Acute effects of delta-9-tetrahydrocannabinol on dopaminergic activity in several rat brain areas.

In this work, we examined the acute effects of two doses of delta-9-tetrahydrocannabinol (THC) on several pre- and postsynaptic biochemical measures of dopaminergic activity in the striatum, limbic forebrain, and hypothalamic-anterior pituitary area of adult male rats. The exposure to a low dose of THC (0.5 mg/kg bw) decreased the number of striatal D2 dopaminergic binding sites, but did not affect their affinity. Treatment with a higher dose of THC was ineffective. In addition, both doses decreased the number of D1 dopaminergic binding sites in the limbic forebrain without changing their affinity. We did not find any changes in the dopamine (DA) or L-3,4-dihydroxyphenylacetic acid (DOPAC) content, or in the DOPAC/DA ratio, in either the striatum or limbic forebrain. THC treatment produced a dose-related decline in plasma prolactin (PRL) levels. Furthermore, both the basal and DA-inhibited in vitro release of PRL were reduced in animals exposed to THC in a dose-dependent manner. This inhibitory effect of THC on PRL release was accompanied by a decreased DOPAC/DA ratio in medial basal hypothalamus that, in turn, may be a result of the fall in PRL levels rather than a direct action of the drug. These data show that acute exposure to THC can alter brain dopaminergic neurotransmission. Our results suggest that the reduction of PRL release following THC exposure, both in vivo and in vitro, might be elicited by a direct action of THC on the pituitary.     

A physiological dose of progesterone affects rat striatum biogenic amine metabolism

Ovariectomized rats injected with progesterone (50 micrograms s.c.) showed a peak in striatum dopamine (DA) concentration after 15 min followed by a decrease at 60-75 min and a return to control values 90 min after the steroid injection. The DA metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased after the progesterone injection, with a peak at 45 min and a return to control values after about 2 h. Striatum serotonin (5-HT) concentrations remained unchanged after the progesterone injection while its metabolite 5-hydroxyindoleacetic acid (5-HIAA) was increased at 45 min and returned to control values after 2 h. The peak plasma progesterone concentration occurred 15-30 min after the steroid injection while estradiol concentrations were unchanged indicating no significant conversion of progesterone into estradiol. A similar experiment was performed in male rats. As with female rats, a progesterone injection led to a progesterone peak at 30 min while plasma estradiol levels remained unchanged. Male rats responded to the progesterone injection with a maximal increase of DA, DOPAC and HVA concentrations as soon as after 15 min and these amines remained elevated up to 75 min after the steroid injection. 5-HT and 5-HIAA remained unchanged after the progesterone injection. Thus, very small physiological doses of progesterone can increase striatum dopaminergic activity in rats of both sexes while serotonergic activity is influenced only in female rats. This effect is seen within minutes and is relatively short. It is probably non-genomic, presynaptic and similar to the effect of a small dose of a DA releasing agent.     

The new tripeptoid neurotensin analog dilept selectively affects dopamine turnover in nucleus accumbens and hypothalamus

The effects of dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) - a new peptidomimetic of neurotensine - on the level of monoamines and their main metabolites in four functionally important brain structures has been studied upon single and subchronic administration in intact rats and in those pretreated with the NMDA receptor blocker ketamine. Repeated administration of dilept favors the accumulation of DOPAC and accelerates the dopamine (DA) turnover in nucleus accumbens, as manifested by an increase in the DOPAC/DA ratio. The opposite effect (decrease in the DOPAC/DA ratio) was observed in the hypothalamus, where the subchronic treatment with dilept completely inhibited the activating action of ketamine on the DA turnover. The selective influence of dilept on the dopaminergic system activity in nucleus accumbens (but not in striatum), together with the previously obtained behavioral data, suggest that dilept is a new atypical neuroleptic producing no extrapyramidal side effects.     

Dopamine in the basal ganglia and benzodiazepine-induced sedation

The effects of the anxiolytic benzodiazepine flurazepam on motor activity and the turnover of dopamine were measured in rats. Changes in motor activity were measured using a doppler-shift device; changes in extracellular homovanillic acid (HVA), monitored by linear sweep voltammetry with carbon paste electrodes implanted in the striatum and nucleus accumbens and ex vivo measurements of changes in 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios in the striatum and nucleus accumbens were used as indices of changes in the turnover of dopamine. Injection of vehicle increased the nocturnal rise in the concentration of HVA and the ex vivo DOPAC/DA ratio in the nucleus accumbens. Injection of flurazepam decreased the nocturnal rise in HVA and DOPAC/DA ratio in the nucleus accumbens below control levels. There was also a decrease in the nocturnal rise in motor activity. Neither injection of vehicle nor injection of flurazepam caused changes in either the concentration of HVA or the DOPAC/DA ratio in the striatum. The correlation coefficient for motor activity compared to concentration of HVA remained high for the nucleus accumbens but was reduced for the striatum after administration of flurazepam. The results suggest that the sedative effect of flurazepam may be due to an action on the mesolimbic but not the nigrostriatal dopaminergic pathway.     

