Self-administration of cocaine, alfentanil, and nalbuphine under progressive-ratio schedules: consumer demand and labor supply analyses of relative reinforcing effectiveness.

Progressive-ratio (PR) schedules of intravenous (i.v.) drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs.

Importance of B-cell responses for immunological control of variant strains of simian immunodeficiency virus.

The properties of three variants of cloned simian immunodeficiency virus strain 239 (SIV239) were compared. One strain (M5) lacked five sites for N-linked carbohydrate attachment in variable regions 1 and 2 (V1 and V2) of the gp120 envelope protein, one strain (DeltaV1-V2) completely lacked V1 and V2 sequences, and another (316) had nine mutations in the envelope that impart high replicative capacity for tissue macrophages. All three strains were capable of significant levels of fusion independent of CD4, and all three were considerably more sensitive to antibody-mediated neutralization than the parent strain from which they were derived.

Characterization of an in vitro rhesus macaque blood-brain barrier.

The blood-brain barrier (BBB) has been modeled in vitro in a number of species, including rat, cow and human. Coculture of multiple cell types is required for the correct expression of tight junction proteins by microvascular brain endothelial cells (MBEC). Markers of inflammation, especially MHC-II, and cell adhesion molecules, such as VCAM-1, are not expressed on the luminal surface of the barrier under resting conditions.

Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors.

Rationale: The discriminative stimulus effects of zolpidem in squirrel monkeys trained at doses greater than or equal to 3.0 mg/kg differ from those of conventional benzodiazepines (BZs), but the extent to which these effects reflect the selectivity of zolpidem for GABA(A)/alpha(1) receptors is not known.

Objectives: The present study investigated the ability of GABA(A)/alpha(1)-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.

Suppression of tetradecanoyl phorbol acetate-induced lytic reactivation of Kaposi's sarcoma-associated herpesvirus by K1 signal transduction.

The K1 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic region and elicits cellular signal transduction through this motif. To investigate the role of K1 signal transduction in KSHV replication, we expressed full-length K1 and CD8-K1 chimeras in BCBL1 cells. Unlike its strong signaling activity in uninfected B lymphocytes, K1 did not induce intracellular calcium mobilization or NF-AT activation at detectable levels in KSHV-infected BCBL1 cells.

Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/alpha1-preferring antagonist beta-CCt in squirrel monkeys.

Rationale: Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. OBJECTIVES. The purpose of the present study was to investigate the role of GABAA/alpha1 receptors in the sedative and motor-impairing effects of benzodiazepines.

Distribution and immunophenotype of DC-SIGN-expressing cells in SIV-infected and uninfected macaques.

DC-SIGN (dendritic cell-specific ICAM-3 grabbing nonintegrin), an external C-type lectin expressed on dendritic cells (DCs), has been proposed to play a pivotal role in trafficking HIV/SIV from mucosal surfaces to lymphoid tissues. Although the location of DC-SIGN expression has been established in a limited number of human tissues, its distribution in the rhesus macaque has not yet been determined. This study characterized the distribution and immunophenotype of DC-SIGN-expressing cells in SIV-infected and uninfected macaque tissues by immunohistochemistry (IHC) and confocal microscopy.

Kaposi's sarcoma-associated herpesvirus mitochondrial K7 protein targets a cellular calcium-modulating cyclophilin ligand to modulate intracellular calcium concentration and inhibit apoptosis.

On viral infection, infected cells can become the target of host immune responses or can go through a programmed cell death process, called apoptosis, as a defense mechanism to limit the ability of the virus to replicate. To prevent this, viruses have evolved elaborate mechanisms to subvert the apoptotic process. Here, we report the identification of a novel antiapoptotic K7 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) which expresses during lytic replication.

Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development.

Rationale: The illicit use of cocaine is a persistent health problem worldwide. Currently, there are no broadly effective pharmacotherapies to treat cocaine addiction. A prerequisite for development of useful anti-cocaine medications is an understanding of the pharmacological basis of cocaine's effects.

