Dihydroxyphenylacetic Acid Concentrations Research Articles

Measurement of extracellular basal levels of serotonin in vivo using nafion-coated carbon fibre electrodes combined with differential pulse voltammetry

Carbon fibre electrodes combined with differential pulse voltammetry have been used for a number of years to monitor changes in the extracellular concentrations of ascorbic acid, dihydroxy-phenylacetic acid, and 5-hydroxyindoleacetic acid. However, the primary objective of in vivo electrochemists has been to monitor changes in the extracellular concentrations of the neurotransmitter amines; dopamine and serotonin rather than their metabolites. In this paper we describe a new chemically- and electrically-pretreated Nafion-coated carbon fibre electrode which can be used to monitor basal levels of serotonin in the extracellular fluid in the frontal cortex and the dorsal raphe nucleus of rat. These electrodes combined with differential pulse voltammetry detect dopamine (Peak A at —70 mV) and serotonin (Peak B at +240V) oxidation peaks in vitro but not the oxidation of ascorbic acid, dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid or uric acid, at concentrations up to 10 /gmM. These electrodes were able to detect serotonin concentration as large as 1 nM in vitro. When used in vivo the oxidation peaks obtained in the frontal cortex and dorsal raphe indicate the basal concentrations of serotonin to be 5 nM and 10 nM respectively. Pharmacological interventions in rats implanted with normal carbon fibre electrodes or with Nafion carbon fibre electrodes further demonstrate that the new Nafion electrodes measure serotonin in vivo. The Nafion-coated electrodes therefore may be a useful tool for the study of serotoninergic systems in vivo with the added advantage that they cause minimal damage due to their small tip size (30 μm).

Phenylalanine administration influences dopamine release in the rat's corpus striatum

We used intracerebral dialysis to monitor extracellular levels of dopamine and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum. Levels of these compounds were determined after intraperitoneal administration of phenylalanine (200, 500 and 1000 mg/kg). A dose of 200 mg/kg phenylalanine increased basal dopamine release by 59%, peaking at 75 min. There was no change in basal dopamine release after the 500 mg dose, whereas the 1000 mg/kg dose significantly reduced (26%) dopamine release. No significant changes were observed in the concentrations of DOPAC and HVA with any of the treatments, indicating that changes in brain phenylalanine and tyrosine levels may selectively affect production of the dopamine molecules that are preferentially released into synapses.

An in vitro model of 1-methyl-4-phenyl-pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis.

1. Slices of rabbit caudate nucleus were preincubated for up to 24 h in vitro in the presence of the neurotoxic compound 1-methyl-4-phenyl-pyridinium (MPP+). Subsequently the levels of endogenous monoamines in the slices were determined by h.p.l.c. with electrochemical detection. MPP+, in concentrations higher than 32 nM significantly diminished the dopamine levels within the slices in a concentration- and time-dependent manner; at 32 microM the depletion was more than 95%. The concentration of the major metabolite of dopamine, dihydroxyphenyl acetic acid (DOPAC) was decreased at concentrations of MPP+ that did not alter dopamine levels. Thus, MPP+ increased the dopamine/DOPAC ratio. 2. In contrast, both 5-hydroxytryptamine (5-HT) levels and 5-HT/5-hydroxyindolacetic acid (5-HIAA) ratios were increased at nanomolar concentrations of MPP+. 5-HT was significantly reduced only at 32 microM. 3. The dopamine uptake inhibitor nomifensine reduced the depletory effect of MPP+ on dopamine and DOPAC content. 4. Following 24 h pretreatment with MPP+, the uptake of [3H]-dopamine into rabbit caudate nucleus slices was either enhanced (at 0.32 microM, 1 microM and 3.2 microM MPP+) or reduced (at 32 microM MPP+). 5. Preincubation of slices with 10 microM MPP+ for only 1 h increased their 3H-labelling (in contrast to 24 h pretreatment) whereas after 9 h no net increase was detectable. After 1 and 9 h MPP+ pretreatment, much less deaminated metabolites of [3H]-dopamine were found in the incubation medium of MPP+ treated slices than in the medium of control slices. These findings suggest that MPP+ strongly inhibits the enzyme monoamine oxidase (MAO) within dopaminergic (and 5-hydroxytryptaminergic) terminals before destroying them. 6. To validate the proposed in vitro model functionally, the electrically evoked release of [3H]-acetylcholine ([3H]-ACh) was investigated in MPP+ treated slices and controls. MPP+ reduced both the facilitatory effect of the D2-receptor antagonist domperidone and the inhibitory effect of the catecholamine uptake inhibitor nomifensine on [3H]-ACh release; effects compatible with a diminished inhibitory dopaminergic input on cholinergic neurones. 7. These findings also show that the terminal region of dopaminergic neurones, the caudate nucleus, is a site for MPP+ toxicity. The present in vitro model may be useful for investigating the effects of MPP+ and its interaction with other drugs under defined conditions.