Study of the turnover or the release of brain dopamine in rats after administration of N-linoleyl dopamine]

Wistar male rats received N-linoleyl dopamine (L-DA) at doses of 10, 50 or 100 mg/kg (i.p.). 2 h after these injections they were decapitated and dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), as well as the ratio DOPAC/DA, which could represent the DA turnover, were determined in the striatum, the frontal cortex or the hypothalamus, while homovanillic acid (HVA) as well as the ratio HVA/DA, which could represent the DA release, were determined in the striatum by high performance liquid chromatography (HPLC). Except a small rise of DA and DOPAC in the hypothalamus, at high L-DA doses, no significant modifications in DA, DOPAC, DOPAC/DA, HVA or HVA/DA were observed in the other brain areas studied. These results, in good agreement with the recent data obtained with other dopaminergic agonists, could show the absence of correlation between the hypomotility, on the one hand and the decreasing of the turnover or the release of the brain DA, on the other hand. Together with the data obtained recently by scandinavian and italian authors, they could raise questions about the position and the role of dopaminergic autoreceptors.     

Differences in effects of Ca2+ channel antagonists on dopamine metabolism in the limbic and extrapyramidal dopaminergic structures

The effect of single and multiple administration of Ca²⁺ channel antagonists, nifedipine and verapamil, on concentrations of dopamine and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), was investigated in the mesolimbic (cortex, nucleus accumbens) and extrapyramidal (striatum) structures in Wistar rats. A single dose of nifedipine (10 mg/kg IP) produced some activation of the dopaminergic system in both cortex (increase in DOPAC) and n. accumbens (increase in HVA); verapamil (20 mg/kg IP) produced an increase in HVA in the cortex only. Chronic treatment with either Ca²⁺ channel antagonist produced more marked activation of dopamine metabolism in the cortex and nucleus accumbens. Those changes were most expressed 1 h after the last treatment, but lasted for at least 24 h. No changes in dopamine metabolism were observed in the striatum. The present data suggest that Ca²⁺ channel antagonists after chronic treatment specifi- cally activate the dopaminergic system in limbic structures. Received: 22 December 1995/Final version: 31 May 1996     

Naloxone-precipitated changes in biogenic amines and their metabolites in various brain regions of butorphanol-dependent rats

Influence of a naloxone (an opioid receptor antagonist) challenge (5 mg/kg, IP) on levels of biogenic amines and their metabolites in various brain regions of rats infused continuously with butorphanol (a μ/δ/κ mixed opioid receptor agonist; 26 nmol/μl/h) or morphine (a μ-opioid receptor agonist; 26 nmol/μl/h) was investigated using highperformance liquid chromatography with electrochemical detection (HPLC-ED). Naloxone precipitated a withdrawal syndrome and decreased the levels of: dopamine (DA) in the cortex and striatum, 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, homovanilic acid (HVA) in the striatum, limbic, midbrain, and pons/medulla regions in butorphanol-dependent rats. However, the levels of norepinephrine (NE), serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in the regions studied were not affected by naloxone-precipitated withdrawal. In addition, naloxone increased the HVA/DA ratio in the cortex, while this ratio was reduced in the limbic, midbrain, and pons/medulla. The reduction of 5-HIAA/5-HT ratio was also detected in the limbic area. In the animals rendered dependent on morphine, the results obtained were similar to those of butorphanol-dependent rats except for changes of 5-HIAA levels in some brain regions. These results suggest that an alteration of dopaminergic neuron activity following a reduction of DA and its metabolites in specific brain regions (e.g., striatum, limbic, midbrain, and pons/medulla) play an important role in the expression of the opioid withdrawal syndrome.     

Striatal dopamine activity and unilateral barpressing in rats

A micro-punch tissue assay was used to measure changes in dopamine content at twenty-six sites within the striatum of rats trained to barpress exclusively with one forepaw for food pellets. Analysis of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was carried out using HPLC with electrochemical detection. The barpress group had a significantly higher DOPAC/DA ratio in both the contralateral and ipsilateral hemispheres when compared to feeding and homecage controls. The DOPAC/DA ratio is considered to be a measure of dopaminergic neuronal activity, thus suggesting a bilateral activation of the neostriatal dopaminergic afferents as a result of the motor performance. Topographical analysis within the barpress group revealed an anterior-posterior, medial-lateral gradient of dopaminergic activity with the posterior and lateral sites showing the greatest increases over the controls. The results of this experiment indicate that localized changes in neuronal activity can be monitored with the micro-punch assay-HPLC/EC technique and that voluntary motor behavior produces an activation of the striatal dopamine system.     

