Temporal synergism of neurotransmitter affecting drugs and seasonal reproductive responses of Indian Palm Squirrel,Funambulus pennanti

Summary Daily injections of L-dihydroxyphenylalanine (L-DOPA, dopamine precursor) given 12 hour after 5-hydroxytryptophan (5-HTP, serotonin precursor) eliminated annual testicular regression in seasonally breeding sub-tropical Palm Squirrel that undergoes seasonal changes in responsiveness to day-length and humidity. Other temporal relations (L-DOPA given 0, 4, 8, 16 and 20 hours after 5-HTP administration) decreased/delayed the rate of regression and maintained the reproductive system at intermediate level. 12-hour-relation maintained full breeding condition (maximum gonad and accessory sex organs) unlike control, which exhibited complete atrophy of primary and accessory sex organs.It seems likely that these injections entrained the circadian serotonergic and dopaminergic oscillations and the interaction/phase relation of these two systems through their many circadian expressions (neural/hormonal) accounts for the seasonal interpretation of environmental factors. It is suggested that response in the present study is not a pharmacological effect of drugs but temporal synergism of neural acitivities affected the seasonality of reproduction as only 12-hour-relation of 5-HTP and L-DOPA maintained breeding activity during post reproductive phase of annual gonad cycle in Palm Squirrel.     

Elimination of testicular regression by 12-hr temporal relationship of serotonergic and dopaminergic activity in Indian Palm Squirrel,Funambulus pennanti

Summary Specific temporal relationship (12-hr) of serotonin and dopamine activity was induced by precursor drugs (5-HTP and L-DOPA) in Indian Palm SquirrelFunambulus pennanti during testicular regression phase. This treatment established breeding condition unlike control, which experienced complete atrophy of testes and accessory sex organs.It is obvious that seasonal testicular regression of Indian Palm Squirrel can be eliminated by 12hr relation of 5-HTP and L-DOPA, which is not a pharmacological effect but actually is an alteration of seasonality in this annually breeding subtropical mammal. It may be concluded that specific phase relation (12-hr) between circadian serotonergic and dopaminergic oscillations may induce breeding condition in regressing gonad of Indian Palm Squirrel during post-reproductive phase of annual gonadal cycle. It is also suggested that inspite of the different environmental factors (photoperiod, humidity etc.) used by different species to time their annual reproduction, basic regulatory mechanism of seasonality appears to be the same, i.e., temporal synergism of neurotransmitter activity.     

Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson''s disease

Transport processes operating in astrocytes were examined by measuring unidirectional fluxes of 42K and 36Cl in primary cultures of mouse astrocytes, at steady-state with respect to ion composition. The total K+ uptake rate was 2025 nmol X mg-1 protein X min-1. This rate was not influenced by furosemide (2 mM), an inhibitor of Cl- uptake and K+-K+ exchange, or acetazolamide (0.1 mM), a carbonic anhydrase inhibitor. Ouabain (1 mM) inhibited the uptake rate by 541 nmol X mg-1 X min-1. The equilibrated K+ content was determined to be 696 nmol X mg-1. The rate constant for efflux was 2.76 min-1. This equals an efflux rate of 1921 nmol X mg-1 X min-1, i.e. a similar value as the influx. Furosemide and ouabain did not inhibit the efflux. The equilibrated Cl- content was found to be 167 nmol X mg-1 and it decreased in furosemide-treated cells to 68.1 nmol X mg-1. The total Cl- uptake was 35 nmol X mg-1 X min-1 and it was inhibited by furosemide or bumetanide by 27 nmol X mg-1 X min-1. The mean resting membrane potential was found to be -77.4 mV. From these data we conclude: (1) that the K+ uptake rates are high, as can be expected from estimates based on literature data for K+ conductance in mammalian glial cells in situ; and (2) that the cells possess a very low relative Cl- permeability.     

