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.     

Comparison of changes in locomotor activity with striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations following the bilateral intranigral injection of dopamine agonist drugs in rats

Bilateral injection of apomorphine (2.5 micrograms) into the substantia nigra zona reticulata of rats reduced both locomotor activity and striatal HVA and DOPAC concentrations. Bilateral injection of dopamine (10 micrograms) did not affect locomotor activity whereas a higher dose of dopamine (50 micrograms) enhanced locomotor activity. Striatal HVA and DOPAC concentrations were unchanged following injection of dopamine. Bilateral injection of (+/-)-3PPP (0.1 or 2.5 micrograms) into the zona reticulata of the substantia nigra did not alter locomotor activity while a higher dose (10 micrograms) enhanced locomotion. Injection of (+/-)-3PPP (0.1-10 micrograms) into the zona reticulata was without effect on striatal HVA or DOPAC concentrations. The bilateral manipulation of nigral dopaminergic neurotransmission alters motor activity and nigrostriatal dopamine turnover in conscious rats. However, the changes in motor activity are not necessarily related to altered nigrostriatal activity, suggesting the involvement of dopamine receptors located at non-dopaminergic sites within the substantia nigra.     

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

The effects of Ro 15-4513, FG 7142 and beta-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 beta-CCM (8 mg/kg s.c.), two beta-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and beta-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.     

Failure by tricyclic antidepressants to affect the increase of dopamine extracellular concentrations produced by haloperidol in the caudate and accumbens nuclei of rats.

The effect of different inhibitors of monoamine uptake on dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) neuronal outflow was studied in the caudate and accumbens nuclei of rats, using the in vivo brain microdialysis method coupled to HPLC electrochemical detection. Under conditions of DA receptor blockade (as produced by the i.p. administration of 0.25 mg/kg of haloperidol), cocaine, GBR-12909 and d-amphetamine increased the concentration of extracellular DA beyond the effect produced by haloperidol alone in both areas studied. GBR-12909 and cocaine also increased DOPAC concentration, while d-amphetamine decreased it. On the contrary, the tricyclic antidepressants (TCA), desipramine and chloripramine, failed to modify the effect of haloperidol on DA and DOPAC neuronal outflow. It was concluded that: (a) nonadrenergic and serotonergic nerve terminals do not take up DA released from dopaminergic neurons, and (b) TCA have no effect on dopaminergic terminals.     

Behavioral and neurochemical correlates of morphine and hypoxia interactions

Decreased oxygen availability (hypoxia) impairs the synthesis of dopamine and serotonin in parallel with a decline in open-field behavior. If hypoxic-induced deficits in dopamine and serotonin metabolism are physiologically important, then stimulation of their synthesis may help reverse hypoxic-induced neurochemical and behavioral deficits. Acute morphine sulfate (50 mg/kg) increased dihydroxyphenylacetic acid/dopamine ratios (DOPAC/DA) (+20%), the conversion of [3H]tyrosine to [3H]dopamine (+73%) and open-field activity (+130%) in CD-1 male mice. However, morphine failed to significantly alter the incorporation of [3H]tryptophan to [3H]serotonin. Morphine antagonized the hypoxic-induced impairment of dopamine metabolism and locomotor activity. DOPAC/DA ratios of hypoxic animals that were treated with morphine were identical to controls, and conversion rates of [3H]tyrosine to [3H]dopamine were increased. Total distance in an automated activity monitor following the combination of morphine and hypoxia increased 79% compared to a 48% decrease with hypoxia alone. These results suggest that both hypoxia and morphine alter the dopaminergic system, but in opposite directions. These interactions may help to explain why morphine is able to ameliorate hypoxic-induced changes in behavior.     

Food-related stimuli increase the ratio of 3,4-dihydroxyphenylacetic acid to dopamine in the hypothalamus

Rats were restricted for three weeks to a schedule of 4-hr daily access to food. The regional concentrations of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the forebrain were then determined after the rats: (1) were food-deprived overnight; (2) ate for the first hour of the scheduled feeding period; or (3) remained in their cages without receiving food but while other rats fed. A group of controls had food available continuously. The DOPAC/DA ratio, a metabolic index of DA activity, increased in the hypothalamus of rats that fed and in the rats exposed to food-related stimuli without eating. This ratio did not change in the striatum, olfactory tubercle, amygdala-pyriform lobe or nucleus accumbens. Furthermore, this index did not differ from controls in any region of the forebrain in deprived rats that were not exposed to stimuli signalling the availability of food. Together, these data suggest that environmental stimuli associated with feeding after deprivation, and not the act of feeding, increased dopaminergic activity in the hypothalamus.     