THC does not affect striatal dopamine release: microdialysis in freely moving rats.

The hypothesis that cannabinoids potentiate the motor effects of neuroleptics and produce their abuse potential by stimulating dopaminergic activity was tested by measuring the ability of THC to increase extracellular dopamine concentrations. Male Long-Evans rats were implanted with guide cannulae for the striatum or nucleus accumbens. Fifteen hours prior to testing, removable microdialysis probes were inserted through the guide cannulae. Dialysis samples were collected during resting baseline, after 1.0 mg/kg, 10 mg/kg THC, or vehicle of olive oil with 5% ETOH (by gavage) followed by amphetamine (1.5 mg/kg) or fluphenazine (0.3 mg/kg). THC produced no change in the extracellular concentrations of DA, DOPAC, and HVA, nor in 5-HIAA. THC also had no effect on the enhancement of extracellular DA produced by amphetamine nor on the transient increase in DA, DOPAC, and HVA produced by fluphenazine. There were also no behavioral differences between groups during any of these treatments.     

Effects of inhibition of monoamine oxidase on the levels of 5-S-cysteinyl adducts of catechols in dopaminergic regions of the brain of the guinea pig

The occurrence of 5-S-cysteinyl adducts of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) in brain tissue, appears to reflect in vivo autoxidation of DA, DOPA and DOPAC, respectively. In the striatum and in the limbic system of guinea pig, the levels of DOPAC and 5-S-cysteinyl-DOPAC were markedly reduced after treatment with pargyline (75 mg/kg, i.p., 17 hr) and pargyline plus reserpine (75 mg/kg, i.p., 17 hr plus 5 mg/kg, i.p., 18 hr) compared to controls. However, the depletion of 5-S-cysteinyl adduct was less severe than that of DOPAC, suggesting a slower turnover of the adduct. Dopamine and 5-S-cysteinyl-DA increased significantly and to the same extent in the striatum, after pargyline alone. In the limbic system DA was significantly increased, whereas no change was found for levels of 5-S-cysteinyl-DA. 5-S-Cysteinyl-DOPA decreased significantly in the striatum after treatment with pargyline plus reserpine and non-significantly after pargyline alone. The data are compatible with a slight inhibitory effect of MAO inhibition on catechol autoxidation. This effect was, however, overridden by the increased level of DA.     

千金藤啶碱对大鼠脑内单胺代谢的影响

1-千金藤啶碱(1-SPD 15～120 mg/kg)能增加大鼠纹状体和边缘区的多巴胺代谢物DOPAC和HVA(+150～300%),并有剂量相关关系。此作用于给药后60 min达峰值,给药后4 h虽有恢复趋势,但仍明显高于对照值。SPD还能中等度地降低上述两个脑区的DA和NA(-18～48%)。DA转换率(表现为代谢物增加)的升高支持SPD为DA受体阻断剂。但DA和NA下降表明,除有受体阻断作用外,不能排除药物对单胺递质的贮存、释放或再摄取的影响。纹状体内的5-HIAA含量亦有明显升高。     

千金藤啶碱对大鼠脑内单胺代谢的影响

1-千金藤啶碱(1-SPD 15～120 mg/kg)能增加大鼠纹状体和边缘区的多巴胺代谢物DOPAC和HVA(+150～300%),并有剂量相关关系。此作用于给药后60 min达峰值,给药后4 h虽有恢复趋势,但仍明显高于对照值。SPD还能中等度地降低上述两个脑区的DA和NA(-18～48%)。DA转换率(表现为代谢物增加)的升高支持SPD为DA受体阻断剂。但DA和NA下降表明,除有受体阻断作用外,不能排除药物对单胺递质的贮存、释放或再摄取的影响。纹状体内的5-HIAA含量亦有明显升高。     

Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids

1. The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. 2. The DOPAC + HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. 3. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. 4. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. 5. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems.     

Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats.