Simultaneous determination of in vivo hydroxylation of tyrosine and tryptophan in rat striatum by microdialysis-HPLC: relationship between dopamine and serotonin biosynthesis

Summary Using a microdialysis technique, the rat striatum was perfused with NSD-1015, an inhibitor of aromatic L-amino acid decarboxylase, and the amount of L-3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytrytophan (5-HTP) accumulating in dialysate was measured as an index of in vivo activities of tyrosine hydroxylase and tryptophan hydroxylase. NSD-1015 increased the concentration of L-DOPA much higher than that of 5-HTP in a dose-related manner (1–100 mol/L). In order to examine the relationship between dopaminergic and serotonergic neurons in the striatum, either 5-HTP or L-DOPA was injected intraperitoneally to rats pretreated with benserazide, an inhibitor of peripheral decarboxylase. 5-HTP administration increased 5-HTP, but decreased L-DOPA in a dose-dependent manner. Conversely, 5-HTP concentration decreased in an association with the increased content of L-DOPA following L-DOPA administration. The decrease of 5-HTP caused by L-DOPA administration was not as remarkable as that of L-DOPA by 5-HTP injection. These results suggest that L-DOPA and 5-HTP, the precursor amino acids for catecholamines and indoleamines, could affect mutually each other neuronal activity through the inhibition of their rate-limiting enzymes.Abbreviations AADC aromatic L-aminoacid decarboxylase - ANOVA analysis of variance - DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - ECD electrochemicaldetection - 5-HIAA 5-hydroxyindoleacetic acid - HPLC high performance liquid chromatography - 5-HT 5-hydroxytryptamine (serotonin) - 5-HTP 5-hydroxytryptophan - HVA homovanillic acid - Km Michaelis constant - L-DOPA L-3,4-dihydroxyphenylalanine - (6 R)BH₄ (6R)-L-erythro-tetrahydrobiopterin - TH tyrosine hydroxylase - TRH tryptophan hydroxylase - TRP tryptophan - TYR tyrosine     

Differential effects of subchronic treatments with atypical antipsychotic drugs on dopamine D2 and serotonin 5-HT2A receptors in the rat brain

Summary. The effects of 3-week treatment with a typical antipsychotic drug chlorpromazine and three atypical antipsychotic drugs (risperidone, olanzapine and perospirone) on the binding to dopamine D₂ and serotonin 5-HT_2A receptors were examined in the rat stratum and frontal cortex, respectively. Subchronic treatment with chlorpromazine (10 mg/kg) and perospirone (1 mg/kg) significantly increased D₂ receptors, while no increase was observed with lower dose of chlorpromazine (5 mg/kg), perospirone (0.1 mg/kg), risperidone (0.25, 0.5 mg/kg) or olanzapine (1, 2 mg/kg). On the other hand, 3-week administration of chlorpromazine (5, 10 mg/kg) and olanzapine (1, 2 mg/kg) significantly decreased 5-HT_2A receptors, but risperidone (0.25, 0.5 mg/kg) or perospirone (0.1, 1 mg/kg) had no effect. The measurement of in vivo drug occupation for D₂ and 5-HT_2A receptors using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) suggested that high occupation of 5-HT_2A receptors with lower D₂ receptor occupancy might be involved in the absence of up-regulation of D₂ receptors after subchronic treatment with some atypical antipsychotic drugs. Received September 24, 1999; accepted December 1, 1999     

Behavioral depression produced by an uncontrollable stressor: Relationship to norepinephrine, dopamine, and serotonin levels in various regions of rat brain

This paper presents two experiments that continue efforts to determine the neurochemical changes responsible for stress-induced behavioral depression. These expriments measured active motor behavior in a swim tank as well as levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in various brain regions of rats after the animals had (a) been exposed to electric shocks they could control (Avoidance-escape condition), or (b) received the same shocks with no control over them (Yoked condition), or (c) received no shock (No-shock condition). In the first experiment, measures were taken 90 min after the shock session ended. In the swim test, Yoked animals showed a depression of active behavior relative to the other groups. From measures of monoamine levels, the change found to be most closely related to this post-stress behavioral depression was in NE in the locus coeruleus (LC), where Yoked animals showed a considerable depletion of NE. In the second study, the same measures were taken 48 h and 72–96 h after the stress session. Yoked animals tested at 48 h post-stress showed motor depression, but those tested after 72–96 h did not. NE in the LC was significantly depleted in Yoked animals tested at 48 h post-stress but showed only slight (and non-significant) depletion in those tested 72–96 h post-stress. These results, together with others, suggest that large stress-induced depletion of NE in the LC is involved in mediating behavioral depression brought about by severe stress. It is further suggested that the time course for behavioral recovery and for the disappearance of NE depletion in the LC that was seen in Yoked animals after stress parallels the time course previously reported by other investigators for induction of catecholamine-synthesizing enzymes — tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) — in the LC, so that induction of TH and DBH activity may be a neurochemical mechanism to bring about recovery from poststress behavioral depression.     

