Search

Previous findings have demonstrated a protective role for dopamine D3/D2receptor agonists in the convulsant and lethal effects of acutely administered cocaine. Data are provided here to establish that the protection occurs through a D3-linked mechanism and that protection is extended to seizure kindling. The D3antagonist SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1 H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the anticonvulsant effect of the D3/D2receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4 a,10 b-tetrahydro-4-propyl-2 H,5 H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on cocaine-induced seizures. The protection afforded by the D3/D2agonist, (+)-PD-128,907, was eliminated in D3receptor-deficient mice. In D2receptor knockout mice, the anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of cocaine-kindled seizures engendered by repeated daily dosing with 60 mg/kg cocaine. (+)-PD-128,907 also blocked the seizures induced in mice fully seizure kindled to cocaine. Although repeated dosing with cocaine increased the potency of cocaine to produce seizures and lethality (decreased ED50values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with cocaine and (+)-PD-128,907, the density, but not the affinity, of D3receptors was increased. The specificity with which (+)-PD-128,907 acts upon this cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a GABAAreceptor antagonist, pentylenetetrazol. Taken together and with literature findings, the data indicate that dopamine D3receptors function in the initiation of a dampening mechanism against the toxic effects of cocaine, a finding that might have relevance to psychiatric disorders of drug dependence, schizophrenia, and bipolar depression.

Previous findings have demonstrated a protective role for dopamine D(3)/D(2) receptor agonists in the convulsant and lethal effects of acutely administered cocaine. Data are provided here to establish that the protection occurs through a D(3)-linked mechanism and that protection is extended to seizure kindling. The D(3) antagonist SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the anticonvulsant effect of the D(3)/D(2) receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on cocaine-induced seizures. The protection afforded by the D(3)/D(2) agonist, (+)-PD-128,907, was eliminated in D(3) receptor-deficient mice. In D(2) receptor knockout mice, the anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of cocaine-kindled seizures engendered by repeated daily dosing with 60 mg/kg cocaine. (+)-PD-128,907 also blocked the seizures induced in mice fully seizure kindled to cocaine. Although repeated dosing with cocaine increased the potency of cocaine to produce seizures and lethality (decreased ED(50) values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with cocaine and (+)-PD-128,907, the density, but not the affinity, of D(3) receptors was increased. The specificity with which (+)-PD-128,907 acts upon this cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a GABA(A) receptor antagonist, pentylenetetrazol. Taken together and with literature findings, the data indicate that dopamine D(3) receptors function in the initiation of a dampening mechanism against the toxic effects of cocaine, a finding that might have relevance to psychiatric disorders of drug dependence, schizophrenia, and bipolar depression.

[3H]Quinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptor subtypes. A variety of drugs, most notably monoamine oxidase inhibitors (MAOls), inhibit the binding of [3H]quinpirole, but not [3H]spiperone or [3H](-)N-n-Propylnorapomorphine, in rat striatal membranes by a mechanism that does not appear to involve the enzymatic activity of MAO. This study extends the characterization of MAOI-displaceable [3H]quinpirole binding in rat brain. Clinically antidepressant MAOIs exhibited selectivity between sites labeled by [3H]quinpirole and [3H]spiperone as did a number of structurally related propargylamines and N-acylethylenediamine derivatives and other drugs such as debrisoquin and phenylbiguanide. The MAOIs clorgyline and Ro 41-1049 were the most potent. Anti-depressant MAOIs inhibited [3H]quinpirole binding with the following rank order of potency: phenelzine > pargyline > tranyl-cypromine > isocarboxazid > nialamide > moclobemide. In striatal membranes, MAOI Ro 41-1049 inhibited [3H]quinpirole binding with similar potency at a variety of incubation temperatures (4-37 degrees C), assay tissue concentrations (5-20 mg original wet weight/ml), and time points (2 min-4 hr) and in the presence or absence of K+, Mg2+, Ca2+ ions, ascorbate, EDTA and NaCl. The regional distribution of Ro 41-1049-displaceable [3H]quinpirole binding in brain paralleled that of D2-like receptors. These data suggest that MAOIs interact with a novel binding site that is labeled by [3H]quinpirole or that modulates [3H]quinpirole binding. This site may be associated with D2-like dopamine receptors.