Immune evasion strategies of Kaposi's sarcoma-associated herpesvirus.

To establish lifelong infection in the presence of an active host immune system, herpesviruses have acquired an impressive array of immune modulatory mechanisms that contribute to their success as long-term parasites. Kaposi's sarcoma-associated herpesvirus (KSHV) is the most recently discovered human tumor virus and is associated with the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV has acquired a battery of genes to assist in viral survival against the host immune response.

Caffeine: behavioral effects of withdrawal and related issues.

Acquired tolerance to some behavioral effects of caffeine in humans is widely assumed to occur but is poorly documented and appears, at most, to be of low magnitude. Withdrawal from regular consumption of caffeine has been reported to result in a variety of symptoms, including: irritability, sleepiness, dysphoria, delerium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains and flushed face. Some of these same symptoms have been reported following excess intake of caffeine.

Herpesviral protein targets a cellular WD repeat endosomal protein to downregulate T lymphocyte receptor expression.

Herpesvirus saimiri Tip associates with Lck and downregulates Lck signal transduction. Here we demonstrate that Tip targets a lysosomal protein p80, which consists of an N-terminal WD repeat domain and a C-terminal coiled-coil domain. Interaction of Tip with p80 facilitated lysosomal vesicle formation and subsequent recruitment of Lck into the lysosomes for degradation.

Dopamine transporter-dependent induction of C-Fos in HEK cells.

The psychostimulants cocaine and amphetamine increase expression of the immediate early gene (IEG) c-fos indirectly, via D1 dopamine receptor activation. To determine whether dopamine transporter substrates and inhibitors can affect c-Fos expression directly, we investigated their effects on c-Fos protein and c-fos mRNA in HEK-293 (HEK) cells transfected with the human dopamine transporter (hDAT). In untransfected HEK cells, methylphenidate and cocaine produced a small but statistically significant increase in c-Fos, whereas dopamine and amphetamine did not.

Enhanced expression of proinflammatory cytokines in the central nervous system is associated with neuroinvasion by simian immunodeficiency virus and the development of encephalitis.

Inflammatory cytokines are believed to play an important role in the pathogenesis of human immunodeficiency virus type 1-associated encephalitis. To examine this in the simian immunodeficiency virus (SIV)-infected macaque model of neuroAIDS, inflammatory cytokine gene expression was evaluated in the brains of macaques infected with pathogenic SIV(mac251) by reverse transcriptase PCR. Interleukin-1 beta was readily detected in the brains of all animals evaluated, regardless of infection status or duration of infection.

Mechanisms of protection against simian immunodeficiency virus infection.

One of the obstacles to the development of an effective AIDS vaccine has been the limited information on the mechanisms of protective immunity to HIV. In macaques, immunization with attenuated simian immunodeficiency viruses (SIV) has proved to be one of the most effective strategies to induce protection against infection or disease with pathogenic lentiviruses. Infection with attenuated SIV strains induces a broad range of SIV-specific immune responses, including relatively potent cytotoxic T lymphocyte (CTL) and antibody responses.

Role of GABAA/benzodiazepine receptors containing alpha 1 and alpha 5 subunits in the discriminative stimulus effects of triazolam in squirrel monkeys.

Rationale: Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABA(A) receptors containing alpha(1), alpha(2), alpha(3), or alpha(5) subunits. The role of these different GABA(A) receptor subtypes in mediating the subjective effects of BZs remains largely unknown.

Objective: The purpose of the present study was to evaluate the role of GABA(A) receptors containing the alpha(1) or alpha(5) subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist triazolam.

Kaposi's sarcoma-associated herpesvirus OX2 glycoprotein activates myeloid-lineage cells to induce inflammatory cytokine production.

Kaposi's sarcoma is an inflammatory cytokine-mediated angioproliferative disease which is triggered by infection by Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV contains an open reading frame, K14, that has significant homology with cellular OX2, designated viral OX2 (vOX2). In this report, we demonstrate that vOX2 encodes a glycosylated cell surface protein with an apparent molecular mass of 55 kDa.

