Increase In Homovanillic Acid Research Articles

Acute and delayed effects of adrenocorticotropic hormone on dopamine activity in man

This study was designed to test the hypothesis that administration of synthetic adrenocorticotropic hormone (co-syntropin) to healthy human subjects produces an increase in plasma levels of homovanillic acid (HVA), the principal dopamine metabolite. Co-syntropin 0.25 mg was administered intravenously at 8:35 <AM to healthy volunteer subjects having no active medical problems, personal psychiatric history, or family psychiatric history. In a sample of 12 subjects, plasma levels of cortisol and HVA were measured at baseline and then at 30 min intervals over the 3.5 h following co-syntropin. In a subgroup of six subjects, these same measurements were obtained at baseline, then in the morning and afternoon on each of the 2 days following the day of co-syntropin administration. We did not observe an increase in plasma HVA over the 3.5 h following co-syntropin, but a statistically significant increase in plasma HVA was observed over the subsequent 2 days. These results suggest that ACTH may exert delayed effects on dopamine activity in man, although confirmation of our findings with a larger sample will be required. Depression 2:292–296 (1994/1995). © 1995 Wiley-Liss, Inc.

Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running

HATTORI, S., M. NAOI AND H. NISHINO. Striatal dopamine turnover during treadmill running in the rat: Relation to the speed of running. BRAIN RES BULL 35(1) 41–49, 1994.—To evaluate the physiological action of Striatal dopamine (DA) in exercise, rats were trained to run on a straight treadmill. Extracellular DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC), and homovanillic acid (HVA) were measured by in vivo microdialysis, and striatal tissue tyrosine hydroxylase (TH) activity and monoamine oxidase (MAO) activity were measured using high performance liquid chromatography (HPLC) and spectrophotometer. DA turnover was increased by running, and the increase in DOPAC and HVA was closely related to the speed of running, while the increase in DA had no relationship to the speed. The threshold for the increase in DA, DOPAC, and HVA was between 300 and 660 cm/min. Striatal tissue TH activity was elevated up to 135% of basal values after the rats were trained for 7 days to run at 1800 cm/min. Just after running for 20 min, there was a further increase to 180%. These values became 150% and 90% of basal values at 2 h and 6 h, showing a similar time course as DA detected by microdialysis. MAO-B activity increased up to 160% of basal values after 7 days training but decreased to 130% and 110% just after and 2 h after running, then increased to 145% 6 h after running. MAO-A showed a similar variation as MAO-B. These data suggest that both the synthesis and metabolism of DA have a close relationship with physical exercise and might contribute to adjusting extracellular DA levels within an adequate range in response to exercise intensity.

Dopamine increase in the prefrontal cortex correlates with reversal of haloperidol-induced catalepsy in rats

The mechanism by which forced swimming reverses haloperidol-induced catalepsy was examined by measuring dopamine (DA) turnover in the nucleus accumbens-ventromedial caudate (NAC-C) and the prefrontal cortex (PFC) in rats. DA and its metabolites 3,4-dihydroxi-phenylacetic acid (DOPAC) and homovanillic acid (HVA) were assessed by microdialysis and high pressure liquid chromatography with electrochemical detection (HPLC-ED) after systemic administration of a cataleptic dose of haloperidol (5 mg/kg) or saline. Haloperidol-induced catalepsy was temporarily suppressed by forced swimming. Haloperidol-treated rats showed an increase of DA, DOPAC, and HVA overflow in the PFC and the NAC-C. This increase was greater in the PFC of rats that were forced to swim. Rats that were not treated with haloperidol but were forced to swim (control group) showed an increase of DA, DOPAC, and HVA in the PFC but not in the NAC-C. Zero micrograms, 5 μg, 10 μg, and 20 μg of DA was bilaterally injected in the PFC of cataleptic rats to evaluate the hypothesis that DA in the PFC reverses catalepsy. Haloperidol-induced catalepsy was diminished by bilateral microinjections of 10 μg and 20 μg but not by 5 μg of DA in the PFC. The higher the dose of DA, the longer the decrease of catalepsy. These results suggest that an increase of DA turnover in the PFC might mediate temporal suppression of haloperidol-induced catalepsy. The mechanism by which the mesocortical DA system reduces catalepsy is discussed.

Sex differences in ethanol-induced dopamine release in nucleus accumbens and in ethanol consumption in rats.

