User:Memantine714/research

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1910092/pdf/brjpharm00203-0195.pdf

-- D2 autoreceptors and amphetamine DA release good article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1910092/pdf/brjpharm00203-0195.pdf

Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. [My paper] Vera C Campbell, Theresa A Kopajtic, Amy Hauck Newman, Jonathan L Katz Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine (DA) transporter (DAT) but generally have behavioral effects different from those of cocaine, suggesting either unique actions at the DA transporter or that another action of these drugs interferes with cocaine-like effects. Because the parent compound has histamine-antagonistic effects, the affinity of its analogs for histamine H(1), H(2), and H(3) receptors were compared with DA transporter affinity to assess whether those differences predicted the amount of cocaine-like activity. All of the compounds displaced [(3)H]mepyramine from H(1),[(125)I]iodoaminopotentidine from H(2), and [(3)H]N-alpha-methylhistamine from H(3) histamine receptors with affinities ranging from 15.7 to 37,600, 218 to >4430, and 4040 to >150,000 nM, respectively. Affinities at histamine H(1) receptors were, respectively, approximately 25- or 300-fold greater than those at H(2) or H(3) histamine receptors. Relative affinities for H(1) and DAT binding did not reliably predict the degree of cocaine-like stimulation of locomotor activity. In addition, interactions of various histaminic agents with cocaine assessed whether an action at any of the histamine sites could interfere with cocaine-like effects. None of the histaminic agents fully substituted for cocaine in rats trained to discriminate 10 mg/kg cocaine from saline nor did any of the compounds antagonize or otherwise diminish the discriminative stimulus effects of cocaine. The results suggest that affinity for histamine receptors cannot account for the diminished cocaine-like effects of the BZT analogs and suggest alternatively that these compounds have actions different from those of cocaine but likely mediated by their interaction with the DAT. Most cited papers: Eur J Pharmacol. 1976 Mar ;36 (1):163-71 177297 Cit:200

Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid. [My paper] R H Roth, L C Murrin, J R Walters Stimulation of the nigro-neostriatal or mesolimbic dopamine pathway results in a stimulus dependent increase in the accumulation of dihydroxyphenylacetic acid (DOPAC) in the neostriatum and olfactory tubercles, respectively. A block of impulse flow induced pharamacologically by administration of gamma-butyrolactone or by placement of a lesion in the dopamine pathway results in a decrease in the steady state levels of DOPAC. Drugs which have previously been shown to alter impulse flow in central dopaminergic neurons also produce a predictable change in the brain levels of DOPAC. Drugs which increase impulse flow in nigro-neostriatal or mesolimbic dopamine neurons increase DOPAC levels in the striatum and olfactory tubercles and drugs which reduce impulse flow cause a reduction in DOPAC. Pargyline, a monoamine oxidase inhibitor, causes a rapid depletion of striatal DOPAC suggesting that this metabolite is rapidly cleared from the brain. Administration of benztropine, a potent inhibitor of dopamine reuptake, causes a significant decrease in striatal DOPAC and partially prevents the stimulus-induced increase in the accumulation of DOPAC. These observations together with the finding that about 85% of the DOPAC in the striatum disappears when the dopamine neurons in the nigro-neostriatal pathway are destroyed suggests that the majority of striatal DOPAC is formed within the dopaminergic neurons and may reflect the metabolism of dopamine which has been released and recaptured. We conclude that short-term changes in brain levels of DOPAC appear to provide a useful index of alterations in the functional activity of central dopaminergic neurons. Nature. 1974 Apr 12;248 (449):596-7 4150951 Cit:147

Anti-muscarinic properties of neuroleptics and drug-induced Parkinsonism. [My paper] R J Miller, C R Hiley J Neurosci. 2003 Jul 16;23 (15):6315-26 12867516 Cit:124

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. [My paper] Takanori Hashimoto, David W Volk, Stephen M Eggan, Karoly Mirnics, Joseph N Pierri, Zhuoxin Sun, Allan R Sampson, David A Lewis Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia. Life Sci. 1976 Dec 1;19 (11):1783-9 1004134 Cit:124

Dopamine and norepinephrine innervated cells in the rat prefrontal cortex: pharmacological differentiation using microiontophoretic techniques. [My paper] B S Bunney, G K Aghajanian Neuroscience. 1986 Oct ;19 (2):427-45 3095678 Cit:92