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.     

Enhanced motor activity and brain dopamine turnover in mice during long-term nicotine administration in the drinking water

Nicotine was administered chronically to NMRI mice in their drinking water in gradually increasing concentrations to measure gross motor activity and brain nicotine concentrations over 24 h on the 50th day of nicotine administration. Also, the striatal postmortem tissue concentrations and accumbal extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured to study the role of dopaminergic systems in nicotine-induced hyperactivity in mice. The cerebral nicotine concentration was at its highest at the end of the dark period. The activity of nicotine-treated mice and their striatal DA metabolism were parallelly increased at 2 to 3 h after midnight and in the forenoon. Microdialysis experiments carried out in the forenoon showed that the extracellular levels of DA and DOPAC were elevated in the nucleus accumbens of these mice. Nicotine did not alter the circadian rhythmicity of activity in the mice. Rather, our findings suggest that the mice consume more nicotine when active and this might lead to enhanced release and metabolism of DA and further, to enhanced motor behavior. These findings support the suggestions that nicotine's effects on limbic and striatal DA are critical for its stimulating effects.     

Glucocorticoid effects on mesotelencephalic dopamine neurotransmission.

Multiple neurochemical estimates were used to examine peripheral corticosterone (CORT) effects in dopaminergic terminal regions. Acute CORT administration, which elevated plasma CORT (5 h), slightly decreased dihydroxyphenylacetic acid (DOPAC) to dopamine (DA) ratios in the striatum but not in other regions examined. Two weeks of adrenalectomy (ADX) increased both medial prefrontal cortex DOPAC/DA and homovanillic acid (HVA)/DA and striatal HVA/DA. A reciprocal pattern of changes was observed with CORT replacement in ADX animals. In contrast, CORT replacement in ADX animals did not significantly influence tyrosine hydroxylase content, basal dihydroxyphenylalanine (DOPA) accumulation after NSD 1015 treatment or the decline in DA after alpha-methyl-para-tyrosine, suggesting that neither DA neuronal activity nor release are altered by CORT. Moreover, neither gamma-hydroxybutyric acid lactone-induced increases in DOPA accumulation or stress-induced increases in DA utilization were influenced by CORT replacement, indicating that neither autoreceptor regulation of DA synthesis nor acute stress regulation of DA utilization are changed by CORT. The findings are most consistent with direct inhibition of basal DA metabolism in the medial prefrontal cortex and striatum. The possible physiological and behavioral significance of this inhibition is being further explored.     

Long-term social isolation and medial prefrontal cortex: dopaminergic and cholinergic neurotransmission

Rearing rats in social isolation has been suggested as an animal model of schizophrenia, based mainly on the similarity between the attenuation of prepulse inhibition (PPI) in isolated rats and in schizophrenic patients. The medial prefrontal cortex (mPFC) plays a major role in the pathophysiology of schizophrenia. Thus, a postmortem micropunch analysis measuring dopamine (DA), DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) in the dorsal and ventral subregion of the mPFC, the caudate putamen (CPu) and nucleus accumbens (NAc) was carried out on socially isolated or group-housed male Sprague-Dawley (SD) rats. Additionally, in vivo microdialysis with D-amphetamine (1 mg/kg ip) stimulation was performed in isolated animals and their controls, examining the ventral mPFC for acetylcholine (ACh), DOPAC and HVA levels. Simultaneously, recording of motor activity was performed. In the neurochemical postmortem tissue analysis we found no difference in any of the brain regions tested between isolated and group-reared animals. Amphetamine increased ACh levels in the mPFC, induced a decrease in DOPAC and HVA levels, and increased motor activity. A close to significant Drug x Housing interaction reflected the fact that the amphetamine-induced decrease of DOPAC was confined to the group-housed animals. In conclusion, social isolation leads only to moderate changes in the dopaminergic system in the mPFC, whereas the cholinergic system remains unaffected.     