In vivo microdialysis was used to examine changes in nucleus accumbens and striatal dopamine, dihydrophenylacetic acid (DOPAC), and homovanillic acid (HVA) following acute administration of ethanol (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) in male and female Long-Evans rats. Following dialysis, rats were trained to bar-press for oral ethanol reinforcement. In nucleus accumbens, females showed significant increases in extracellular dopamine following 0.25 or 0.5 g/kg ethanol, but did not show significant increases over baseline at the higher doses. Males showed slight increases in dopamine at the lower doses and decreased dopamine at 2.0 g/kg. In striatum, both sexes showed increased dopamine at the lower doses and decreased dopamine at 2.0 g/kg. There were slight increases in nucleus accumbens DOPAC and HVA at some doses in both sexes, but no changes in striatal metabolite levels. In addition to showing increased responsiveness to ethanol-induced mesolimbic dopamine stimulation, females consumed more ethanol than males during behavioral testing. The pattern of both greater ethanol-induced nucleus accumbens dopamine release and greater ethanol consumption in females supports the hypothesis that ethanol reward is mediated, at least in part, by the mesolimbic dopamine system.

Interaction with pups enhances dopamine release in the ventral striatum of maternal rats: A microdialysis study

A growing body of evidence suggests that an interference with dopamine (DA) transmission disrupts maternal behavior in the rat. The present brain microdialysis study was therefore conducted to investigate whether infants can modulate ventral striatal DA release in mother rats. There was a significant rise in the extracellular concentrations DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the ventral striatum when mothers were reunited with their litters following separation overnight. Nursing was the predominant behavior during this phase of the experiment. More active behaviors were elicited by soiling pups with flowerpot earth, and this was accompanied by further increases in DA, DOPAC, HVA, and 5-HIAA. It is suggested that pup-induced stimulation of ventral striatal DA release facilitates parental responses such as pup retrieval.

Synaptophysin: A test of the etiological hypotheses

Developing and adult Sprague-Dawley rats were tested after acute or repeated haloperidol administration. Although 8-day-old rat pups showed a form of immobility in response to a single injection of haloperidol (1 mg/kg), 14-day-old rats did not show any behavioral response to the neuroleptic. By 21 days of age, an acute dose of haloperidol induced a cataleptic response similar to that described for adult animals. Following 7 days of repeated haloperidol administration, the cataleptogenic effects of haloperidol were attenuated in animals aged 21 days and older, but not in 8- and 14-day-old rats. Subjects were sacrificed 70 min after the injection of the test dose of haloperidol or saline and the corpus striatum and olfactory tubercles were dissected for HPLC determination of dopamine (DA) and its metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). In the corpus striatum, an area believed to be important for DA-related catalepsy, acute and repeated haloperidol induced a slight increase in concentrations of HVA in 8-day-old rats, and an increase in both DOPAC and HVA concentrations in animals aged 14 days and older. Tolerance after repeated haloperidol administration, in the form of an attenuation of the haloperidol-induced increase in DA metabolites, was not apparent until 35 days of age. These data contrast with the behavioral data, which indicate that the ability to develop a tolerance to the cataleptogenic effects of haloperidol matures by 21 days of age. The pattern of responses in the olfactory tubercles differed from those observed in the striatum. Following acute haloperidol, subjects did not show any increase in HVA until 14 days of age, and in both HVA and DOPAC until 21 days of age. At no age, including adults, was one week of repeated administration of haloperidol sufficient to induce tolerance to the effects of haloperidol on DA metabolites in the olfactory tubercles. In addition to providing information about the development of certain aspects of DA systems in rats these studies suggest that an attenuation of the haloperidol-induced increase in DA metabolites is not necessary for the development of tolerance to haloperidol-induced catalepsy.