Quantification of the dopamine innervation in adult rat neostriatum. [My paper] G Doucet, L Descarries, S Garcia Conditions leading to specific and integral visualization of dopamine axon terminals (varicosities) were tested in adult rat cerebral hemisphere slices incubated with [3H]dopamine and processed for high resolution radioautography. Specific visualization of the dopamine endings was achieved after incubation with 10(-6) M [3H]dopamine in the presence of a monoamine oxidase inhibitor (pargyline 10(-4) M), and of desipramine (5 X 10(-6) M), an inhibitor of catecholamine uptake by noradrenaline and serotonin neurons.[3H]Dopamine varicosity labeling was eliminated by the addition of 5 X 10(-5) M benztropine (an inhibitor of catecholamine uptake by catecholamine neurons), and was almost absent when dopamine nerve cell bodies of the midbrain had been previously destroyed with 6-hydroxydopamine. In dopamine-denervated neostriatum incubated without desipramine, a second set of labeled terminals was also visible. These were identified as serotoninergic, since their labeling was suppressed by citalopram, an inhibitor of monoamine uptake highly specific for serotonin neurons. There was no desipramine-sensitive but citalopram-resistant varicosity labeling suggestive of neostriatal noradrenaline innervation. In normal striatum, incubation at 35 degrees C always resulted in a labeling of dopamine varicosities restricted to a narrow band which followed the contours and cut surface of this anatomical region. This unusual distribution was the result of an uptake barrier generated by the tightly packed dopamine varicosities. Indeed, the striatal dopamine varicosity labeling was more widespread after partial 6-hydroxydopamine denervation or in normal tissue incubated either with a higher [3H]dopamine concentration (5 X 10(-6) M), in the presence of relatively low benztropine concentrations (10(-5) M), or at lower temperature (15 degrees C). Material incubated at 15 degrees C for 90 min was suitable for purposes of quantification: labeled varicosities were then visualized throughout the striatum and across the full thickness of the slices; moreover, the number of labeled varicosities plotted against radioautographic exposure time increased in parallel and reached a plateau at the same time in neostriatal sectors with widely different innervation densities. At a rostral transverse level across neostriatum, the dorsolateral quadrant showed hyperdense "patches" of labeled terminals distinguishable from an already dense surrounding "matrix", whereas, ventromedially, the dopamine innervation appeared more uniform and somewhat less dense.(ABSTRACT TRUNCATED AT 400 WORDS) J Neurochem. 1993 Feb ;60 (2):527-35 8419534 Cit:89

Amphetamine and other weak bases act to promote reverse transport of dopamine in ventral midbrain neurons. [My paper] D Sulzer, N T Maidment, S Rayport Department of Psychiatry, Columbia University, New York, New York 10032. Amphetamine-like psychostimulants are thought to produce rewarding effects by increasing dopamine levels at mesolimbic synapses. Paradoxically, dopamine uptake blockers, which generally increase extracellular dopamine, inhibit amphetamine-induced dopamine overflow. This effect could be due to either inhibition of amphetamine uptake or inhibition of dopamine efflux through the transporter (reverse transport). We used weak bases and dopamine uptake blockers in ventral midbrain neuron cultures to separate the effects on blockade of amphetamine uptake from reverse transport of dopamine. Amphetamine, ammonium chloride, tributylamine, and monensin, at concentrations that produce similar reductions in acidic pH gradients, increased dopamine release. This effect was inhibited by uptake blockers. Although in the case of amphetamine the inhibition of release could have been due to blockade of amphetamine uptake, inhibition also occurred with weak bases that are not transporter substrates. This suggests that reduction of vesicular pH gradients increases cytoplasmic dopamine which in turn promotes reverse transport. Consistent with this model, extracellular 3,4-dihydroxyphenylacetic acid was increased by ammonium chloride and monensin, as would be expected with elevated cytoplasmic dopamine levels. These findings extend the weak base mechanism of amphetamine action, in which amphetamine reduces vesicular pH gradients resulting in increased cytoplasmic dopamine that promotes reverse transport. Eur J Pharmacol. 1987 Jul 23;139 (3):345-8 3666010 Cit:86