The behavioural and biochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine and memantine, and the competitive NMDA receptor antagonist, CGP 39551, were investigated in rats. Systemic injections of dizocilpine (0.33 mg/kg) increased locomotion and rearing in an open field, whereas memantine (20 mg/kg) increased only locomotor activity. CGP 39551 (10 and 20 mg/kg) did not change open field activity. Dopamine (DA) metabolism--as measured by the ratio of dihydroxyphenylacetic acid/dopamine (DOPAC/DA)--increased in response to dizocilpine in the prefrontal cortex and the nucleus accumbens. Memantine enhanced DOPAC/DA in the prefrontal cortex, the nucleus accumbens and to a lesser degree in the posterior striatum. In contrast to non-competitive NMDA receptor antagonists, CGP 39551 did not increase DA metabolism of subcortical structures and even decreased DOPAC/DA in the prefrontal cortex. These results indicate that competitive and non-competitive NMDA receptor antagonists affect spontaneous locomotion differentially in rats. The biochemical data imply that the stimulant actions non-competitive NMDA receptor antagonists are at least partially due to activation of ascending dopaminergic systems. Potential mechanisms involved in the differential effects of both types of NMDA receptor antagonists are discussed.     

The effect of phencyclidine and DL-2-amino-5-phosphonovaleric acid on N-methyl-D-aspartic acid induced changes in extracellular concentration of dopamine and DOPAC in the rat neostriatum.

The effects of N-methyl-D-aspartic acid (NMDA) and phencyclidine (PCP) on extracellular levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat were studied using in vivo microdialysis. Intrastriatal infusion of NMDA produced a significant dose-dependent increase in extracellular DA and a decrease in concentrations of DOPAC. Whereas both 2-amino-5-phosphonovalerate (APV) and PCP antagonized the NMDA-induced increase in extracellular levels of DA, the effect on NMDA-induced changes in extracellular concentrations of DOPAC were different for the two compounds. The APV significantly attenuated the decrease in extracellular DOPAC produced by smaller concentrations of NMDA, whereas PCP did not prevent decrease in DOPAC produced by any concentrations of NMDA. Phencyclidine alone produced a dose-dependent increase in extracellular DA but had no effect on the extracellular concentration of DOPAC. This study demonstrated that PCP, at concentrations which did not produce an increase in extracellular DA, antagonized the effect of the NMDA on DA. The data also indicated that both APV and PCP antagonized the NMDA-evoked release of DA over a range of concentrations of NMDA, even though they did so by different mechanisms.     

Similarities and differences between d-ALA2 MET5 enkephalin amide and morphine in the induction of tolerance to their effects on catalepsy and on dopamine metabolism in the rat brain

Summary Rats were made tolerant to morphine or to DALA, a synthetic analogue of met-enkephalin, by prolonged exposure to these compounds. Tolerance was assessed by evaluating the resistance of the treated rats to present catalepsy after an acute dose of the opiates. Both morphine and DALA induced tolerance and cross-tolerance to the cataleptic effect. Acute administration of morphine and DALA increased the concentration of DOPAC in striatum, limbic area and s.nigra of control rats. This increase was not present when morphine was given acutely to chronically morphine-treated rats, indicating that these animals were tolerant to this effect. Chronically morphine-treated rats given DALA presented partial tolerance to the biochemical effect of the peptide in limbic area and in s.nigra but not in striatum, indicating that only in certain areas was crosstolerance produced by chronic morphine. When DALA was administered at different doses to chronically DALA treated rats, the peptide induced rise in DA catabolite was similar to that produced in control animals, so clearly there was no tolerance to this biochemical effect. In these animals cross tolerance to morphine's effect on DA metabolism was present in s.nigra but not in the other two areas, indicating that s.nigra is particularly sensitive to opiate-induced tolerance on DA metabolism.Supported by CNR-ROME Grant no. CT81.00258.04     

Activation of mesolimbic dopaminergic neurons following central administration of histamine is mediated by H1 receptors

Summary The effect of intracerebroventricular administration of histamine on the activity of mesolimbic and nigrostriatal dopaminergic (DA) neurons was determined in male rats. The activity of these neurons was estimated by measuring: (1) the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after administration of a decarboxylase inhibitor, and (2) the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens and striatum, which contain the terminals of these neurons. Central administration of histamine increased both DOPA accumulation and DOPAC concentrations in the nucleus accumbens, but was without effect in the striatum. The increase in DOPAC concentrations in the nucleus accumbens occurred within 10 min and was sustained for at least 120 min. The H₁ antagonist mepyramine blocked whereas the H₂ antagonist zolantidine did not affect histamine-induced increases in DOPAC concentrations in the nucleus accumbens. Neither mepyramine nor zolantidine affected basal DOPAC concentrations in the nucleus accumbens. These results indicate that central administration of histamine stimulates mesolimbic DA neurons through an action at the H₁ receptor, but has no effect upon the activity of nigrostriatal DA neurons.Correspondence to A. E. Fleckenstein at the above address     

Regional effects of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine release and metabolism in the rat brain.