Central nervous activation as a psycho- physiological aspect of motor processes

Baclofen (20 mg/kg) caused an increase in the content of homovanillic acid (HVA) and dopamine (DA) in rat brain 2–3 h after drug injection without appreciable changes in the level of other monoamines and their main metabolites. Six and eight hours after baclofen, the content of HVA but not that of DA was reduced. Moreover, baclofen initially (20 min after injection) reduced, but later (105 min post drug) enhanced the accumulation of HVA induced by probenecid. The shortlasting (20 min) initial reduction of HVA elevation in probenecid-pretreated animals as well as the longlasting (6–8 h) decrease of HVA levels in rats injected with baclofen alone are interpreted to be due to a decreased release and metabolism of DA, probably as a consequence of the blockade of impulse flow in mesolimbic and nigro-striatal DA neurones. The increase in HVA and DA seen during the first few hours is thought to result from enhanced DA synthesis similar to that known for γ-hydroxybutyrate (GHB). This initial rise in HVA due to synthesis stimulation probably masked a reduction of HVA to be expected immediately after baclofen injection. The similarity between baclofen and GHB is stressed by the finding that baclofen counteracted the increase of HVA occuring after chlorpromazine and D-amphetamine but not that induced by the benzoquinolizine derivative, Ro 4-1284.

Dopaminergic responsivity during cocaine abstinence: a pilot study

This preliminary study investigated dopamine (DA) function in six hospitalized cocaine-dependent subjects ( DSM-III-R) who received 1.5 mg/kg of active cocaine by mouth, t.i.d., for 3 days followed by 9 days of placebo cocaine. During early and late abstinence from cocaine, plasma growth hormone (GH), homovanillic acid (HVA), prolactin, and 3-methoxy-4-hydroxyphenethylene-glycol responses to the placebo-controlled administration of oral L-dopa 250 mg/carbidopa 25 mg (Sinemet®) were measured. Sinemet caused significantly greater placebo-corrected increases in GH and HVA during early as compared with late abstinence. Acute abstinence from cocaine may be associated with increased DA responsivity, which normalizes over time.

Diazepam antagonizes effects on dopamine metabolism produced by pcp receptor agonists

1. 1. Male rats were injected with either saline, diazepam, MK-801, or diazepam plus MK-801. 2. 2. In previous work with phencyclidine (PCP), diazepam significantly reduced the increase in homovanillic acid (HVA) in olfactory tubercle and prefrontal cortex. 3. 3. Diazepam also lowered the HVA increase following MK-801 in caudate, olfactory tubercle, and prefrontal cortex. 4. 4. Benzodiazepine receptors may modify dopaminergic function at PCP receptors that affect dopamine neurotransmission.

Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats

Ibogaine, an indolalkylamine, proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic system acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopamine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at several time points, between 1 h and 1 month post-injection. One hour after ibogaine-administration (40 mg/kg i.p.) a 50% decrease in DA along with a 37–100% increase in HVA were observed in all 3 brain regions studied: striatum, nucleus accumbens and prefrontal cortex. Nineteen hours after ibogaine-administration a decrease in DOPAC was seen in the nucleus accumbens and in the striatum. A week after administration of ibogaine striatal DOPAC levels were still reduced. A month after ibogaine injection there were no significant neurochemical changes in any region. We also investigated the effects of ibogaine pretreatment on morphine-induced locomotor activity, which is thought to depend on DA release. Using photocell activity cages we found that ibogaine pretreatment decreased the stimulatory motor effects induced by a wide range of morphine doses (0.5–20 mg/kg, i.p.) administered 19 h later; a similar effect was observed when morphine (5 mg/kg) was administered a week after ibogaine pretreatment. No significant changes in morphine-induced locomotion were seen a month after ibogaine pretreatment. The present findings indicate that ibogaine produces both acute and delayed effects on the tissue content of DA and its metabolites, and these changes coincide with a sustained depression of morphine-induced locomotor activity.

Activation of cerebral dopaminergic systems by noise and whole-body vibration

To clarify the involvement of the central nervous system in responses of organisms to noise and whole-body vibration, the activity of dopamine (DA) neuron systems was estimated by examining DA turnover rates in various discrete regions of the brains of rats exposed to noise (broad band, 102 dB) or whole-body vibration (20 Hz, 4G) for 90 min. Plasma corticosterone level (COR) was determined simultaneously as an index of stress-induced autonomic-nervous and endocrine functions. Noise and whole-body vibration increased both COR and DA turnover rates (shown by an increase of homovanillic acid (HVA) and/or HVA/DA ratio) in the frontal cortex (FC) and the nucleus accumbens (NAc). Only noise increased the DA turnover rate in the amygdala (AMY). Furthermore, strong positive correlations of the HVA/DA ratios in the FC and the NAc with COR were observed in rats exposed to noise or vibration. These results suggest that the responses of organisms to noise and whole-body vibration may be critically mediated by cerebral DA systems, in particular by the mesocortical DA system, indicating that change of DA in the AMY can be considered a specific response to noise.