Ro 15-4513, like anxiogenic β-carbolines, increases dopamine metabolism in the prefrontal cortex of the rat

The effects of Ro 15-4513, FG 7142 and β-CCM on the activity of the mesocortical dopaminergic system were examined by measuring the changes in the content of the principal dopamine (DA) metabolite, dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex of the rat. Ro 15-4513 increased the DOPAC content in the prefrontal cortex in a dose-dependent manner (5–40 mg/kg i.p.) but had no effect on DA concentrations. A similar increase in DOPAC content was induced by FG 7142 (40 mg/kg i.p.) and β-CCM (8 mg/kg s.c.), two β-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and β-CCM on DA metabolism in the prefrontal cortex are mediated via benzodiazepine recognition sites, since they were prevented by the administration of the benzodiazepine antagonists Ro 15-1788 and ZK 93426. These data indicate that Ro 15-4513 is an inverse agonist at benzodiazepine recognition sites.

Age-Related Changes in Secretion of Luteinizing Hormone and Metabolism of Hypothalamic Aminies in Bull Calves Prior to Puberty1

Effects of age and castration on secretion of luteinizing hormone (LH) and metabolism of hypothalamic monoamines were determined in Holstein bulls. Calves were assigned to be intact or castrated and killed at 8, 12, or 24 wk of age. Animals were castrated and bled every 10 min for 6 h at 96 and 24 h prior to slaughter, respectively. The stalk median eminence (SME), medial basal (MBH), and anterior-preoptic (AHA-POA) hypothalamic regions were obtained at slaughter and assayed for norepinephrine (NE), dopamine (DA), dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindole-acetic acid (5-HIAA) using high performance liquid chromatography with electrochemical detection (HPLC-EC). Concentrations of LH and testosterone in plasma were determined by radioimmunoassay (RIA). In intact calves, LH pulse frequency (pulses/6 h) increased between 8 and 12 wk (1.4 vs. 3.4) and then declined (1.6 at 24 wk of age). Frequency of LH discharges did not change during the first 72 h post-castration in calves 8 (1.4 vs 1.0) and 12 (3.4 vs. 3.8) wk of age, but increased in 24-wk-old calves during this time (1.6 vs. 6.4). The amplitude of LH pulses increased with age (p less than 0.05) and after castration (p less than 0.05). There were marked regional differences in concentrations of monoamines. However, effects of age and castration on concentrations of monoamines were observed only within the SME where DA, DOPAC and NE increased significantly with age. Plasma concentrations of testosterone were correlated with concentrations of NE and DOPAC within the SME. Changes in 5-HT with age were biphasic; at each age, 5-HT increased after castration. From these data, it is concluded that 1) different mechanisms regulate LH pulse frequency and amplitude in calves as early as 8 wk of age, and 2) differences in hypothalamic metabolism of monoamines may be related to maturational changes in secretion of LH in bull calves.