1. The effects of single-dose regimens of amphetamine, cocaine, nomifensine and GBR 12909 on the dynamics of dopamine (DA) release and metabolism were evaluated in the frontal cortex, hypothalamus, nucleus accumbens and striatum. The regimens selected are known to produce substantial behavioural effects. 2. 3-Methoxytyramine (3MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used to assess DA metabolism by catechol-O-methyltransferase and monoamine oxidase respectively. The rate of formation of 3MT was used as an index of synaptic DA. The ratio and sum, respectively, of 3MT and DOPAC rates of formation were used to assess DA reuptake inhibition and turnover. 3. The effects of amphetamine on 3MT production and DOPAC steady-state levels were similar in all regions, suggesting similar pharmacodynamic actions. Amphetamine increased 3MT formation and steady-state levels, and reduced DOPAC steady-state levels. DOPAC formation was significantly reduced only in the nucleus accumbens and striatum. Total DA turnover remained unchanged except in the nucleus accumbens. Apparently, the amphetamine-induced increase in DA release occurred at the expense of intraneuronal DA metabolism and did not require stimulation of synthesis. 4. Nomifensine elevated 3MT formation in all regions. A similar effect was produced by cocaine except in the nucleus accumbens. GBR 12909 elevated 3MT production only in the hypothalamus, the striatum and the nucleus accumbens. 5. Cocaine selectively reduced DOPAC formation in the frontal cortex. Nomifensine increased and reduced, respectively, DOPAC formation in striatum and hypothalamus. GBR 12909 elevated DOPAC formation in all regions except the cortex, where pargyline did not reduce DOPAC levels in GBR 12909-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of epibatidine and nicotine on the output of dopamine in the dorsal and ventral striatum of freely-moving rats

The effects of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine on the extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal (caudate-putamen) and the ventral striatum (nucleus accumbens) of freely-moving male Wistar rats were studied by in vivo microdialysis. In the dorsal striatum, epibatidine (3.0 microg/kg s.c.) significantly elevated the extracellular concentrations of DA, DOPAC and HVA. In contrast, epibatidine did not alter the extracellular DA concentration in the ventral striatum, but elevated significantly the concentration of DOPAC and also tended to elevate that of HVA. In parallel experiments, nicotine (0.5 mg/kg s.c.) significantly increased DA output in the ventral striatum whereas only a modest and non-significant increase of extracellular DA concentration was found in the dorsal striatum. Earlier studies have shown that the doses of epibatidine and nicotine used in the present study are about equieffective at least with respect to the analgesia-producing or hypothermic effects of the drugs. Comparison of the effects of epibatidine and nicotine suggests that the responses of the mesolimbic and nigrostriatal dopaminergic systems to the two nicotinic receptor agonists differ. Epibatidine, in contrast to nicotine, preferentially stimulates the nigrostriatal vs. the mesolimbic dopaminergic system. Therefore, novel nicotinic AChR ligands structurally related to epibatidine may have low abuse potential.     

Postmortem instability of dopamine and its metabolites in rat striatum and limbic forebrain.

The level of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were determined in the brains of rats kept 24 h after death at two different temperatures, 4 degrees C and 22 degrees C. The estimations were carried out in the striatum and limbic forebrain containing: nucleus accumbens, septum, limbic cortex, amygdala, tuberculum olfactorium. Brain tissue of control rats was dissected immediately after decapitation, frozen over solid CO2 and stored at -70 degrees C until assayed. DA and its metabolites were measured, using high-performance liquid chromatography (HPLC) with electrochemical detection. The levels of DA, DOPAC and HVA in the striatum were significantly decreased (from 50% to 80%) when rats were kept 24 h after death. The changes were more pronounced at 22 degrees C than at 4 degrees C. As the decrease in DA concentration was stronger than that of its final metabolite HVA, the ratio of HVA/DA concentration measured as an index of the rate of DA metabolism was even increased (from 8 to 11). Different changes occurred in the limbic region, where the levels of DA and HVA did not change neither at 4 degrees C nor 22 degrees C. The level of intraneuronally formed DA metabolite-DOPAC was elevated (by about 60%). The level of 3-MT, extraneuronally formed DA metabolite, was significantly increased both in the striatum (200%) and limbic DA structures (500%). These data demonstrate regional postmortal differences in stability of DA and its metabolite levels, which are in the striatum temperature-, time-, and storage-dependent. That implicates a careful assessment of postmortem studies when measuring the neurotransmitter dynamics in human necropsy material.