Extracellular dopamine increases in the neonatal olfactory bulb during odor preference training

Young rats learn to approach an odor that has been paired with tactile stimulation. This attraction is accompanied by changes in the metabolism and anatomy within the olfactory bulb glomerular layer. In this study, we examined the changes that occur in the olfactory bulb during early olfactory learning, rather than after such pairings have occurred. Specifically, we determined whether the pairing of an odor with tactile stimulation would produce a modified response by olfactory bulb glomerular-layer neurons. To monitor one large subgroup of these neurons during early learning, we used in vivo microdialysis to assess the activity of dopaminergic neurons in the olfactory bulb of postnatal day (PND) 3 rats during simultaneuous presentation of odor and tactile stimulation, tactile stimulation alone, odor alone, or clean air alone. Clean air evokes no change in extracellular dopamine (DA), while both odor alone and stroking alone induce and prolonged increases in DA peaking at about 200% of baseline. The combination of odor and tactile stimulation, which allows an olfactory preference to be formed, induces a prolonged increase in DA which peaks at about 400% of baseline. The level of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) increases only in pups receiving both odor and tactile stimulation and peaks at about 200% of baseline. With the exception of the pups exposed to clean air, all groups show an increase in homovanillic acid (HVA) of between 150–200% following sitmulation. The large and prolonged increase in DA may be linked to the longer term anatomical and physiological changes in the glomerular layer of the bulb that form as a consequence of early olfactory preference training.

Comparison of the effects of repeated oral versus subcutaneous fenfluramine administration on rat brain monoamine neurons: Pharmacokinetic and dose-response data

The importance of the route of drug administration (oral vs. subcutaneous) on the neurochemical effects and pharmacokinetics of repeated d,1-fenfluramine administration in rats (1-24 mg/kg b.i.d., i.e., 2-48 mg/kg/day for 4 days) was examined. Overall, comparable dose-dependent alterations in brain monoamine markers were observed following repeated oral (PO) and subcutaneous (SC) administration of fenfluramine. Doses of 1 and 2 mg/kg fenfluramine were without significant effects on the density of 3H-paroxetine-labeled serotonin (5-HT) uptake sites. Higher doses of fenfluramine (4, 12 and 24 mg/kg) produced dose-dependent decreases in 5-HT, 5-hydroxyindoleacetic acid and 5-HT uptake sites with maximal decreases (80-90%) occurring at the 12 mg/kg dose. Fenfluramine administration produced dose-dependent and biphasic effects on brain dopamine markers with increases in homovanillic acid (HVA) observed at 2 hours, whereas decreases in the levels of dopamine, HVA and dihydroxyphenylacetic acid were evident at 18 hours posttreatment. Norepinephrine levels were only decreased at the highest dose of fenfluramine. Significantly higher levels of brain fenfluramine were observed following SC than following PO administration of the drug. On the other hand, comparable levels of its active metabolite norfenfluramine were present in the brain following the two routes of fenfluramine administration. These data suggest the importance of norfenfluramine levels in the brain in determining the high-dose neurotoxic effects of fenfluramine on brain 5-HT neurons in rats.

Effects of halothane anaesthesia on extracellular levels of dopamine, dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindolacetic acid in rat striatum: a microdialysis study

The effects of halothane anaesthesia on striatal extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5HIAA) were investigated in microdialysis experiments. Induction of anaesthesia was accompanied by a rapid increase in dopamine levels and a slower increase in DOPAC and HVA. 5HIAA was not affected. The reduction of dopamine levels induced by apomorphine 0.05 mg/kg appeared with a shorter latency in conscious rats than in anaesthetised rats but the maximum decrease was unaffected by anaesthesia. The decreases in dopamine and DOPAC induced by alpha-methyl-p-tyrosine 50 mg/kg were affected in opposite directions by halothane: the dopamine reduction was more pronounced while the DOPAC reduction was less pronounced in anaesthetized than in conscious animals. In no case was a qualitative shift in the response observed. It is concluded that halothane may influence the levels of dopamine as well as the response to dopaminergic drugs.

