Response of extrapyramidal and limbic neurotensin systems to phencyclidine treatment.

Although phencyclidine (PCP) has several neurochemical effects, the most pharmacologically relevant are thought to be its ability to antagonize the activity of N-methyl-D-aspartate (NMDA)-type glutamate receptors and to increase extracellular dopamine concentrations. In order to elucidate the nature and consequence of PCP actions on glutamatergic and dopaminergic pathways, this study examined the response of extrapyramidal and limbic neurotensin systems to this drug. Multiple, but not single, doses of PCP caused increases in striatal neurotensin-like immunoreactivity content of 150-200% of control. These effects were blocked by the dopamine D1 receptor antagonist, SCH 23390, suggesting they were caused by PCP-mediated enhanced dopamine activity at dopamine D1 receptors. In contrast, MK-801 (dizocilpine), a selective NMDA receptor antagonist that acts at the same site as PCP, had no effect on neurotensin-like immunoreactivity content when given alone. In addition, coadministration of MK-801 with PCP did not alter the effect of PCP on striatal neurotensin-like immunoreactivity content. This lack of effect suggests that the actions of PCP on NMDA receptors was not involved in the neurotensin response. The PCP effect on neurotensin striatal pathways also appeared not to be associated with the dopamine D2 or gamma-aminobutyric acid (GABA) systems: a possible role for the sigma receptor in this effect could not be eliminated. Administration of multiple doses of PCP also affected neurotensin-like immunoreactivity content in the nucleus accumbens (160% compared to control) and frontal cortex (40% compared to control), but not the substantia nigra. The neurotensin effects of PCP are compared to those of another psychotomimetic drug of abuse, methamphetamine.

Dynamic dopaminergic regulation of neuropeptide Y systems in discrete striatal and accumbens regions.

In this study we evaluated the effects of multiple administrations of selective dopamine D1 and D2 receptor agonists and antagonists on striatal, nigral, accumbens, pallidal and cortical neuropeptide Y systems. Treatment with the D1 receptor agonist, SKF 38393, decreased, while that with the D1 receptor antagonist, SCH 23390, increased neuropeptide Y-like immunoreactivity in the globus pallidus and several regions within the caudate-putamen. SCH 23390 did not change accumbens neuropeptide Y-like immunoreactivity levels but SKF 38393 increased neuropeptide Y-like immunoreactivity levels in anterior and decreased neuropeptide Y-like immunoreactivity levels in the posterior nucleus accumbens. Interestingly, reductions in neuropeptide Y-like immunoreactivity content occurred in response to administrations of both D2 receptor agonist, quinpirole, or antagonist, sulpiride, in all identified regions of each structure at some time point. These data suggest that the neuropeptide Y systems studied may be regulated by selective activity at postsynaptic or presynaptic dopamine receptors. They further suggest that within structures such as the caudate-putamen and nucleus accumbens are multiple distinct neuropeptide Y systems which are uniquely influenced by dopamine receptors.

Differential regulation of neuropeptide Y systems in limbic structures of the rat.

Neuropeptide Y-like immunoreactivity (NPYLI) in the frontal cortex and nucleus accumbens was significantly decreased after acute and multiple administrations of phencyclidine-HCl (PCP). The role of dopamine, serotonin and sigma receptors in these PCP-induced effects was evaluated. Neither the dopamine D1 antagonist SCH 23390 nor the D2 antagonist sulpiride by itself altered cortical neuropeptide systems, but in combination they totally blocked the PCP-induced changes. In contrast, sulpiride alone significantly decreased accumbens NPYLI content and enhanced the PCP-induced decreases, whereas SCH 23390 alone had no effect on accumbens NPYLI levels but did attenuate PCP-induced effects. Neither depletion of serotonin nor blockage of the sigma "receptor" had any effect on PCP-induced changes in either structure. The effects of the selective, noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 on cortical and accumbens NPYLI content were similar to those of PCP, suggesting an N-methyl-D-aspartate receptor mechanism in these effects. Administration of gamma-aminobutyric acid-transaminase (GABA-T) inhibitors, gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) or aminooxyacetic acid alone had no effect on cortical NPYLI content; however, administration of aminooxyacetic acid alone decreased accumbens NPYLI levels. Co-administration of these GABA-T inhibitors with PCP completely blocked PCP-induced cortical NPYLI decreases and attenuated NPYLI changes in the accumbens. These data suggest that limbic neuropeptide systems are differentially modulated by N-methyl-D-aspartate and dopaminergic activity and that glutamatergic influences on cortical and accumbens NPY systems are mediated, at least in part, by GABAergic mechanisms.

Characterization of phencyclidine-induced effects on neuropeptide Y systems in the rat caudate-putamen.

Multiple administrations of the psychotomimetic drug, phencyclidine-HCI (PCP), decreased striatal neuropeptide Y-like immunoreactivity (NPY-LI) levels in a dose-dependent manner. Single or multiple PCP administrations decreased striatal NPY levels after 10-12 h; levels returned to control 24 h after a single dose or 58 h after multiple doses. In contrast, no significant changes were seen in nigral NPY levels with either acute or multiple-dose PCP treatments. The role of monoamine, sigma or opioid receptors in PCP-induced striatal NPY changes was evaluated. When administered alone, the alpha 1-adrenergic antagonist, prazosin, the sigma antagonist, BMY 14802, and the dopamine D2 antagonist, sulpiride decreased striatal NPY levels; however, only prazosin and the dopamine D1 antagonist, SCH 23390, significantly attenuated PCP-induced changes. Administration of the gamma-aminobutyric acid transaminase (GABA-T) inhibitors, amino-oxyacetic acid (AOAA) or gamma-vinyl-GABA (GVG, vigabatrin, MDL 71,754) alone had no effect on striatal NPY-LI levels while administration of these indirect GABA agonists prior to or concurrently with PCP treatment completely blocked PCP-induced changes in striatal NPY-LI levels. The effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on striatal NPY-LI content resembled that of PCP and was also blocked by the two indirect GABA agonists. These data suggest that NPY systems are modulated by glutamatergic activity (specifically by the NMDA receptor) and that the interaction between these two transmitter systems is mediated by GABAergic mechanisms.

N-Methyl-D-aspartate receptors mediate dopamine-induced changes in extrapyramidal and limbic dynorphin systems.

The N-methyl-D-aspartate (NMDA)-type glutamate receptor was shown to mediate dopamine-induced dynorphin A (Dyn) changes in extrapyramidal and limbic structures. MK801, a potent noncompetitive antagonist of the NMDA receptor, blocked increases in striatal and nigral Dyn content following single and multiple administrations of methamphetamine (METH). Significant attenuation of the METH-induced increases occurred with MK801 doses of 0.1 mg/kg/dose with complete blockade at 2.5 mg/kg/dose. Similar to METH, NMDA itself caused significant increases in striatal and nigral Dyn content. The NMDA-induced increase in striatal Dyn content was blocked by coadministration of an intermediate dose of MK801. The Dyn system associated with the nucleus accumbens responded in a similar manner in that MK801 totally blocked the METH-induced increases; moreover, NMDA elevated the Dyn content in this structure. The inability of MK801 to alter the quinpirole-induced decrease in striatal Dyn content suggests that the NMDA receptor is not involved in the D2 receptor regulation of striatal Dyn systems.