortex and on the acetylcholine-induced contraction of the guinea pig ileum. In all three preparations, amoxapine was found to be a considerably weaker antagonist of muscarinic cholinergic receptors than either imipramine (4-27 fold) or amitriptyline (51-300 fold). These results indicate that for amoxapine, no correlation exists between the magnitude of muscarinic receptor inhibition and the extent of 'anticholinergic' side effects found in the clinic. Neither the metabolites of amoxapine nor species differences could account for this discrepancy.
Subject(s)
Amoxapine/pharmacology , Dibenzoxazepines/pharmacology , Receptors, Muscarinic/drug effects , Acetylcholine/pharmacology , Animals , Antidepressive Agents/pharmacology , Binding, Competitive , Brain/drug effects , Brain/metabolism , Carbachol/pharmacology , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Inositol Phosphates/metabolism , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Quinuclidinyl Benzilate/metabolism , RatsABSTRACT
A simple, sensitive, and efficient HPLC method for the determination of calmodulin levels in brain tissue extracts is described. The assay is linear with respect to both calmodulin and protein concentrations. The specificity and validity of this assay for calmodulin is demonstrated by parallel radioimmunoassay determinations which give equivalent results. Determination of calmodulin levels in various brain regions revealed a high concentration of this protein in the hypothalamus, by comparison to other areas examined.
Subject(s)
Brain Chemistry , Calmodulin/analysis , Chromatography, High Pressure Liquid , Animals , Hypothalamus/analysis , Male , Radioimmunoassay , Rats , Rats, Inbred Strains , Tissue DistributionABSTRACT
A comparison was made of human postmortem muscarinic-cholinergic, beta-adrenergic and serotonergic (presynaptic) recognition sites in cortical tissues derived from suicide and homicide (control) victims. An elevation of 47% and 35% in the suicide group compared to controls was observed in receptor ligand binding for 3H-quinuclidinyl benzilate (QNB, muscarinic antagonist) and 3H-imipramine (IMI, a presynaptic serotonin marker), respectively. In contrast, no appreciable differences in 3H-dihydroalprenolol (DHA, beta-adrenergic antagonist) binding were observed between the two groups. Additionally, tissues from both groups of subjects were analyzed for tricyclic antidepressive agent (TAD) content. High performance liquid chromatographic (HPLC) tissue analysis revealed no detectable levels of tricyclic agents with an assay sensitivity of 50 picograms/mg tissue. The results presented herein demonstrate neurotransmitter-receptor alterations in suicide subjects compared to homicide (control) victims. The attendant roles of serotonergic and muscarinic-cholinergic processes in the psychobiology of suicide and depression are addressed.
Subject(s)
Brain/metabolism , Receptors, Neurotransmitter/metabolism , Suicide , Antidepressive Agents, Tricyclic/pharmacology , Cerebral Cortex/metabolism , Dihydroalprenolol , Humans , Imipramine , In Vitro Techniques , Nerve Tissue Proteins/metabolism , Quinuclidinyl BenzilateABSTRACT
Specific [3H]-diazepam binding and [3H]-GABA binding were measured in cortical membranes of untreated rats and rats which had been administered unlabeled diazepam (5.0 mg/kg, IP) thirty minutes prior to sacrifice. Washed and unwashed membranes from control animals showed identical levels of [3H]-diazepam binding. Unwashed membranes of diazepam-treated animals showed consistently and significantly lower binding of [3H]-diazepam than membranes derived from control animals and treated similarly. [3H]-GABA was almost non-existent in unwashed membranes of either group of animals. The binding capability of membranes of treated animals for [3H]-diazepam returned to control levels upon washing with buffer prior to the binding assay. The specific binding of [3H]-GABA in membranes derived from either group of animals also improved after the buffer washes. However, no difference could be detected in [3H]-GABA binding between control and diazepam-treated animals. The failure of diazepam to modulate [3H]-GABA binding in unwashed membranes and the participation of an endogenous inhibitory material repressing [3H]-GABA binding are discussed.
Subject(s)
Diazepam/pharmacology , Frontal Lobe/drug effects , Receptors, Cell Surface/drug effects , Receptors, Drug/drug effects , gamma-Aminobutyric Acid/metabolism , Animals , Diazepam/metabolism , Frontal Lobe/metabolism , Male , Rats , Rats, Inbred Strains , Receptors, Cell Surface/metabolism , Receptors, Drug/metabolism , Receptors, GABA-ASubject(s)
Amoxapine/pharmacology , Antipsychotic Agents , Dibenzoxazepines/pharmacology , Adenylyl Cyclases/metabolism , Animals , Biogenic Amines/metabolism , Dopamine/pharmacology , Hydroxylation , In Vitro Techniques , Norepinephrine/metabolism , Rats , Serotonin/metabolism , Spiperone/pharmacology , Synaptic Membranes/metabolism , Synaptosomes/metabolismABSTRACT
The effects of loxapine and its hydroxylated metabolites 7-hydroxyloxapine and 8-hydroxyloxapine on 3H-spiroperidol binding to rat striatal membranes were investigated. Whereas 7-hydroxyloxapine and loxapine displayed strong affinities for 3H-spiroperidol binding sites, 8-hydroxyloxapine was essentially inactive. The potency of 7-hydroxyloxapine to displace 3H-spiroperidol is 1.5 times and 8 times those of haloperidol and chlorpromazine, respectively. These results suggest that the combined effects of loxapine and 7-hydroxyloxapine on the postsynaptic dopamine receptors in the brain may explain the clinical efficacy of loxapine in the treatment of schizophrenia.
