Monoamine oxidase inhibitor-induced blockade of locomotor sensitization to quinpirole: role of striatal dopamine uptake inhibition.

Previous studies have shown that the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. However, clorgyline is also an inhibitor of striatal dopamine uptake, and this mechanism could account for the effect of clorgyline on quinpirole sensitization. To investigate this possibility, the effects of clorgyline and pargyline were examined. Of these two MAOIs, only clorgyline inhibits dopamine uptake in the striatum. Rats received subcutaneous injections of clorgyline (1 mg/kg), pargyline (10 mg/kg) or vehicle 90 min prior to each injection of quinpirole (0.5 mg/kg, s.c., x8, twice weekly) or saline. Clorgyline and pargyline blocked the development of quinpirole-induced locomotor sensitization and sensitized self-directed mouthing behaviors in quinpirole rats. Thus, it is unlikely that clorgyline blocks locomotor sensitization to quinpirole via an inhibition of striatal dopamine uptake. Both MAOIs increased dopamine metabolism in the striatum, showed opposite effects in the prefrontal cortex, and eliminated the correlation between prefrontal dopamine and striatal DOPAC content found in quinpirole sensitized rats. We suggest that clorgyline and pargyline may affect the behavioral and neurochemical response to quinpirole via a previously reported MAOI-displaceable quinpirole binding site, a site which we hypothesize serves as a 'switch' to select what motor output becomes sensitized to repeated injections of quinpirole.

Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control.

BACKGROUND: A previous report showed that the open field behavior of rats sensitized to the dopamine agonist quinpirole satisfies 5 performance criteria for compulsive checking behavior. In an effort to extend the parallel between the drug-induced phenomenon and human obsessive-compulsive disorder (OCD), the present study investigated whether the checking behavior of quinpirole rats is subject to interruption, which is an attribute characteristic of OCD compulsions. For this purpose, the rat's home-cage was placed into the open field at the beginning or the middle of a 2-hr test. RESULTS: Introduction of the home-cage reduced checking behavior, as rats stayed inside the cage. After 40 min, checking resurfaced, as quinpirole rats exited the home-cage often. An unfamiliar cage had no such effects on quinpirole rats or saline controls. CONCLUSIONS: Checking behavior induced by quinpirole is not irrepressible but can be suspended. Results strengthen the quinpirole preparation as an animal model of OCD compulsive checking.

A switch mechanism between locomotion and mouthing implicated in sensitization to quinpirole in rats.

RATIONALE: Chronic treatment with the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D2/D3 dopamine agonist quinpirole. It is unknown whether this blockade occurs via inhibition of the MAO enzyme or by another mechanism. OBJECTIVES: While clorgyline and moclobemide are equally effective MAOIs, only clorgyline has a high affinity for the MAOI-displaceable quinpirole binding site (MQB). This study compares the effects of both drugs on quinpirole sensitization. METHODS: To examine development of sensitization, rats received clorgyline (1 mg/kg/day), moclobemide (5 mg/kg/day), or vehicle via osmotic mini-pumps and were injected with quinpirole (0.5 mg/kg, s.c.) or saline every 3 days; locomotor and mouthing activity was recorded for each of the eight injections. A similar protocol was used to examine the expression of sensitization in rats previously sensitized to quinpirole. RESULTS: Clorgyline, but not moclobemide, blocked the development of locomotor sensitization to quinpirole. Clorgyline, but not moclobemide, blocked the sensitized locomotor response to quinpirole following the 25th day of treatment. Mouthing showed sensitization in quinpirole-treated rats co-treated with clorgy-line, but not moclobemide; this sensitized mouthing was predominantly directed towards self. Clorgyline and moclobemide equally inhibited MAO-A and had equal effects on tissue concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, and serotonin in the striatum. CONCLUSIONS: Clorgyline (1) inhibits the development and the maintenance of locomotor sensitization to quinpirole by a mechanism that does not involve MAO and (2) changes the sensitized response to quinpirole from locomotion to mouthing. We suggest that clorgy-line affects the response to quinpirole via MQB and that this site acts as a switch that selects the motor pathway for sensitization to quinpirole.

Monoamine oxidase inhibitor sensitive site implicated in sensitization to quinpirole.