Effects of acute administration of SCH 23390 on dopamine and serotonin turnover in major dopaminergic areas and mesencephalic raphe nuclei — Comparison with ritanserin

1. The effects of acute administration of SCH 23390 (0.05 and 0.25 mg/kg s.c.), a dopamirie D-1 receptor antagonist having also a moderate serotonin-S₂ (5-HT-2) receptor blocking activity, and ritanserin (0.5 mg/kg), a specific 5-HT-2 antagonist, on dopamine (DA) and serotonin (5-HT) turnover were investigated in dopaminergic (nucleus caudatus, nucleus accumbens, substantia nigra, A10 area) and serotonergic (nucleus raphe dorsalis and nucleus raphe medialis) rat brain nuclei.

2. Acute SCH 23390 (both doses) increased the metabolism of DA and tended to augment the rate of DA synthesis (accumulation of DOPA after inhibition of aromatic acid decarboxylase) in the nucleus accumbens, but not in the nucleus caudatus. In addition, SCH 23390 had a moderate effect on DA metabolism in substantia nigra. SCH 23390 did not alter the turnover of 5-HT in any of the nuclei studied.

3. Acute administration of ritanserin did not modify 5-HT or DA turnover in any of the nuclei studied.

4. In conclusion, these results suggest that acute SCH 23390 administration preferentially activates the mesolimbic DA system. The lack of effect of ritanserin on DA or 5-HT turnover in nigrostriatal and mesolimbic DAergic areas suggests that under basal conditions the blockade of 5-HT₂ receptors do not change monoamine metabolism in these areas. The role of 5-HT-2 blockade in the actions of SCH 23390 on DA turnover appears thus to be of a minor importance.     

In vivo occupation of dopamine D1, D2 and serotonin2A receptors by novel antipsychotic drug, SM-9018and its metabolite, in rat brain

Summary. In vivo occupation of dopamine D₁, D₂ and serotonin (5-HT)_2A receptors by a novel antipsychotic drug, SM-9018 (perospirone hydrochloride; cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride) and its major metabolite (ID-15036; N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1-hydroxy-1,2-cyclohexanedicarboximide) was measured in rat brain using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist, at these receptor sites. SM-9018 and its metabolite, ID-15036, dose-dependently reversed EEDQ-induced 5-HT_2A and D₂ receptor inactivation, but not D₁ receptor inactivation. At lower doses (0.1 mg/kg i.p.), SM-9018 showed a preferential occupation of the 5-HT_2A receptors, with only a small effect on the D₂ receptors; while at higher doses (1.0 and 5.0 mg/kg i.p.), it was nearly equipotent in its occupation of both the D₂ (77.8%) and the 5-HT_2A receptors (78.6%). On the other hand, ID-15036 was more potent in occupying the 5-HT_2A than the D₂ receptors even at higher doses (1.0 and 5.0 mg/kg i.p.). We previously reported that atypical antipsychotic drugs, such as clozapine, were characterized by a high occupancy of the 5-HT_2A receptors, with a low or minimum occupancy of the D₂ receptors in vivo. The present study suggests that SM-9018 and its metabolite ID-15036 show a preferential tendency to occupy 5-HT_2A receptors, and that the clozapine-like atypical properties of SM-9018 may be due to some pharmacological action of both the SM-9018 itself and its metabolite, ID-15063. Accepted December 26, 1997; received July 23, 1997