The putative D2 dopamine receptor agonist quinpirole (LY 171,555) is the most widely used D2 agonist in in vivo and in vitro studies of D2 receptor-mediated effects. In addition, quinpirole may have even higher affinity for the recently described D3 dopamine receptor. The present study describes the in vitro binding properties of newly developed [3H]quinpirole in rat brain. [3H]Quinpirole binding was characterized in striatal membrane homogenate preparations using a filtration assay. Nonspecific binding was defined by 1 microM (+)-butaclamol. Specific [3H]quinpirole binding was saturable, and dependent on temperature, membrane concentration, sodium concentration and guanine nucleotides. Saturation analysis revealed high affinity binding characteristics (KD = 2.3 +/- 0.3 nM) which were confirmed by association-dissociation kinetics. The pharmacological profile of [3H]quinpirole binding in striatum was: (-)-N-n-propylnorapomorphine (+/-)-2-amino-6,7-dihydroxyl-1,2,3,4-tetrahydronaphthalene greater than or equal to quinpirole greater than apomorphine greater than bromocriptine greater than dopamine greater than SKF 38393 much greater than 5-hydroxytryptamine for putative dopamine agonists; spiperone greater than (+)-butaclamol greater than haloperidol greater than (-)-sulpiride greater than clozapine greater than SCH 23390 much greater than cinanserin for antagonists. [3H]Quinpirole binding exhibited stereoselectivity: (-)-sulpiride greater than (+)-sulpiride and (+)-butaclamol greater than (-)-butaclamol. This pharmacological profile is similar, though-not identical, to that observed for [3H] spiperone-labeled D2 receptors. The regional distribution of [3H]quinpirole binding sites roughly paralleled the distribution of [3H]spiperone binding sites, with greatest densities present in the striatum, nucleus accumbens and olfactory tubercles.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic treatment with the antipsychotic drug haloperidol or the potential antipsychotic BMY 14802 produce increases in regional neurotensin concentrations which are similar with respect to regional specificity (nucleus accumbens and caudate), time course, magnitude of increase and precedence by an increase in proneurotensin mRNA. The present study characterizes further the effects of haloperidol and BMY 14802 on regional brain neurotensin concentrations and compares certain of their effects to those of sulpiride. Neurotensin concentrations in discrete brain regions of adult, male, Sprague-Dawley rats were determined by radioimmunoassay. Both acute and chronic treatment with BMY 14802 produced significant decreases in the concentration of neurotensin in the frontal cortex. When administered concomitantly, low doses of haloperidol and BMY 14802 produced additive increases in neurotensin content in the nucleus accumbens and caudate. Increases in neurotensin content resulting from concomitant treatment, or with doses which produce maximal effects individually, were not greater than those produced by either drug alone. Concomitant administration of SCH 23390 and sulpiride attenuated the neurotensin increases observed after treatment with sulpiride. Increases in neurotensin concentrations produced by haloperidol and BMY 14802 were not antagonized by SCH 23390. These findings support the hypothesis that haloperidol and BMY 14802 modulate regional neurotensin concentrations through a common or similar mechanism which is distinct from that of sulpiride.