The effect of benserazide on the peripheral and central distribution and metabolism of levodopa after acute and chronic administration in the rat

1. The effects of levodopa alone (50 mg kg-1) and levodopa (10 mg kg-1) plus benserazide (50 mg kg-1) were tested on the levels of dopa, dopamine, 3-methoxytyrosine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), measured by h.p.l.c. with electrochemical detection, in samples of plasma, CSF, urine, striatum and hypothalamus of rats taken 30 min after injection. Levodopa plus benserazide produced significantly higher levels of dopa in plasma and brain than levodopa alone and reduced the peripheral synthesis and metabolism of dopamine. 2. When given chronically over 6 weeks the advantages of adding benserazide (50 mg kg-1 day-1) to levodopa (40 mg kg-1 day-1) were less marked and although more dopamine was present in the striatum than with levodopa given alone (200 mg kg-1 day-1) there was no evidence of any increase in its metabolites (HVA and DOPAC) and therefore of its turnover and utilisation. 3. The most striking effect of chronic treatment with levodopa plus benserazide was the appearance of large quantities of 3-MT in plasma, CSF and brain. 4. When levodopa alone, or levodopa plus benserazide, was given as an acute challenge to animals receiving the same treatment chronically, it was found that levodopa alone still produced increases in striatal dopamine, DOPAC and HVA in those animals dosed chronically on levodopa, but it was less effective in this respect when given with benserazide to the animals dosed with levodopa plus benserazide. 5. It is concluded that this difference in levodopa distribution may depend on the persistence in benserazide-treated animals of 3-MT, which has a long half-life and may compete with dopa for transport into the blood and brain. 6. The implication of these findings to the treatment of Parkinsonism is discussed.

Effects of acute and subacute cocaine administration on the CNS dopaminergic system in Wistar-Kyoto and spontaneously hypertensive rats: I. Levels of dopamine and metabolites

Effects of acute and subacute cocaine administration on dopamine (DA) and its metabolites in striata and nucleus accumbens of nine week-old Wistar-Kyoto and spontaneously hypertensive rats were studied. Levels of DA,3,4-dihydroxphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by HPLC-EC. There were no differences in DA levels in striata and nucleus accumbens between control WKY and SHR. Levels of DA in two brain regions were unaffected in groups treated acutely with cocaine. Both strains showed a significant increase in striatal HVA 2 hr after cocaine injection. Seven day treatment declined DA levels in striatum of WKY and in nucleus accumbens of SHR. However, only WKY treated subacutely with cocaine showed significantly increased HVA either with or without changes in DOPAC in nucleus accumbens and striatum, respectively. Increased DOPAC/DA and HVA/DA ratios appeared only in striatum of WKY and in nucleus accumbens of SHR following subacute treatment. These results suggest that subacute cocaine administration affects DA levels in striata and nucleus accumbens differently between WKY and SHR.

Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle

1. After physical (knife-cut) or chemically-mediated (tetrodotoxin 300 nM, 1.5 microliters; 1.0 microliters min-1) interruption of nerve conduction in the nigrostriatal tract, there was a marked increase in the synthesis and metabolism of dopamine in the isolated dopaminergic nerve terminals of the striatum. The effect peaked at 4 h post-transection, at which time 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased by 300% and 700% respectively (DOPAC: 27 +/- 13 vs 80 +/- 17 nmol g-1; HVA: 6.66 +/- 3.57 vs 54 +/- 18 nmol g-1). The increases in dopamine content and metabolism are secondary to an increase in the rate of synthesis on the lesioned side, versus the intact, control side. 2. In both experimental situations, haloperidol (1.0 mg kg-1, i.p.) retained its known ability to induce a significant increase in DOPAC and HVA in the striatum, despite the interruption of nerve conduction in the nigrostriatal tract. 3. Six days after cutting the left nigrostriatal tract, dopamine in the left striatum was reduced to less than 5% of the control value, and DOPAC and HVA were not detectable. In the denervated, left striatum, the synthesis of dopamine (from injected L-DOPA), and its metabolism to DOPAC and HVA, occurred to the same degree as in the intact right side. In these DOPA-treated rats, haloperidol (1.0 mg kg-1, i.p.) caused a further increase in DOPAC and HVA in the intact striatum, but not in the denervated striatum. 4. Under non-stressful conditions, using a combination of anaesthetic treatments, electrical stimulation (400 muA, 0.4 ins, 15 Hz, 15 min) of the nigrostriatal tract did not increase DOPAC or HVA in the striatum on the stimulated side. 5. It is concluded (a) that there is a significant presynaptic, and/or local circuit mechanism capable of activating the synthesis and metabolism of dopamine in the isolated, striatal, dopaminergic nerve terminals. Furthermore, haloperidol can act directly on the striatal, dopaminergic nerve terminal, to cause an increase in the synthesis and metabolism of striatal dopamine. (b) After degeneration of the striatal dopaminergic nerves, the denervated striatum retains the ability to synthesize (from L-DOPA) and metabolize dopamine, to the same degree as the intact, innervated, contralateral striatum. (c) When stress is minimized, and release of dopamine is induced by electrical stimulation of the medial forebrain bundle, the catabolism of dopamine (to DOPAC and HVA) during the release-uptake cycle may not be a significant factor under physiological conditions. (d) When dopamine synthesis is increased in the striatum, the normal blood concentration of tyrosine is adequate to sustain the increased synthesis, and precursor availability is not a limiting factor. (e) These results suggest that some of the basic concepts about the neurochemical/neurophysiological regulation of monoaminergic neurones may require further reevaluation.