Caerulein peripheral injection: a study on the correlation with dopaminergic metabolism

Immunocytochemical and electrophysiological studies indicate the existence of a functional relationship between Cholecystokinin (CCK) and dopaminergic transmission. In order to gain more information on this relationship, the effect of Caerulein, a CCK stable analogue, on rat spontaneous locomotor activity and on biochemical markers of dopaminergic transmission were measured simultaneously. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and the spontaneous or K+ evoked release of dopamine were studied in rat striatum and nucleus accumbens immediately after testing for motor activity. An almost complete reduction in locomotor activity but not significant changes in DOPAC content and dopamine release were observed in rats injected with the peptide (0.25/microgram/Kg, intraperitoneally). DOPAC concentrations were slightly (30%) decreased by increasing 200 folds caerulein dose. In addition, a very minute dose of haloperidol (25 /microgram/Kg) potentiated the caerulein (0.25/microgram/Kg) induced hypomotility, while the parameters of dopaminergic metabolism were unaffected. Our results indicate the existence of a relevant pharmacological interaction between caerulein and dopamine antagonists, although it is not clear whether this interaction takes place at the dopamine terminals level.     

Partial lesions of the nigrostriatal pathway in the rat. Acceleration of transmitter synthesis and release of surviving dopaminergic neurones by drugs

In rats with partial, unilateral lesions of the dopaminergic nigrostriatal pathway, synthesis of dopamine (DA) per surviving neurone was assessed by measuring the ratio of DOPA accumulated after inhibition of aromatic amino acid decarboxylase to dopamine (DOPA/DA ratio). Release of DA per surviving neurone was assessed by measuring the ratios of the concentrations of 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) to DA. In striata ipsilateral to the lesion, the DOPA/DA ratio was elevated 4-fold, and the DOPA/DA and HVA/DA ratios were elevated 2-fold as compared to values in contralateral striata. Administration of gamma-butyrolacetone (750 mg/kg, 30 min), i.e. of a drug which accelerates synthesis of DA, further increased the DOPA/DA ratio in lesioned striata to levels 37 times higher than those measured on the control side of saline-injected controls. Morphine (20 mg/kg, 30 min) and haloperidol (2.5 mg/kg, 60 min), i.e. drugs known to accelerate the turnover and release of DA, further elevated the DOPAC/DA and HVA/DA ratios in lesioned striata to levels approx. 5 times higher than the ratios measured on contralateral sides of saline-treated controls. The data indicate that dopaminergic neurones surviving partial lesions of the nigrostriatal pathway synthesize and release DA at an elevated but submaximal rate. Synthesis and release of DA can be further enhanced to a large extent by drugs.     

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.     

Time-course of the effects of ovarian steroids on the activity of limbic and striatal dopaminergic neurons in female rat brain

This paper studies the time-course of the effects of pharmacological administrations of ovarian steroids on the functional state of dopaminergic terminals in the striatum and the limbic forebrain, using the ratio between the contents of dopamine (DA) and its metabolite, L-3,4 dihydroxyphenylacetic acid (DOPAC), as an index of nerve activity. Estradiol produced an increase in the dopaminergic activity of both limbic and striatal neurons, reflected in the high DOPAC/DA ratio observed in both areas. This estrogenic effect was only observed at 4 hours, disappearing in the subsequent times studied. The effect was antagonized by progesterone in both tissues, since a single injection of this steroid to estrogen-pretreated rats restored to control values the estradiol-induced increase, suggesting the existence of negative interactions between both steroids. Furthermore, treatment with progesterone produced also a late decrease of the DOPAC/DA ratio in the striatum, which was observed only in the animals nonpretreated with estrogens.     

Early Minocycline Treatment Prevents a Decrease in Striatal Dopamine in an SIV Model of HIV-Associated Neurological Disease

HIV-infected individuals, even with antiretroviral therapy, often display cognitive, behavioral and motor abnormalities and have decreased dopamine (DA) levels. Minocycline prevents encephalitis and neurodegeneration in SIV models, suggesting that it might also protect against nigrostriatal dopaminergic system dysfunction. Using an SIV/macaque model of HIV-associated CNS disease, we demonstrated that striatal levels of DA were significantly lower in macaques late in infection and that levels of the metabolite DOPAC also tended to be lower. DA levels declined more than its metabolites, indicating a dysregulation of DA production or catabolism. Minocycline treatment beginning at 12 but not 21?days postinoculation prevented striatal DA loss. DA decline was not due to direct loss of dopaminergic projections to the basal ganglia as there was no difference in tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 or synaptophysin between minocycline-treated and untreated macaques. SIV-infected macaques had significantly higher monoamine oxidase (MAO) activity than uninfected macaques, although MAO activity was not affected by minocycline. Oxidative/nitrosative stress was examined by nitrotyrosine staining in the deep white matter and was lower in SIV-infected, minocycline-treated macaques compared with untreated macaques. These data suggest that minocycline, which has antioxidant activity, has a protective effect on DA homeostasis when administered at an appropriate time in SIV neuropathogenesis.     