Dopamine neurochemical profile of atypical antipsychotics resembles that of D-1 antagonists

The release and metabolism of dopamine in the mouse caudate-putamen were determined after the oral administration of antipsychotic drugs at doses equal to or sixfold greater than the ED50 dose for their inhibition of apomorphine-induced climbing. Dopamine release was equated with concentrations of 3-methoxytyramine (3-MT) and metabolism was equated with concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Like the D-1 antagonists SCH 23390 and SKF 83566, most antipsychotic agents with an atypical preclinical profile suggestive of low extrapyramidal symptomatology (CGS 10746B, flumezapine, CL 77328, rimcazole, clozapine, RMI 81582, and fluperlapine) never increased dopamine release and produced variable increases in dopamine metabolism. Other atypical antipsychotics (thioridazine, mesoridazine, melperone) increased dopamine release at only one dose tested but increased dopamine metabolism at most doses. Antipsychotic agents associated with extrapyramidal side effects (setoperone, perlapine, haloperidol, chlorpromazine, and metoclopramide) increased dopamine release and metabolism at almost every dose tested. Thus, atypical antipsychotics increase the metabolism but not release of dopamine at behaviorally effective doses. The resemblance of these minimal effects on dopamine release to those obtained with D-1 antagonists that also have an atypical preclinical profile suggests that a mechanism related to D-1 receptor antagonism may contribute to the action of atypical antipsychotics.

Changes in neurotransmitter turnover in locus coeruleus produced by changes in arterial blood pressure

The effect of drug-induced hypertension and hypotension on neurotransmitter metabolism in the locus coeruleus (LC) of urathen anesthetized rats ws studied using in vivo electrochemical methods. Peaks were seen at +0.15 V and +0.28 V. Studies with alpha-methylparatyrosine, fusaric acid and pargyline showed the first peak was produced by extracellular fluid dihydroxyphenylacetic acid (DOPAC) while the second peak was 5-hydroxyindoleacetic acid (5-HIAA). Phenylephrine was infused intravenously to raise the blood pressure by 50 mmHg, nitroprusside IV was used to reduce the blood pressure by 20 mmHg. During phenylephrine hypertension, the electrochemical signal for DOPAC showed an initial small reduction followed by a later significant increase which persisted even after the infusion was stopped. The signal for 5-HIAA rose with the onset of hypertension and remained elevated. Nitroprusside hypotension did not change the DOPAC peak but did lead to an immediate and persistent increase in the electrochemical 5-HIAA peak. To confirm the electrochemical findings, other groups of rats were decapitated during and after hypertensive and hypotensive drug infusions and the LC was assayed for norepinephrine, dopamine, DOPAC, serotonin, and 5-HIAA using HPLC with electrochemical detection. Changes in tissue DOPAC and 5-HIAA concentrations supported the electrochemical electrode observations. The effect of clonidine on the electrochemical recordings from LC was also studied. Clonidine reduced the catechol peak. No change was observed in the 5-HIAA peak during the infusion, but the 5-HIAA peak went up after the infusion was stopped. These experiments show that hypertension, hypotension, and alpha-2 agonists lead to changes in catecholamine and indoleamine metabolism in LC.

Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered methylenedioxymethamphetamine (MDMA)

