Antipsychotic drug effects in schizophrenia: a review of longitudinal FMRI investigations and neural interpretations.

The evidence that antipsychotics improve brain function and reduce symptoms in schizophrenia is unmistakable, but how antipsychotics change brain function is poorly understood, especially within neuronal systems. In this review, we investigated the hypothesized normalization of the functional magnetic resonance imaging (fMRI) blood oxygen level dependent signal in the context of antipsychotic treatment. First, we conducted a systematic PubMed search to identify eight fMRI investigations that met the following inclusion criteria: case-control, longitudinal design; pre- and post-treatment contrasts with a healthy comparison group; and antipsychotic-free or antipsychotic-naive patients with schizophrenia at the start of the investigation. We hypothesized that aberrant activation patterns or connectivity between patients with schizophrenia and healthy comparisons at the first imaging assessment would no longer be apparent or "normalize" at the second imaging assessment. The included studies differed by analysis method and fMRI task but demonstrated normalization of fMRI activation or connectivity during the treatment interval. Second, we reviewed putative mechanisms from animal studies that support normalization of the BOLD signal in schizophrenia. We provided several neuronal-based interpretations of these changes of the BOLD signal that may be attributable to long-term antipsychotic administration.

Endothelial cell expression of the intercellular adhesion molecule-1 (ICAM-1) in the central nervous system of guinea pigs during acute and chronic relapsing experimental allergic encephalomyelitis.

This study investigated the expression of intercellular adhesion molecule-1 (ICAM-1; CD54) by cells of the central nervous system (CNS) during acute experimental allergic encephalomyelitis (EAE) and chronic relapsing EAE (CREAE). In the CNS of normal guinea pigs, only a few endothelial cells expressed detectable levels of ICAM-1, whereas during the active phases of the disease ICAM-1 was present on cells of the perivascular infiltrate and the endothelia of both lesion- and non-lesion-associated blood vessels. In addition, cultured cerebrovascular endothelia maintained in 'standard' culture medium did not express ICAM-1, but they could be induced to express this antigen on incubation in a lymphocyte-conditioned medium. These findings suggest that the induction of ICAM-1 on CNS endothelia may be important in antigen presentation or in promoting lymphocyte extravasation across the blood-brain barrier in inflammatory disorders of the CNS.

Induction of chronic relapsing experimental allergic encephalomyelitis in Biozzi mice.

Experimental allergic encephalomyelitis (EAE) was induced in Biozzi AB/H (antibody high) mice by sensitization with spinal cord homogenate in adjuvant. Biozzi AB/H mice were highly susceptible to EAE induction and followed a chronic relapsing pattern of disease. Disease episodes were characterized by mononuclear infiltration of the central nervous system, with demyelination being particularly evident in relapse. The cellular infiltrates, which were associated with immunoglobulin deposition, consisted of macrophages and primarily CD4-positive T lymphocytes. However, similarly treated Biozzi AB/L (antibody low) mice were markedly less susceptible to EAE induction than AB/H mice. Thus, Biozzi mice should prove valuable for the study of chronic relapsing EAE.

Presentation of myelin basic protein by normal guinea-pig brain endothelial cells and its relevance to experimental allergic encephalomyelitis.

Previous studies have shown that endothelial cells in the central nervous system (CNS) of normal guinea-pigs constitutively express certain MHC class II determinants, whilst the expression of other determinants is apparent during the acute phase of chronic relapsing experimental allergic encephalomyelitis (CREAE). The expression of MHC class II determinants is retained by endothelial cells derived from normal guinea-pig brain tissue and maintained in culture. This present study demonstrates that the MHC class II molecules on these cells can be recognized by allogeneic lymphocytes, resulting in a proliferative response which is enhanced by the addition of exogenous IL-2. The endothelial cells were incapable of presenting either purified protein derivative or ovalbumin, but they could present autologous myelin basic protein (MBP), an encephalitogen implicated in the pathogenesis of EAE. The resulting lymphocyte proliferative response was of the same magnitude as that obtained when a control population of macrophages was used to present MBP. These results, therefore, suggest that cerebrovascular endothelia have the potential to play a role in the pathogenesis of EAE.

Differential expression of guinea pig class II major histocompatibility complex antigens on vascular endothelial cells in vitro and in experimental allergic encephalomyelitis.

