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K M Merchant

Publications and source records attributed to K M Merchant.

At least 37 records · Page 2Linked to original sources
PubMed1993

Differential induction of neurotensin and c-fos gene expression by typical versus atypical antipsychotics.

Precise neural mechanisms underlying the pathophysiology and pharmacotherapy of psychotic disorders remain largely unknown. Present studies investigated the effects of various antipsychotic drugs on expression of the gene encoding the purported endogenous antipsychotic-like peptide neurotensin (NT) in striatal regions of the rat brain. The results demonstrate that several clinically efficacious antipsychotic drugs selectively and specifically increase expression of NT/neuromedin N (NT/N) mRNA in the shell of the nucleus accumbens, a region of the forebrain associated with limbic systems. On the other hand, only typical antipsychotics that cause a high incidence of acute motor side effects increased the expression of NT/N mRNA in the dorsolateral striatum, an extrapyramidal region primarily involved in motor control. In addition, it appears that distinct mechanisms may be involved in the effects of antipsychotics on NT/N gene expression in the dorsolateral striatum versus the accumbal shell. Thus neuroleptic-induced increases in NT/N mRNA expression in the dorsolateral striatum were preceded by a rapid and transient activation of c-fos mRNA, whereas none of the antipsychotics affected c-fos mRNA expression in the accumbal shell. The anatomical characteristics of NT/N gene expression induced by typical versus atypical antipsychotics raise the possibility that increased activity of specific NT neurons may contribute to the therapeutic effects (NT neurons in the accumbal shell) or motor side effects (NT neurons in the dorsolateral striatum) of these drugs.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

BMY 14802, a potential antipsychotic drug, increases expression of proneurotensin mRNA in the rat striatum.

Treatment with efficacious antipsychotic drugs, such as haloperidol, increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. The increases in NT content produced by haloperidol have been shown to be associated with an increase in NT biosynthesis as assessed by the level of expression of proNT mRNA. The potential antipsychotic drug and sigma receptor ligand BMY 14802 has been shown to produce increases in the concentrations of NT in the nucleus accumbens and caudate that are similar to those produced by haloperidol with respect to the magnitude of the increases and the time course over which they occur. This study evaluated the effects of BMY 14802 on the expression of proNT mRNA and NT concentration in the rat striatum. Three hours after a single injection of BMY 14802 (35 mg/kg, i.p.) expression of proNT mRNA was significantly increased in the nucleus accumbens and caudate. Labeling was most intense in the dorsal caudate. NT concentrations were unaltered at this time point. Eighteen hours after injection, significant increases in NT concentration in the nucleus accumbens and caudate were detected. At this time, expression of proNT mRNA was substantially reduced compared to 3 h after treatment although labeling of the dorsal and medial caudate was still greater than that observed in controls.

Amino Acid Sequence↗
PubMed1992

Expression of the proneurotensin gene in the rat brain and its regulation by antipsychotic drugs.

In this chapter, we have presented evidence for several potential levels of interaction of NT/N gene products with dopaminergic systems of the brain. We have focused on one manifestation of this interaction related to the effects of antipsychotic drugs on expression of the NT/N gene in two anatomically discrete populations of neurons. It appears that certain antipsychotic drugs can dramatically increase expression of this gene in the dorsolateral striatum by blocking dopamine D2 receptors, perhaps by increasing expression of the gene encoding the transcriptional regulator fos. In addition, a second group of NT cells in the shell region of the nucleus accumbens also respond to these drugs by increasing NT/N gene expression. Several other peptides have been suggested to respond to treatment with antipsychotic drugs. However, there are some important differences with respect to their effects on the NT cells we have studied. The most important of these is the differential responsiveness of the DLSt and nucleus accumbens NT neurons to typical and atypical antipsychotics. We showed that all antipsychotic drugs tested increased NT/N mRNA gene expression in the accumbens, a region thought to be involved in dopaminergic disturbances underlying psychosis. However, only the typical neuroleptics that have a high propensity to induce acute extrapyramidal motor side effects influenced NT/N gene expression in the dorsolateral striatum, a structure importantly involved in regulation of motor functions. We hypothesize, therefore, that NT/N-expressing neuronal systems in the nucleus accumbens may mediate some or all of the antipsychotic effects, whereas those in the dorsolateral striatum may be involved in motor effects of neuroleptic drugs. Thus, examination of the effects of these drugs on these neuronal populations will not only clarify their mechanism of action, but in addition may provide a useful "screening" assay for new drugs with enhanced antipsychotic activity, but reduced propensity to induce the debilitating extrapyramidal side effects that are a major cause of patient noncompliance. Future studies will focus on the effects of antipsychotic drugs on NT neurons in clinically relevant models of chronic administration, and on the molecular events involved in their effects on expression of the NT/N gene in the brain.