MDMA is an amphetamine analog prescribed by some health professionals in the field of psychotherapy and used as a recreational drug by the general public. In recent reports, investigators have suggested that MDMA produces acute neurotoxicity when administered by subcutaneous injection. In order to determine if MDMA produces lasting neurochemical alterations after oral administration, groups of six rats (adult male Sprague-Dawley) were dosed by gavage with either 40 or 80 mg/kg of MDMA or saline vehicle once every 12 hr for 4 days. These rats were terminated 2 weeks after the first dose along with an additional group of rats (80 mg/kg) terminated 4 weeks after the first dose. Brain regions including the hippocampus (H), caudate nucleus (CN), hypothalamus (HY), frontal cortex (FC), and brain stem (BS) were analyzed by HPLC with electrochemical detection for concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE). In the CN, 40 mg/kg MDMA produced no change in DA, DOPAC, or HVA, but a 50–60% decrease in 5-HT and 5-HIAA concentrations was observed at 2 weeks. Similar effects were observed at 80 mg/kg at both 2 weeks and 4 weeks. A temporary decrease was also seen in DA (21%) and in HVA (34%) 2 weeks but not 4 weeks after the 80 mg/kg dose regimen. In the H, MDMA (40 or 80 mg/kg) produced no change in NE, but a 50–60% decrease was seen in 5-HT and 5-HIAA concentrations at 2 weeks. Concentrations of 5-HT and 5-HIAA were significantly decreased in the HY and FC by all MDMA treatments, but DA and DOPAC concentrations were not altered as compared to vehicle controls. BS was least affected by treatment with no change in DA, DOPAC, or 5-HIAA concentrations and only a slight decrease in 5-HT (19–33%) concentrations at 2 weeks but not at 4 weeks. To determine the sensitivity of the nonhuman primate to MDMA, a total of nine rhesus monkeys were dosed with vehicle or 5 or 10 mg/kg MDMA ( n = 3) by gastric intubation twice per day for 4 days. One month after MDMA dosing, a dose-related reduction from vehicle control values for 5-HT and 5-HIAA was observed. These results indicate that the monkey may be more sensitive than the rat to the persistent serotonergic neurotoxicity of MDMA. Histological assessment in the rat with a stain specific for degenerating fibers and terminals 18 hr after a single treatment with MDMA (40 and 80 mg/kg, po) indicated a significant enhancement of the density of silver-impregnated terminals in the CN as compared to vehicle controls. Selective reductions in brain 5-HT and 5-HIAA concentrations, along with histologically observed neuronal degeneration, suggest that orally administered MDMA produces selective destruction of serotonergic nerve terminals.

Intraventricular microdialysis: a new method for determining monoamine metabolite concentrations in the cerebrospinal fluid of freely moving rats

A new method is described to estimate the cerebrospinal fluid (CSF) concentrations of monoamine metabolites (dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) in the lateral ventricle of freely moving rats by use of in vivo microdialysis. Both the baseline concentrations of these metabolites and the rate of dopamine (DA) turnover (estimated by the accumulation of total DA metabolites after 200 mg/kg probenecid) were within the range reported when other methods were used to sample CSF. A series of preliminary studies were conducted to demonstrate that this method can be used to repeatedly sample CSF, and to show that the method is sensitive to local changes in dopaminergic activity induced by lesions, drugs or grafts. (1) Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra produced a significant decrease in the CSF concentrations of DOPAC and HVA ipsilateral to the lesion, relative to the contralateral side or to concentrations in animals without lesions. (2) When left and right lateral ventricles were sampled simultaneously in animals with a unilateral 6-OHDA lesion, haloperidol induced an increase in DOPAC and HVA concentrations in CSF on both sides of the brain. Interestingly, the haloperidol-induced increase in CSF concentrations of DA metabolites was greater adjacent to the intact striatum of rats with unilateral 6-OHDA lesions than in animals with no lesion. (3) Finally, in animals with adrenal medulla tissue grafted into the lateral ventricle there was an increase in the CSF concentration of DOPAC compared to pregraft values or to those of animals with control grafts.

Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats

It has been hypothesized that striatal dopamine (DA) terminals undergo compensatory changes in response to partial damage of the mesostriatal DA system, which results in higher concentrations of DA in the extracellular space than would be predicted by DA concentrations in post-mortem tissue. But, this hypothesis has never been tested directly in vivo, and therefore, the present study was designed to do so. Microdialysis was used in freely moving rats to estimate the concentrations of DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in striatal extracellular fluid; simultaneously from the hemisphere with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra and from the intact hemisphere. It was found that following recovery from a 6-OHDA lesion, and during the resting state, the extracellular concentrations of DA were normal on the lesion side, even after that side was depleted of up to 99.0% of the DA measured in post-mortem tissue. Furthermore, the extracellular concentrations of DA were elevated in the intact hemisphere of animals with a >95% DA depletion. In rats with a <95% DA depletion amphetamine (1.5 mg/kg) caused a large increase in the extracellular concentration of DA in both the lesion and intact hemispheres (intact > lesion), but in rats with a > 95% tissue DA depletion amphetamine only enhanced extracellular DA on the intact side; on the lesion side amphetamine produced a progressive decrease in extracellular DA to nondetectable levels. Animals rotated towards the lesion side. Unlike DA, the extracellular concentrations of DOPAC and HVA were greatly reduced on the lesion side, and the extent of the depletion was highly correlated with lesion size. It is concluded that following partial unilateral damage to mesostriatal DA projections there are massive changes in the remaining DA terminals that are sufficient to normalize the extracellular (and presumably synaptic) concentrations of DA. The normalization of extracellular DA concentrations seen after extensive (but incomplete) damage to the mesostriatal system must play a major role in the sparing and recovery of behavioral function that is so characteristic of this system. After extensive damage the capacity of the remaining DA neurons to respond to increased demand is limited, however, and this may explain why behavioral deficits can be reinstated by stimuli that challenge the system.

Neurochemical effects of cyclopiazonic acid in chickens.

Chickens dosed (per os) with cyclopiazonic acid (CPA) at 0.5, 5.0, and 10 mg/kg body weight showed significant (P less than or equal to 0.05) increases in brain dopamine and serotonin concentrations 96 hr after dosing. The increases coincide with significant decreases in homovanillic acid and subtle increases of dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid concentrations. The elevated dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid concentrations may be related to the elevated concentrations of dopamine and serotonin, respectively. The observed changes in neurotransmitter/metabolite concentrations 96 hr after dosing parallel elimination of CPA from the birds skeletal muscles; however, they do not correlate with the significant weight losses in these birds at 48 and 96 hr after dosing. The brain weights of the treated birds were statistically insignificant from their respective controls, although increases in brain weight-body weight ratio within treatments and with time correlated with CPA toxicity. No significant changes were observed in dopamine, dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid concentrations among the treatments at 3, 24, and/or 48 hr after dosing.

Intranigral injection of dynorphin in combination with substance P on striatal dopamine metabolism in the rat

The effects of intranigral injection of dynorphin(1–13), substance P and their combination on striatal dopamine (DA) metabolism as well as circling behavior were studied in rats. Dynorphin(1–13) produced a significant dose-dependent increase of dihydroxyphenyl acetic acid (DOPAC) concentration as well as the number of contralateral circling. No change in dopamine (DA) concentration was observed. Substance P caused a dose-dependent increase of DOPAC concentration. At large doses it also produced an increase in DA concentration. Combined intranigral dynorphin(1–13) and substance P brought about an additive effect for the increase of DOPAC and the number of contralateral circling. No additive effect was found when dynorphin(1–13) and neurokinin A were injected together intranigrally.

Relation between brain dopamine loss and D2 dopamine receptor density in MPTP monkeys.

The relationship between dopamine (DA), dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA) concentrations and [3H]spiperone binding to D2 DA receptors in caudate nucleus, putamen and nucleus accumbens following DAergic lesion with MPTP in monkeys was investigated. The level of DA depletion varied from 37% to 100% while a mean elevation in [3H]spiperone binding density of 114.8 +/- 4.7% of control (P less than 0.01) was observed when DA depletion was at least 90% of control values. A logarithmic correlation (y = -7.19 In x +111.15; r = -0.54, P less than 0.01) between DA concentrations (x) and the density of [3H]spiperone binding sites (y) was observed in all brain regions. The correlation between DOPAC or HVA concentrations and [3H]spiperone binding was best represented by linear rather than logarithmic equations. These results indicate that supersensitivity of DA receptors develops after MPTP lesion in monkeys when the number of remaining nerve fibers becomes too few to compensate for the DA loss.