Multiple endocytic trafficking pathways of MHC class I molecules induced by a Herpesvirus protein.

The K3 protein of a human tumor-inducing herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), down-regulates major histocompatibility complex (MHC) class I surface expression by increasing the rate of endocytosis. In this report, we demonstrate that the internalization of MHC class I by the K3 protein is the result of multiple, consecutive trafficking pathways that accelerate the endocytosis of class I molecules, redirect them to the trans-Golgi network (TGN), and target MHC class I to the lysosomal compartment. Remarkably, these actions of K3 are functionally and genetically separable; the N-terminal zinc finger motif and the central sorting motif are involved in triggering internalization of MHC class I molecules and redirecting them to the TGN.

Campylobacter-induced enteritis and diarrhea in captive cotton-top tamarins (Saguinus oedipus) during the first year of life.

A prospective study of 43 cotton-top tamarins, from infancy to 6 to 17 months of age, was conducted to determine the epidemiology of Campylobacter spp. infection. Nine infants followed for one year in an isolation unit, where attendants wore protective clothing, did not become infected.

Decreased frequency of cytomegalovirus (CMV)-specific CD4+ T lymphocytes in simian immunodeficiency virus-infected rhesus macaques: inverse relationship with CMV viremia.

The frequency of cytomegalovirus (CMV)-specific CD4+ T lymphocytes was determined in CMV-seropositive rhesus macaques with or without simian immunodeficiency virus (SIV) infection by using the sensitive assays of intracellular cytokine staining and gamma interferon ELISPOT. Both techniques yielded 3- to 1,000-fold-higher frequencies of CMV-specific CD4+ T lymphocytes than traditional proliferative limiting dilution assays. The median frequency of CMV-specific CD4+ T lymphocytes in 23 CMV-seropositive SIV-negative macaques was 0.

Expression of peripherin in the brain of macaques (Macaca mulatta and Macaca fascicularis) occurs in astrocytes rather than neurones and is associated with encephalitis.

Peripherin is a member of the type III intermediate filament family, expressed in neurones of the peripheral nervous system of many species and in a discrete subpopulation of neurones of the central nervous system (CNS) during early development in rodents. Previous studies on rats have shown that peripherin immunoreactivity increased significantly in cell bodies of spinal motor neurones following axonal injury. Our study examined the expression of peripherin in the cerebrum of normal macaques (Macaca mulatta and Macaca fascicularis) and those with encephalitis of viral (simian immunodeficiency virus and simian virus 40) or autoimmune (experimental allergic encephalomyelitis) aetiology.

The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD).

The dopamine transporter is elevated in adults with attention deficit hyperactivity disorder (ADHD) compared with healthy controls [Lancet 354 (1999) 2132]. The findings have been confirmed by others in a different population using a different probe for the dopamine transporter. Notwithstanding the need to confirm these findings in a multi-center trial, several hypotheses are presented to account for these observations.

A replication-competent, neutralization-sensitive variant of simian immunodeficiency virus lacking 100 amino acids of envelope.

Coding sequences for the first two variable loops of the gp120 envelope glycoprotein were removed from simian immunodeficiency virus (SIV) strain 239 (SIVmac239). This deletion encompassed 100 amino acids. The resulting virus replicated poorly after transfection into immortalized T-cell lines, with peak replication occurring only after 25 to 30 days.

Viral persistence: HIV's strategies of immune system evasion.

In contrast to most animal viruses, infection with the human and simian immunodeficiency viruses results in prolonged, continuous viral replication in the infected host. Remarkably, viral persistence is not thwarted by the presence of apparently vigorous, virus-specific immune responses. Several factors are thought to contribute to persistent viral replication, most notably the destruction of virus-specific T helper cells, the emergence of antigenic escape variants, and the expression of an envelope complex that structurally minimizes antibody access to conserved epitopes.