Aging↗
PubMed1992

Differential effects of haloperidol and clozapine on neurotensin gene transcription in rat neostriatum.

A single dose of typical neuroleptic, haloperidol, has been demonstrated to increase the expression of neurotensin/neuromedin N (NT/N) mRNA in the dorsolateral striatum within 1 hr of its administration (Merchant et al., 1991). The present study further investigated neuroleptic-induced regulation of NT/N gene transcription. Levels of NT/N mRNA were examined at various times following a single dose of haloperidol (1 mg/kg, i.p.) or the atypical antipsychotic clozapine (20, 30, or 40 mg/kg, i.p.) by in situ hybridization histochemistry and quantitative solution hybridization. In the dorsolateral striatum, the two drugs had strikingly different effects; haloperidol rapidly (within 30 min) increased the expression of mature NT/N mRNA while virtually no increase was observed in response to nontoxic doses of clozapine at any of the time points examined. Following haloperidol, maximal induction occurred at 7 hr, at which time NT/N mRNA levels were an order of magnitude higher than basal levels. By 20 hr after haloperidol, there was a significant decline in striatal NT/N mRNA levels. In situ hybridization analysis using an intron-derived probe revealed that haloperidol-induced increases in mature NT/N mRNA levels in the striatum were preceded by a transient increase in intron-containing NT/N gene transcripts. These data strongly indicate that acute haloperidol treatment results in transient transcriptional activation of NT/N gene, although a concomitant effect on the stability of NT/N primary transcripts cannot be ruled out. In contrast to their differential effects in the dorsolateral striatum, a single dose of both haloperidol and clozapine induced a small but significant increase in NT/N mRNA expression in the shell sector of the nucleus accumbens. These results raise the possibility that NT neurons in the nucleus accumbens may, at least in part, mediate the antipsychotic effects of classical neuroleptics, whereas NT cells in the dorsolateral region of the striatum may be involved in mediating other effects of typical neuroleptics such as extrapyramidal motor symptoms.

Animals↗
PubMed1991

Haloperidol rapidly increases the number of neurotensin mRNA-expressing neurons in neostriatum of the rat brain.

The effects of an acute low dose of haloperidol on neurotensin mRNA-containing cells in rat forebrain was studied using in situ hybridization histochemistry. Within 1 h of a single dose of haloperidol (0.5 mg/kg) a nearly 3-fold increase in the number of cells that express the neurotensin/neuromedin N-encoding mRNA was observed in the dorsolateral striatum. However, the number of hybridization-positive cells did not appear to be affected in the nucleus accumbens, or the septal nuclei following treatment with the neuroleptic.

Animals↗
PubMed1991

Distribution of mRNA for the calmodulin-sensitive adenylate cyclase in rat brain: expression in areas associated with learning and memory.

The Drosophila learning mutant, rutabaga, is deficient in the calmodulin-sensitive adenylate cyclase, and studies of associative learning in Aplysia have implicated this enzyme in neuroplasticity. Therefore, the distribution of mRNA encoding the calmodulin-sensitive adenylate cyclase in rat brain was examined by in situ hybridization. mRNA for this enzyme is expressed in specific areas of brain that have been implicated in learning and memory, including the neocortex, the hippocampus, and the olfactory system. The presence of mRNA for this enzyme in the pyramidal and granule cells of the hippocampal formation provides evidence that it is found in neurons. These data are consistent with the proposal that the calmodulin-sensitive adenylate cyclase plays an important role in learning and memory.