Concurrent on-line analysis of striatal ascorbate, dopamine and dihydroxyphenylacetic acid concentrations by in vivo voltammetry

A new method for on-line analysis of in vivo differential normal pulse voltammograms is reported. They are fitted by least squares to an expression describing the contribution of different electroactive species and the baseline. Its validity for resolving ascorbate (AA), dopamine (DA) and DOPAC signals is evidenced by both in vitro testing and the changes recorded in the striatum of anesthetized rats following drug treatments having well-known effects on DA release and metabolism. Thus, pargyline and amphetamine treatments respectively increased and decreased DA and DOPAC, whereas they both were increased by haloperidol. AA levels followed those of DA except when haloperidol was given.

Modulation of neurotransmitter metabolism by dihydropyridine calcium channel ligands in mouse brain

The regional concentrations of dopamine, serotonin, dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindole acetic acid were measured in mouse brain following administration of the dihydropyridine calcium channle activator BAY K 8644, and antagonist, nifedipine. BAY K 8644 (1–8 mg/kg) produced dose- and time-dependent increases in dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid concentrations in the caudate, without altering dopamine and serotonin levels. No changes in 5-hydroxyindoleacetic acid concentration were observed in the raphe nuclei, hypothalamus, hippocampus and frontal cortex. Nifedipine (4 mg/kg) blocked BAY K 8644- (2 mg/kg) elicited increases in dihydroxyphenylacetic acid in the caudate. Furthermore, a higher dose of nifedipine (8 mg/kg) decreased dihydroxyphenylacetic acid and homovanillic acid, but did not affect dopamine, serotonin or 5-hydroxyindoleacetic acid concentrations, while a lower dose of nifedine (2 mg/kg) significantly increased serotonin, 5-hydroxyindoeleacetic acid and homovanillic acid, but did not affect dopamine and dihydroxyphenylacetic acid concentrations. The findings that both BAY K 8644 and nifedipine affect neurotransmitter metabolism in vivo in a dose- time- and brain region-dependent manner, suggest that high-affinity dihydropyridine calcium channel binding sites play an important role in regulating neurotransmitter turnover in the central nervous system.

Prolactin-induced yawning behavior requires an intact nigro-striatal dopamine system

Herein, we evaluate the importance of the nigro-striatal dopamine system in prolactin-, apomorphine-, and physostigmine-induced yawning behavior. Bilateral 6-OH-dopamine lesions of the substantia nigra were performed on male rats (2–4 months old). The lesioned as well as control rats were injected with either physiological saline, physostigmine (200 μg/kg), apomorphine (50 μg/kg), or ovine prolactin (0.25 μg/kg) 72 hours after the surgical procedure. The results show that bilateral lesions of the substantia nigra did not affect physostigmine-induced yawning whereas both apomorphine- and prolactin-induced yawning were reduced by the lesion. Following the observation period the caudate nuclei were removed and analyzed for dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) content. The lesions reduced DA and DOPAC content in all treatment groups compared to the respective intact groups. Also, both DA and DOPAC concentrations were lower in the intact apomorphine and prolactin treated groups compared to intact saline controls, at times that were temporally related to the display of yawning behavior suggesting a decrease in dopamine activity following apomorphine and prolactin treatment. Interestingly, DA and DOPAC concentrations were higher in the lesioned apomorphine group compared to lesioned saline controls; however, in the lesioned prolactin group only the DA concentrations were higher when compared to lesioned saline controls. These results indicate that prolactin- and apomorphine-induced yawning require an intact nigro-striatal dopamine system and that these substances induce yawning by different mechanisms.

Systemic 1-methyl, 4-phenyl, 1-2-3-6-tetrahydropyridine (MPTP) administration decreases retinal dopamine content in primates

Following MPTP administration, 4 Cynomolgus monkeys developed a parkinsonian syndrome, accompanied by specific changes of both pattern visual evoked potential and electroretinogram. Retinal dopamine and dihydroxyphenylacetic acid contents were measured in the 4 MPTP-treated monkeys and in 3 normal monkeys. Dopamine and dihydroxyphenylacetic acid levels were significantly lower in the retinas of the MPTP-treated animals (p<0.001), suggesting that dopamine has a specific function in the visual system of primates.

Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens

The hypothesis that the dopaminergic system plays a role in feeding behavior was tested in three experiments. First, microdialysis was performed in the nucleus accumbens (NAC) at 20 min intervals during free feeding in rats at 80% of normal body weight. Extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) increased significantly during eating indicating an increase in DA turnover. Second, microdialysis samples were collected from the NAC during bar pressing with a) a signal light on and food available, b) the light on but no food available, c) neither light nor food. Only when food was available did extracellular DA, DOPAC and HVA increase significantly. This increase in DA turnover occurred in the accumbens but not in the ventral striatum. Third, electrical stimulation of the perifornical lateral hypothalamus (LH) that was capable of inducing feeding increased extracellular DA, DOPAC and HVA in the NAC. This occurred whether the animal had food to eat or not. The effect of LH stimulation on DA turnover resembled the effects of free feeding and operant feeding in Experiments 1 and 2. Perifornical LH stimulation did not increase dopamine turnover in the ventral striatum. The results show that perifornical LH stimulation activates the mesolimbic dopamine system and that dopamine release in the accumbens is involved in feeding. The increase in dopamine turnover outlasted the consummatory act. This suggests that accumbens dopamine may be related to sensory input, feeding reflexes, food reward or memory processes and not just to the consummatory act itself.

Chronic morphine and testosterone treatment. Effects on sexual behavior and dopamine metabolism in male rats.

The effects of sustained delivery of morphine and/or testosterone (T) on male rat copulatory behavior, penile reflexes and dopaminergic metabolism in selected brain regions were examined. Castration was followed by (1) a decrease in the number of male rats exhibiting intromissive and ejaculatory behavior in mating tests, (2) decreased erections in ex copula tests, and (3) increases in dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations in the mediobasal hypothalamus (MBH) and the preoptic area-anterior hypothalamus (POA-AH). The decreased incidence of copulatory behavior and penile reflexes seen after castration was effectively prevented by a 4-day treatment with 5-mm T-containing Silastic capsules. Chronic morphine implants, conversely, accentuated the castration-induced decrements in copulatory behavior and prevented the 5-mm-T-induced facilitation, but did not alter the number of animals displaying erection (although the number of erections displayed by testosterone-treated rats was reduced) in ex copula tests. Treatment of castrated rats with 5 mm T, but not morphine alone, nor the combination of 5 mm T plus morphine, significantly reduced dopamine and DOPAC levels in the MBH. In the POA-AH, 5 mm T was without effect, whereas morphine, alone or in combination with 5 mm T, reduced the levels of dopamine and DOPAC. These data suggest that (1) the decline in sexual behavior induced by chronic morphine is primarily due to a failure of sexual arousal, and not of erectile ability, and (2) although the decline in sexual activity seen after castration is associated with alterations in dopaminergic metabolism, the effects of morphine and testosterone on sexual activity are opposite and dissociated from alterations in dopaminergic metabolism.

Chapter 68 Neurochemical correlates of behavioral changes following intraventricular adrenal medulla grafts: intraventricular microdialysis in freely moving rats

Publisher Summary This chapter describes the neurochemical correlates of behavioral changes by measuring concentrations of monoamine metabolites in cerebral spinal fluid (CSF) using microdialysis in freely moving rats before and after intraventricular grafts of adrenal medulla or control tissue. The data indicates that adrenal medulla grafts in the lateral ventricle induce a change in dopaminergic activity in vivo. Dopamine (DA) turnover is increased in animals with adrenal medulla grafts indicated by: (1) an increase in CSF concentrations of dihydroxyphenylacetic acid (DOPAC), (2) a greater response to amphetamine sulfate (AMPH), and (3) a greater rate of DA metabolite accumulation following probenecid. If an adrenal medulla graft is effective in reducing AMPH-stimulated rotational behavior, then the concentrations of DA in the striatum adjacent to the graft are significantly elevated compared to control animals and relative to the graft. This increase in striatal DA concentrations reflects an increase in the functional capacity of striatal DA neurons is supported by preliminary findings that AMPH stimulates DA release from the striatum of animals with adrenal medulla grafts, but not in animals with adrenal cortex grafts.