Acute administration of SCH23390 increases D(1) receptors on nonpyramidal neurons in rat mPFC.

Atypical antipsychotic drugs (APDs) such as clozapine and olanzapine antagonize both D(1) and D(2) receptors; however, little is known regarding their pharmacologic effect on specific neuronal elements within the local circuitry of corticolimbic regions, such as medial prefrontal cortex (mPFC). To characterize the effect of short-term antagonism of the D(1) receptor a high-resolution autoradiographic technique was used to assess the density (B(max)) and affinity (K(d)) of this receptor on pyramidal cells (i.e., large neurons (LNs, >/=100 microm(2))), nonpyramidal cells (i.e., small neurons (SNs, <100 microm(2))) and in the surrounding neuropil (NPL) of layer VI in rat mPFC. Either normal saline or the selective D(1) antagonist SCH23390 (1.0 mg/kg/day) were administered for 48 h via Alzet osmotic pumps. Frozen sections were incubated in [(3)H]SCH23390 (1-8 nM) in the presence or absence of the competitive inhibitor SKF38393 (10 microM). A microscopic adaptation to Scatchard analysis revealed a significant increase (82%) in B(max) for neuronal cell bodies (P < 0.05), but not for neuropil of drug-treated animals. Further analysis indicated that the increase in B(max) was present on SNs (94%, P < 0.05), but not LNs in SCH23390-treated rats. In contrast, K(d) values for LNs, SNs, and NPL were not significantly altered by drug treatment. Since the vast majority of SNs are nonpyramidal in nature, short-term administration of a selective D(1) antagonist seems to be associated with a preferential upregulation of this receptor on interneurons. Overall, these results are consistent with the hypothesis that the mechanism of action of atypical antipsychotic medications involves changes in D(1) receptor activity associated with local circuit neurons in rat mPFC.

Effect of video self-observation on development of insight in psychotic disorders.

Many patients with psychotic disorders lack awareness of being ill. This often presents a serious impediment to treatment compliance. We hypothesized that exposing partially remitted patients to videotapes of themselves, made while they were acutely psychotic, might increase their insight into the nature of their illness. Eighteen acutely psychotic inpatients were assigned randomly to a control or experimental group and interviewed on videotape 24 to 48 hours after admission, using scales that measure insight (Insight and Treatment Attitudes Questionnaire [ITAQ]) and psychopathology (Brief Psychiatric Rating Scale [BPRS]). One to six weeks later, when judged to be significantly improved, subjects were shown either a videotape of their initial interview (experimental group) or a placebo videotape (control group) and then reinterviewed 24 to 48 hours later on videotape, using the BPRS and ITAQ scales. Evaluation of initial and final ITAQ and BPRS scores revealed significantly greater improvement in insight scores and in delusionality in the experimental group. However, no significant difference in overall psychopathology was seen for the two groups. These results suggest that exposure of hospitalized patients to videotapes of their own psychotic behavior may be a cost-effective therapeutic tool for developing personal insight into psychotic illness.

High-resolution scatchard analysis shows D1 receptor binding on pyramidal and nonpyramidal neurons.

In order to better understand the mechanism of action of atypical antipsychotic drugs (APDs), it is important to clarify how the dopamine system is integrated within local corticolimbic circuits. Toward this end, a high-resolution (HR) Scatchard technique has been used to measure the relative density (Bmax) and affinity (Kd) of D1 receptors on large neurons (> 100 microm2), on small neurons (< 100 microm2), and in neuropil (NPL) of rat medial prefrontal cortex (mPFC) and to determine the laminar distribution of these receptors for each neuronal compartment. Using [3H] SCH23390 as a ligand, all Kd and Bmax values were found to be similar indicating that D1 receptor activity is not preferentially localized to either large or small neuronal subtypes in mPFC. The density of D1 receptor binding in all three compartments was found to be almost twice as great in layers V and VI, as compared to superficial layers II and III. These results suggest that the blockade of D1 receptors associated with some atypical APDs may involve both pyramidal and nonpyramidal neurons in the PFC.

Amino acid sequences of myosin essential and regulatory light chains from two clam species: comparison with other molluscan myosin light chains.

We have determined the amino acid sequences of the essential light chains (ELC) and regulatory light chains (RLC) of myosin from two species of clam, Mercenaria mercenaria and Macrocallista nimbosa, using protein chemistry methods. The N-termini of all four proteins were blocked, and sequencing was carried out on various chemically and enzymatically produced peptide fragments. Cleavage of either Mercenaria RLC (MRLC) or Macrocallista RLC (VLC) at its 3 Arg yielded four peptides, three of which could not be sequenced directly, due to an N-terminal blocking group and 2 Arg-Gln bonds in these proteins. The fourth peptide was partially and specifically cleaved at an unusually reactive residue, Met-64, which is invariant in all known RLC sequences. A comparison of all available molluscan ELC and RLC sequences was carried out in search of clues to functionally important features of these proteins in muscles which are regulated by a Ca(2+)-sensitive myosin. By analogy with other RLCs, VRLC and MRLC may be phosphorylated at Ser-11 by an endogenous kinase. All myosin light chains, like troponin C and calmodulin, contain four homologous regions, I to IV, each of which contains a twelve-residue potential Ca(2+)-binding loop flanked on either side by a pair of helices. All RLCs, including those from Ca(2+)-insensitive myosins, contain a divalent cation-binding site in region I. Clam and other molluscan ELCs contain a single Ca(2+)-binding site in region III. This site is present only in the ELCs of myosins that are regulated by direct binding of Ca2+. The ELC site III is likely to play a key role in the regulation of molluscan muscle contraction.