Adenylyl Cyclases↗
PubMed1990

Neurotensin-dopamine interactions in the substantia nigra of the rat brain.

Single or multiple doses of the potent dopamine releaser, methamphetamine (METH), increases the content of neurotensin (NT)-like immunoreactivity (NTLI) in the substantia nigra of the rat brain by 2- to 3-fold. Concurrent blockade of D-1 receptors with METH treatment completely antagonized the increase in nigral NTLI content induced by this drug. These results suggest that activation of D-1 receptors by endogenous dopamine results in an increase in the level of NTLI in the substantia nigra. The present study was performed to characterize further the mechanisms underlying dopaminergic regulation of nigral NT systems. Prior selective destruction of the nigrostriatal dopamine pathway completely prevented the increase in nigral NTLI content induced by treatment with METH, which suggests that the effects of METH on nigral NT systems are mediated by the nigrostriatal dopamine projections. However, unlike METH, treatment of rats with the direct-acting, D-1-selective agonist, SKF 38393, did not alter nigral NTLI content but when combined with stimulation of D-2 receptors, a significant increase in the level of NTLI occurred. Surprisingly, activation of only D-2 receptors caused a significant decrease in nigral NTLI content. These data suggest that although activation of D-2 receptors alone has an effect opposite to that of the D-1 subtype, in combination with D-1 stimulation they facilitate the effect of D-1 receptors on nigral NT systems. In addition to the effects of direct or indirect stimulation of dopamine activity on nigral NT levels, basally released dopamine also appeared to regulate the level of NTLI in the substantia nigra. Thus, interruption of tonic dopamine activity by reserpine-induced depletion of dopamine significantly reduced the level of NTLI in the substantia nigra. The role of D-1 receptors in this tonic dopaminergic regulation of nigral NT systems was evident when concurrent activation of D-1, but not D-2, receptors with reserpine treatment prevented or reversed the decrease in NTLI content caused by dopamine depletion. Additional evidence for the D-1-mediated tonic regulation of NT systems in the substantia nigra was that blockade of D-1 receptors with SCH 23390 decreased the nigral NTLI content but blockade of D-2 receptors with sulpiride had no effect.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain.

Blockade of dopamine D2 receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus alpha-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus alpha-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert their effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D2 receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D2 receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.

Animals↗
PubMed1989

Role of dopamine D-1 and D-2 receptors in the regulation of neurotensin systems of the neostriatum and the nucleus accumbens.

Activation of dopamine D-1 receptors with multiple administrations of SKF 38393 significantly increased the level of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens. However, a similar treatment with the D-2 receptor-selective agonist, LY 171555, decreased the same in both structures; when the two drugs were administered concurrently, their individual effects were blocked. These results suggest that dopamine D-1 and D-2 receptors antagonistically regulate neurotensin systems of the striatum and nucleus accumbens. On the other hand, blockade of D-2 receptors (with sulpiride) elevated, while D-1 receptors blockade (with SCH 23390) caused no change in the level of neurotensin in both these structures. Dopamine D-1 receptors did not appear to contribute to the sulpiride-mediated effect as concurrent administration of SCH 23390 did not alter the response.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Characterization of methamphetamine effects on the striatal-nigral dynorphin system.

Multiple high doses of methamphetamine (METH) induced 200-300% increases in the concentration of striatal and nigral dynorphin-like immunoreactivity (DLI). Increases in striatal and nigral DLI levels also were seen within 6 h following a single administration. The changes in the striatal-nigral dynorphin system had subsided 48 h after either acute or multiple treatments with METH. Selective lesioning of the nigral-striatal dopamine pathway blocked the effects; thus, the METH-induced changes appeared to be mediated by dopamine released from the nigral-striatal dopamine projection. Administration of the METH analog, 3,4-methylenedioxymethamphetamine, appeared to alter striatal and nigral DLI concentrations in a manner similar to that of METH.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Changes in the limbic neurotensin systems induced by dopaminergic drugs.