The use of heterologous expression systems for studying dopamine (DA) transporter (DAT) function has provided important information corroborating and complementing in situ obtained knowledge. Preliminary experiments with human embryonic kidney cells (HEK293) heterologously expressing varying amounts of DAT suggested fluctuations in the potency of cocaine in inhibiting DA uptake and led to the present systematic assessment of the impact of the density of DAT on its function. Transiently expressing intact HEK293 cells, transfected with increasing amounts of DAT cDNA, displayed increasing levels of surface DAT, binding of the cocaine analog [(3)H]2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(3)H]CFT), and uptake of [(3)H]DA, [(3)H]N-methyl-4-phenylpyridinium ([(3)H]MPP(+)), [(3)H]norepinephrine, and [(3)H]serotonin. However, the amount of DAT cDNA and the DAT expression level required to produce 50% of maximal activity was threefold higher for CFT binding than for DA uptake. Increased DAT expression was accompanied by weakened potency in inhibiting [(3)H]DA uptake for cocaine, CFT, benztropine, and its analog JHW025, GBR 12909 and mazindol; their potency in inhibiting [(3)H]CFT binding was unaffected. Inhibition of uptake by the substrates DA, m-tyramine, d-amphetamine, or MPP(+) was also unaffected. Increasing DAT in stably expressing HEK293 cells by stimulation of gene expression with sodium butyrate also decreased the uptake inhibitory potency of a number of the above blockers without affecting the interaction between substrates and DAT. The present results prompt discussion of models explaining how factors regulating DAT expression at the plasma membrane can regulate DAT function and pharmacology.

http://www.jbc.org/content/276/31/29012.full

http://jpet.aspetjournals.org/content/229/3/671.short = PCP and various other DAT-active compounds mechanisms of aciton

Stimulation of the nigro-neostriatal or mesolimbic dopamine pathway results in a stimulus dependent increase in the accumulation of dihydroxyphenylacetic acid (DOPAC) in the neostriatum and olfactory tubercles, respectively. A block of impulse flow induced pharamacologically by administration of gamma-butyrolactone or by placement of a lesion in the dopamine pathway results in a decrease in the steady state levels of DOPAC. Drugs which have previously been shown to alter impulse flow in central dopaminergic neurons also produce a predictable change in the brain levels of DOPAC. Drugs which increase impulse flow in nigro-neostriatal or mesolimbic dopamine neurons increase DOPAC levels in the striatum and olfactory tubercles and drugs which reduce impulse flow cause a reduction in DOPAC. Pargyline, a monoamine oxidase inhibitor, causes a rapid depletion of striatal DOPAC suggesting that this metabolite is rapidly cleared from the brain. Administration of benztropine, a potent inhibitor of dopamine reuptake, causes a significant decrease in striatal DOPAC and partially prevents the stimulus-induced increase in the accumulation of DOPAC. These observations together with the finding that about 85% of the DOPAC in the striatum disappears when the dopamine neurons in the nigro-neostriatal pathway are destroyed suggests that the majority of striatal DOPAC is formed within the dopaminergic neurons and may reflect the metabolism of dopamine which has been released and recaptured. We conclude that short-term changes in brain levels of DOPAC appear to provide a useful index of alterations in the functional activity of central dopaminergic neurons.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.

 Experimental Neurology

Volume 30, Issue 3, March 1971, Pages 484-491

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In order to elucidate the functional role of the dopamine-containing nigrostriatal pathway, bipolar tungsten electrodes were implanted in the region of the substantia nigra and somewhat rostral to it. Stimulation with 100-Hz, 0.5-msec pulses in the medial part of the substantia nigra and the region medial to it elicited contraversive turning behavior. Turning, however, showed rapid fatigue with continued stimulation. Similar turning behavior could be seen with electrodes placed at a point anterior to the substantia nigra on the route probably followed by the nigrostriatal axons. When these electrode tips were used to make electrolytic lesions, the dopamine content of the caudate nucleus on the same side was reduced. If such animals were treated with methylamphetamine they showed a marked tendency to turn toward the side of the lesion These results are consistent with the hypothesis that unilateral activation of the dopamine-containing nigrostriatal pathway results in turning away from the activated side.