ANTICONVULSANT ACTIVITY OF DI‐N‐PROPYLACETATE AND BRAIN MONOAMINE METABOLISM IN THE RAT

1. Sodium di-n-propylacetate (DPA) treatment induced significant increases in brain contents of gamma-aminobutyric acid (GABA), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). Furthermore, the threshold for pentylenetetrazol (PTZ) clonic convulsions was also increased in response to DPA administration. 2. Pretreatment with inhibitors of monoamine synthesis alpha-methyl-p-tyrosine (AMPT) and p-chlorophenylalanine (PCPA) did not alter the anticonvulsant activity of DPA, but when given alone, both AMPT and PCPA caused significant decreases in brain monoamine contents and PTZ threshold seizures. 3. Experiments using probenecid suggest that the increases in 5-HIAA and HVA seen after DPA treatment could have resulted from inhibition of their active transport out of the brain. These data indicate that the anticonvulsant action of DPA is not dependent on changes in monoamine metabolism in the brain.

Effects of defeat experiences on dopamine metabolism in different brain areas of the mouse

Immediately after a single defeat experience, mice presented significant changes in dopamine (DA) metabolism in frontal cortex (FC), nucleus accumbens septi (NAS), tuberculum olfactorium (TO), septum (SEP), hypothalamus (HYP), amygdala (AMY), and bulbus olfactorius (BO) but not in caudatus putamen (CP). In BO, NAS, and TO, where levels of 3-methoxytyramine (3-MT) were detectable with our analytical methods, the increase of this metabolite suggested an increased DA release. Repeatedly defeated mice (3 days) sacrificed 24 hr after the last defeat experience presented significant increase 3-4-dihydroxyphenylacetic acid (DOPAC) levels in the HYP and a significant decrease in DA levels in the FC, showing only minor effects on DA metabolism 24 hr after the last defeat experience. Finally, mice subjected to three daily defeats and then confronted with environmental cues related to their defeat experiences presented an increase of DOPAC, homovanillic acid (HVA), and 3-MT in the BO, NAS, and TO and an increase of DOPAC and HVA in the HYP. Other brain areas did not show significant changes in DA metabolism compared with undefeated mice exposed to the same environmental cues. Taken together these results strongly suggest that changes in DA metabolism produced by defeat in some brain areas are elicited by environmental cues previously paired with the experience of being defeated.

Specificity of plasma HVA response to dexamethasone in psychotic depression

Earlier reports have suggested that dexamethasone significantly increases levels of plasma homovanillic acid (HVA) in normal subjects, but that this effect may be altered in some depressed patients. To investigate the specificity of such alterations, we administered dexamethasone (1 mg p.o. at 11 p.m.) to 33 normal subjects, 27 depressed patients (8 with psychotic features), and 16 schizophrenic patients. Plasma for assay of cortisol and HVA was obtained at 4 p.m. before and on the day following dexamethasone administration. Dexamethasone induced significant increases in plasma HVA in the normal subjects and in the schizophrenic patients, but not in the depressed patients. Indeed, psychotically depressed patients tended to show a dexamethasone-associated decrease in plasma levels of HVA. In contrast to cortisol “suppression” or “nonsuppression”, dexamethasone-induced changes in plasma levels of HVA (i.e., increases or decreases) sensitively and specifically discriminated between patients with affective and nonaffective psychoses.