Single or multiple high doses of the dopamine-releasing drug, methamphetamine, induced 100-150% increases in the content of neurotensin-like immunoreactivity (NTLI) in the nucleus accumbens, but was without effect on the NTLI level in the ventral tegmental area. The increases in NTLI content in the nucleus accumbens were selectively blocked by the dopamine D-1 receptor antagonist, SCH 23390, which failed to exert any significant effect of its own in the same area. In contrast, haloperidol or the selective dopamine D-2 antagonist, sulpiride, when administered alone, significantly raised the NTLI level in the nucleus accumbens and when given concomitantly with methamphetamine, their effects on the amount of NTLI appeared to be additive. Very different patterns of response were observed in neurotensin systems associated with the mesocortical dopaminergic terminal fields of the frontal cortex and olfactory bulbs. Changes in NTLI contents occurred following only multiple doses of methamphetamine and consisted of decreases in levels of this peptide. However, like the nucleus accumbens, these methamphetamine-induced alterations were blocked completely by D-1 antagonism, while D-2 blockade appeared to be additive with the effects of methamphetamine.

Animals↗
PubMed1987

Characterization of dopaminergic influence on striatal-nigral neurotensin systems.

Dopamine depletion by treatment with alpha-methyl-p-tyrosine had no effect on methamphetamine-mediated increases in striatal neurotensin (NT) concentrations but significantly attenuated nigral increases; the attenuation in the nigral response was reversed by L-DOPA. Blockade of D2-receptors, with sulpiride, by itself increased striatal NT levels, while having no effect on the nigral NT system or its response to methamphetamine. In contrast, D1 blockade with SCH 23390 had no effect of its own on NT levels but significantly blocked the methamphetamine-induced actions in both the striatal and nigral NT systems.

Animals↗
PubMed1987

Effects of amphetamine analogs on neurotensin concentrations in rat brain.

The present study investigates the effects of amphetamine-like analogs on neurotensin systems and compares the same to those of methamphetamine. Like methamphetamine, multiple high doses of each of the analogs examined significantly increased the concentrations of neurotensin-like immunoreactivity in the striatum, substantia nigra and nucleus accumbens; these effects were reversible and specific. The changes in the neurotensin systems developed rapidly and were evident within 6 h following a single administration of two of the analogs studied.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat.

In the rat, administration of the psychoactive analog of amphetamine 3,4-methylenedioxymethamphetamine (MDMA), causes selective, pronounced decreases in markers of central serotonergic function. The time course of these neurochemical changes was examined in several serotonergic nerve terminal regions of the brain. Fifteen min after subcutaneous injection of MDMA (10 mg/kg), the enzymatic activity of tryptophan hydroxylase (the rate-limiting enzyme for the biosynthesis of serotonin) was significantly decreased in the frontal cortex; by 1 hr after the injection, the activity of tryptophan hydroxylase had significantly declined in the neostriatum, hippocampus and hypothalamus as well. Although extensive recovery had occurred by 2 weeks, the activity of the enzyme remained significantly depressed in most regions. Decline of the regional content of 5-hydroxytryptamine (5-HT) closely paralleled, but was usually preceded by, that of the enzyme. Concentrations of the primary metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), were less responsive: in most regions levels of 5-HIAA had significantly decreased by 3 hr, but not by 1 hr, following treatment. Markers of dopamine function were altered transiently but had returned to control values by 24 hr. Administration of multiple doses of MDMA (5 doses over a 24-hr period) resulted in significant decreases in serotonergic parameters for up to 110 days after treatment. The rate and extent of recovery varied according to both the dose administered and the region examined. The persistence of these serotonergic deficits suggests that MDMA induced the destruction of serotonin-containing axon terminals.

3,4-Methylenedioxyamphetamine↗