Clorgyline (1.0 mg/kg/day) administered via osmotic minipumps blocked the development of locomotor sensitization to the dopamine receptor agonist quinpirole (0.5 mg/kg every 3 days for 8 injections). In male rats already well sensitized to quinpirole, the continuous infusion of clorgyline (1.0 mg/kg/day for 28 days) produced a progressive decline in locomotor activity, despite a continued regimen of quinpirole injections (0.5 mg/kg every 3 days). It is suggested that the development, as well as the maintenance, of locomotor sensitization to quinpirole is modulated by the activation of an monoamine oxidase inhibitor-sensitive site. This site may be a dopamine D2 receptor-linked monoamine oxidase inhibitor-displaceable quinpirole binding site, the enzyme monoamine oxidase-A, or other clorgyline binding sites.

Effect of lipopolysaccharide on the stimulation of macrophage Fc-dependent phagocytosis by splenic B lymphocytes.

Macrophage phagocytic activity is regulated by a variety of products derived from activated lymphocytes. It has been reported that nonactivated splenic B and T lymphocytes enhance macrophage glucose metabolism. In addition, the enhancement of macrophage glucose metabolism was further increased by direct effects of bacterial lipopolysaccharide (LPS) on B, but not T, lymphocytes. In the present study, the effect of purified murine splenic B and T lymphocytes on Fc-dependent phagocytosis by thioglycollate-elicited peritoneal macrophages in the presence or absence of LPS has been investigated. Fc-dependent phagocytosis was assayed by measuring the ingestion of 51Cr-tagged sheep erythrocytes. After 3 or 4 days in culture, nonadherent spleen cells (NASC) and B and T lymphocytes from C3H/HeN (LPS-responder) mice produced 92 +/- 27%, 83 +/- 13%, and 147 +/- 33% increases in C3H/HeJ (LPS-hyporesponder) macrophage phagocytic activity, respectively. A similar effect was observed in Balb/c mice. Cell-free supernatant from NASC and B lymphocytes precultured for 2 or 4 days produced a 74 +/- 20% and 157 +/- 42% increase in phagocytosis respectively. At concentrations which have been previously shown to markedly enhance the ability of splenic B lymphocytes to stimulate macrophage glucose metabolism, Escherichia coli K235 LPS (10 micrograms/ml) did not alter the stimulatory effects of any of the splenic lymphocyte populations on macrophage Fc-dependent phagocytosis. These data suggest that B lymphocytes produce a soluble factor(s) which stimulates macrophage phagocytosis. In addition, LPS has different effects on the regulation of macrophage phagocytic activity and metabolism by B lymphocytes.

Enhancement of macrophage immune and nonimmune receptor-mediated phagocytosis by a low molecular weight soluble factor from resident thymocytes.

Macrophage phagocytic activity is regulated in part by products of activated T lymphocytes. We previously reported that a heat-stable soluble factor derived from resident (nonactivated) thymocytes increases murine peritoneal macrophage Fc-dependent phagocytosis. In the present study, we further investigate the effect of the thymocyte factor on immune and nonimmune receptor-mediated phagocytosis, Fc receptor expression, and its approximate m.w. After 4 days of incubation, cellfree thymocyte supernatant produced a mean (three experiments) 2.10-, 2.08-, and 1.97-fold increase in macrophage phagocytosis of C3-, IgG-, and tannic acid-treated erythrocytes, respectively. Macrophage IL 1 production was not enhanced by a similar concentration of thymocyte supernatant. The thymocyte factor(s) increased the number of IgG2a Fc receptors (FcRI) from 2.4 x 10(5) to 3.8 x 10(5) receptor sites per macrophage. The number of Fc receptors that bind IgG1 and IgG2b (FcRII) was not altered. The soluble factor(s) that increased Fc-mediated phagocytosis passed through both 6000- to 8000-dalton and 2000-dalton cutoff dialysis membranes and eluted from a Sephadex G-25 Fine column over a m.w. range of 200 to 1000 daltons, with a peak activity at 450 daltons. These data suggest that resident thymocytes enhance macrophage phagocytosis of opsonized and nonopsonized particles through the elaboration of a low m.w. substance(s).