Previous studies have shown that vascular endothelial cells do not normally express major histocompatibility complex (MHC) Class II antigens either in vivo or in vitro. In this investigation it was found that endothelial in the central nervous system (CNS) of normal guinea pigs constitutively express MHC Class II antigens recognized by the monoclonal antibodies HLA-DR, 27E7, and MSgp8. This phenotype is retained when these CNS-derived endothelial cells are propagated in tissue culture. Furthermore, examination of CNS tissue taken from animals in the acute phase of chronic relapsing experimental allergic encephalomyelitis shows that additional epitopes of the MHC Class II antigen, detected by the monoclonal antibodies CI.13.1 and 22C4, are present during the diseased state. This study not only demonstrates constitutive expression of certain MHC Class II determinants by guinea pig endothelial cells, but also shows that other Class II determinants can be differentially expressed in certain disease states.

The localisation of fibrin, fibronectin and class II major histocompatibility complex antigen in the spinal cord in chronic relapsing experimental allergic encephalomyelitis.

Light and electron immunocytochemistry using antibodies recognising a class II major histocompatibility complex antigen, fibrin, fibronectin, albumin and factor VIII related antigen has been used to stain sections of spinal cord from normal guinea pigs and those with chronic relapsing experimental allergic encephalomyelitis (CREAE). It was found that class II MHC antigens, fibrin and fibronectin were present in normal blood vessels and at high levels in lesions from animals at all stages of the disease. The possible immunological roles of these antigens suggest their participation in the initiation and maintenance of disease state.

Morphine exerts testosterone-like effects in the hypothalamus of the castrated male rat.

Previous research has indicated that endogenous opioids participate in the regulation of activity in the hypothalamic-pituitary-luteinizing hormone (LH) axis and mediate the negative feedback control exerted by testosterone. If this assumption is correct, then two predictions can be made. First, the effects of testosterone should be competitively inhibited by narcotic antagonists; and, second, opiates should mimic the acute and chronic effects of testosterone in the castrated male rat. The results of the present investigations support both of these predictions. We found that naloxone competitively antagonized the depressive effects of testosterone on serum LH in the castrated rat and, conversely, that testosterone competitively antagonized the LH-releasing properties of naloxone. In addition, morphine and testosterone both depressed serum LH levels in a dose-dependent fashion in the acutely castrated animal. Moreover, morphine was just as effective as testosterone in reversing the castration-induced fall in hypothalamic-LH-releasing hormone (LH-RH), which occurs in the chronically castrated male rat. On the other hand, morphine failed to reverse the long-term changes in pituitary LH content and increase in serum LH, which is consistent with prior observations that morphine affects only the hypothalamic aspect of the hypothalamic-pituitary-LH axis in the male rat. These results, thus, support the concept that an as yet unidentified opioid-containing neuronal system regulates activity in the hypothalamic-pituitary-LH axis and mediates the effects of testosterone on this axis.

Acute reductions in serum testosterone levels by narcotics in the male rat: stereospecificity, blockade by naloxone and tolerance.

The effects of a single injection of morphine (20 mg/kg) on serum testosterone levels were examined in the male rat. Within 2 hours after the morphine injection, testosterone levels were significantly lower than control levels. The decline in testosterone levels reached a maximum 4 hours after the administration of morphine, at which time testosterone levels were reduced by more than 85% with respect to controls. The ability of a large number of narcotics to depress serum testosterone levels, 4 hours after their administration, was also examined. All narcotics depressed testosterone levels significantly and their potency relative to morphine was comparable to that observed in several other preparations, such as the guinea-pig ileum and mouse vas deferens. The testosterone-depleting effects of the narcotics appear to represent specific narcotic effects since the (-)-isomers of the narcotics were considerably more potent than the (+)-isomers, naloxone competitively inhibited the effects of morphine on testosterone levels and tolerance developed to the testosterone-depleting effects of these drugs. Acute treatment with morphine also lowered serum luteinizing hormone levels, and this reduction preceded the fall in testosterone levels by 1 to 2 hours.

Influence of catecholaminergic agents on narcotic binding in brain.

The effects of various agents on the specific tissue binding of 3H-naloxone and 3H-naltrexone were examined. In addition to the narcotics, alpha-adrenergic blockers and dopamine antagonists also significantly inhibited the specific bindings of these opiates. The binding of naloxone or naltrexone was not significantly altered by beta-adrenergic blockers, agents which block the effects of acetylcholine, serotonin and histamine at the receptor level, and a number of other drugs. Kinetic analyses revealed that the alpha-adrenergic and dopamine antagonists competitively inhibited the binding of naloxone. The results of these studies provide additional evidence for an interaction between the narcotics and catecholaminergic agents.