Altered platelet protein kinase C activity in bipolar affective disorder, manic episode.

Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors.

Continuous infusion of clozapine increases mu and delta opioid receptors and proenkephalin mRNA in mouse brain.

The biochemical mechanisms involved in the actions of the atypical antipsychotic clozapine are still unclear. Because elevated levels of enkephalin in certain areas of the central nervous system may be necessary for antipsychotic activity, we have examined the effect of clozapine on certain receptors and mRNA transcripts involved in the opioid peptidergic system. Clozapine was infused continuously into mice for 21 days and the density of mu and delta opioid receptors was measured in the brains by quantitative receptor autoradiography, and the level of proenkephalin mRNA and dopamine D1 and D2 receptor mRNA were measured by in situ hybridization histochemistry. The results showed that continuous infusion of clozapine increased the density of D1 but not D2 receptors. However, it failed to alter the levels of either D1 or D2 dopamine receptor mRNA. By contrast, clozapine increased the density of mu and delta opioid receptors and increased the levels of proenkephalin mRNA. These results indicate that continuous treatment with clozapine increases opioid peptidergic activity in mouse brain and suggest that alteration of peptidergic activity as well as alteration of dopaminergic activity may be involved in its antipsychotic action.

Cholinergic lesions of mouse striatum induced by AF64A alter D2 dopaminergic behavior and reduce D2 dopamine receptors and D2 dopamine receptor mRNA.

To determine whether dopamine receptors are expressed in acetylcholine-containing neurons intrinsic to the striatum, and to study further the interactions between the dopaminergic and cholinergic systems, the irreversibly acting cholinergic neurotoxin, ethylcholine mustard aziridinium ion (AF64A), was injected unilaterally into the mouse corpus striatum, and rotational behavior induced by dopamine agonists and certain molecular events associated with this lesion were determined 7 days after lesioning. Brains were analyzed for D2 dopamine receptors by autoradiography, using [3H](-)sulpiride as a ligand, and for D2 dopamine receptor mRNA and glutamic acid decarboxylase mRNA by Northern blot analysis, using selective radiolabelled oligonucleotide probes. Choline uptake sites were determined by binding assays using [3H]hemicholinium-3, a selective choline reuptake blocker, as a ligand. Mice with intrastriatal injections of AF64A showed ipsilateral rotational responses to the non-selective dopamine agonist apomorphine and to the D2 dopamine agonists, pergolide and quinpirole, but not to the D1 dopamine agonist SKF 38393. This was associated with a significant reduction in D2 dopamine receptors in the ipsilateral striatum and a significant decrease in the amount of D2 dopamine receptor mRNA. That AF64A produced a relatively selective cholinergic deficit was supported by the evidence showing that AF64A lesions significantly reduced [3H]hemicholinium-3 binding sites but did not alter glutamic acid decarboxylase (GAD) mRNA. Further, hemicholinium-3, prevented the AF64A-induced changes in rotational behavior. These results suggest that striatal cholinergic interneurons contain D2 dopamine receptors and express the D2 dopamine receptor gene, and that these interneurons are involved in dopamine-mediated rotational behavior.

Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors.

Continuous infusion of the dopamine D2 receptor agonist quinpirole into mice with unilateral striatal 6-hydroxydopamine lesions initially produces a supersensitive rotational behavior. This is followed by reductions of dopamine D2-mediated behavior and dopamine D2 receptors. In this study we attempted to determine if it is possible to inhibit the acute increase in D2-mediated behavior while still allowing the reduction of D2-mediated behavioral responses and dopamine D2 receptors to occur. Mice were implanted with Alzet minipumps containing either quinpirole alone or quinpirole combined with the GABA receptor modulator triazolam or the dopamine D2 receptor antagonist sulpiride, and rotational behavior was monitored for the 6 days of infusion. The pumps were then removed, and D2 receptors in striatal membranes were determined. Triazolam completely blocked the initial rotational behavior normally induced by implanting quinpirole. However, the quinpirole-induced reduction of D2-mediated behavioral responses and D2 receptors still occurred. Continuous infusion of sulpiride also inhibited the rotational behavior produced by quinpirole, but it prevented the reduction of dopamine D2 receptors. We conclude that up-regulated dopamine receptors and dopaminergic behaviors can be reversed by the continuous administration of a dopamine receptor agonist and that this reversal can occur without producing an initial exacerbation of dopaminergic responses. These results suggest that this type of treatment regimen might be useful for treating clinical conditions associated with dopaminergic supersensitivity.

AF64A lesions of mouse striatum result in ipsilateral rotations to D2 dopamine agonists but contralateral rotations to muscarinic cholinergic agonists.

Behavioral and anatomical evidence supports an interaction between the dopaminergic and cholinergic systems in regulating certain behavioral conditions and motor functions. In this study, we utilized the cholinotoxin, acetylethylcholine mustard aziridinium ion (AF64A), to lesion the mouse corpus striatum in order to examine the role of cholinergic interneurons in striatum on cholinergic- and dopaminergic-mediated rotational behavior. Mice were unilaterally lesioned with AF64A and then challenged with a variety of dopaminergic and cholinergic agonists and antagonists. The results show that mice with AF64A-induced lesions rotate ipsilaterally to challenge doses of the dopamine agonists, apomorphine and pergolide, but rotate contralaterally to challenge injections of the cholinergic agonist, oxotremorine. The gamma aminobutyric acid (GABA) agonist, muscimol, and the M1 agonist, (4-hydroxy-2-butynyl)-1-trimethylammonium m-chlorocarbanilate chloride failed to elicit rotational behavior. The D1 dopamine receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, inhibited rotations induced by apomorphine at concentrations 10-fold lower than those needed to block the effects of pergolide. However, the D2 dopamine receptor antagonist, sulpiride, blocked pergolide-induced rotations at concentrations about 4-fold lower than those needed to inhibit apomorphine-induced rotational behavior. Atropine blocked oxotremorine-induced contralateral rotations but enhanced apomorphine- and pergolide-induced ipsilateral rotations induced in AF64A-lesioned mice. Atropine was 10 times more effective in blocking oxotremorine-induced rotations than was the M3 antagonist, 4-diphenylacetoxy-N-methyl piperidine methiodide, and was 100 times more potent than the M2 and M1 antagonist, N,N'-bis[6-[[(2- methoxyphenyl)methyl]amino]hexyl]-1,8-octanediamine tetrahydrochloride, or the M1 antagonist, pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins.

We describe genetically proven monozygotic twins with the adult form of adrenoleukodystrophy with significant phenotypic heterogeneity. Myeloneuropathy was common to both patients, but cognitive impairment and affective symptoms with extensive demyelination in the brain were prominent in the older twin, while adrenal insufficiency was predominant in the younger twin. The younger twin, however, exhibited affective symptoms similar to those displayed by his elder twin 10 years later. These findings suggest that nongenetic factors are important in determining the phenotypic variation of adrenoleukodystrophy gene.