Sympathetic nerve activity has been hypothesized to set the timing of cellular maturational events in target tissues. In the current study, this hypothesis was tested by lesioning catecholamine pathways in the periphery and central nervous system through the use of subcutaneous or intracisternal injections of 6-hydroxydopamine. Systemically administered 6-hydroxydopamine completely depleted peripheral norepinephrine. The central treatment completely ablated the developmental rise in brain norepinephrine and dopamine and had little effect on peripheral norepinephrine levels, but has been shown to reduce sympathetic tone. In both the heart and the kidney, either type of lesion resulted in deficits in cell acquisition (DNA) with some evidence of compensatory increases in other macromolecules involved in cell enlargement (particularly RNA), thus maintaining the tissue growth rate at only slightly subnormal levels. The peak effect was always seen during the stages at which sympathetic neuronal synaptogenesis and impulse activity ordinarily undergo their most rapid development. Most of the 6-hydroxydopamine-induced differences in nucleic acids lessened or disappeared toward weaning, and thus these data support the view that sympathetic neuronal input influences the timing of maturational control of macromolecules, but not their final set-point. In combination with earlier studies showing termination of DNA synthesis caused by exposure of heart and kidney acutely to high levels of catecholamines, the results suggest that neuronal activity provides a biphasic signal, with positive trophic effects predominating during early development when sympathetic tone is low, and negative effects appearing when sympathetic tone is elevated during the late preweanling stage.

The putative D2 dopamine receptor agonist quinpirole (LY 171,555) has been extensively used in a variety of in vivo and in vitro studies of D2 receptor-mediated effects and may have even higher affinity for the recently described D3 dopamine receptor. In the present study, conditions for autoradiographic visualization of [3H]quinpirole-labeled D2-like dopamine receptors were optimized and binding to slide-mounted sections was characterized with respect to pharmacology, guanine nucleotide sensitivity and regional distribution. The pharmacological profile of [3H]quinpirole binding in slide-mounted brain sections was: (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene > or = quinpirole > dopamine for putative dopamine agonists; spiperone > (+)-butaclamol > (-)-sulpiride > SCH 23390 > cinanserin > (-)-butaclamol for antagonists. [3H]Quinpirole binding was decreased in the presence of guanine nucleotides in most brain regions except in the islands of Calleja and the molecular layer of cerebellar lobules 9 and 10. The regional distribution of [3H]quinpirole binding sites roughly paralleled the distribution of [3H]-(-)-sulpiride binding sites, with greatest densities present in the olfactory bulb glomerular layer, islands of Calleja, pituitary intermediate lobe, caudate/putamen, olfactory tubercles and nucleus accumbens. However, significantly greater densities of [3H]quinpirole binding than [3H]-(-)-sulpiride binding were observed in the molecular layer of cerebellar lobules 9 and 10, the islands of Calleja and olfactory bulb glomerular layer in concordance with the recently reported distribution of D3 receptor mRNA in these brain regions. Higher concentrations of [3H]quinpirole binding were also observed in the dorsomedial caudate and pituitary intermediate lobe. These data indicate the utility of [3H]quinpirole to label D3 as well as D2 dopamine receptors.

Acute and chronic treatment with antipsychotic drugs, such as haloperidol, selectively increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate of the rat. These increases in NT concentration in the nucleus accumbens and caudate have been hypothesized to underlie the therapeutic and extrapyramidal effects of antipsychotic drugs, respectively. The present study evaluates the effects of the putative antipsychotic and selective sigma receptor "antagonist" BMY 14802 on regional brain NT concentrations. NT concentrations in discrete brain regions of adult, male, Sprague-Dawley rats were measured by a sensitive and specific radioimmunoassay. Like haloperidol (1 mg/kg i.p.), acute and chronic treatment with BMY 14802 (35 mg/kg/day i.p.) produced significant increases in the concentrations of NT in the nucleus accumbens and anterior and posterior caudate. This effect was dose-dependent. Maximal increases in NT concentration were observed 18 hr after a single dose of BMY 14802. Neither acute nor chronic treatment with the sigma "agonist" (+)-SKF 10,047 (20 mg/kg i.p.), the N-methyl-D-aspartate-phencyclidine binding site antagonist MK-801 (0.25 mg/kg i.p.) or the selective D2 antagonist sulpiride (100 mg/kg i.p.), produced the pattern of NT alterations observed after the administration of BMY 14802. These findings suggest that the blockade of sigma receptors modulates NT concentrations in these brain regions.