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 some antioxidative aporphine derivatives on striatal dopaminergic transmission and on MPTP-induced striatal dopamine depletion in B6CBA mice.

(S)-(+)-boldine, an aporphine alkaloid displaying antioxidative and dopaminergic properties, and six of its derivatives (glaucine, 3-bromoboldine, 3-iodoboldine, 8-aminoboldine, 8-nitrosoboldine and 2,9-O,O'-dipivaloylboldine) were tested for these properties in comparison with their parent compound. All the tested compounds displayed in vitro antioxidative properties equal to or slightly weaker than those of boldine, and equal to or stronger than (+/-)-6-hydroxy-2,5,7,8,-tetramethylchromane-2-carboxylic acid (Trolox), a water-soluble vitamin E analogue, used as a reference compound. All the aporphine compounds tested displaced [3H]SCH 23390 and [3H]raclopride from their specific binding sites in rat striatum. When tested on dopamine (DA) metabolism in the striatum of B6CBA mice, all the compounds, except 8-aminoboldine, increased striatal levels of DOPAC and HVA, and the HVA/DA ratio, indicating that they cross the blood-brain barrier and that they seem to act as dopamine antagonists in vivo. B6CBA mice were sensitive to the neurotoxic action of MPTP on dopaminergic neurons as indicated by the strongly decreased striatal levels of DA, DOPAC and HVA following administration of MPTP (20 mg/kg, i.p.). Among these aporphine derivatives, only 3-bromoboldine was able to reduce the MPTP-induced decrease of striatal levels of DA and DOPAC, whereas (R)-apomorphine (5 mg/kg, s.c.) and acetylsalicylic acid (100 mg/kg, i.p.), used as reference compounds, were very active. These data suggest that potent in vitro antioxidative properties and the ability to cross the blood-brain barrier are not sufficient criteria to predict the inhibition of neuronal degeneration induced by MPTP.     

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.     

Regulation of psychomotor functions by dopamine: integration of various approaches

(1)The basal ganglia circuitry mediates a wide rage of brain functions such as motor control, behavioral planning, and reward prediction. Dopamine (DA) transmission plays an essential role in the regulation of these brain functions. DA action not only regulates the firing activity of target neurons but also is involved in the pattern formation of their firing. The striatopallidal neurons containing dopamine D(2) receptor plays a dual role in motor coordination dependent on DA transmission. (2)Activation of presynaptic D(2)-like receptors on GABAergic terminals onto striatal cholinergic interneurons selectively blocks N-type Ca(2+) channels, thereby inhibiting GABA release. In addition, contribution of N-type channels and D(2)-like receptor-mediated presynaptic inhibition decreases in parallel with development, implying some relationship between basal ganglia-related function or dysfunction and age. (3)As an approach to determine dopamine neuronal activity, we monitored neuronal activities by measuring cytosolic Ca(2+) concentration in VTA dopamine neurons. The present study indicates that VTA dopamine neurons are the direct targets of orexin-A and psychostimulants, and the [Ca(2+)](i) signaling is thought to play a significant role in the regulation of dopamine neuronal activity. (4)The excitability of neostriatal neurons is regulated by a balance of glutamatergic and dopaminergic inputs. Glutamate has been shown to modulate dopaminergic signaling. Studies on the regulation of DARPP-32 phosphorylation by glutamate provide a molecular basis for both the synergistic and antagonistic effects of glutamate on dopaminergic signaling. (5) Impairment of function of stem/progenitor cells may be implicated in the pathogenesis of schizophrenia. To test this hypothesis, several experiments are currently ongoing in our laboratory, and the preliminary results obtained are described here.     

Effects of chronic electrode implantation on dopaminergic neurons in vivo

The present study evaluated the effects of chronic electrode implantation on stimulus-dependent increases of the dopamine (DA) metabolite dihydroxyphenylacetic acid (DOPAC) in relationship to a well characterized in vivo model which used electrical stimulation from acute electrode placements in the nigro-striatal pathway. Five days after bipolar electrodes were implanted into the nigro-striatal pathway, non-contingent electrical stimulation (100 microA, 25 Hz, 1.5 msec duration, 20 min session) did not change DA or DOPAC concentrations in the caudate nucleus, nucleus accumbens, or olfactory tubercles, whereas the same stimulation from acute electrode placements causes significant ipsilateral increases in caudate DOPAC. Although DOPAC concentrations did not change when these chronically implanted electrodes were stimulated, similar chronic electrode placement supported intracranial self-stimulation (ICSS). In order to examine the effects of self-stimulation on DOPAC concentrations, five ICSS test groups were established for comparison: implanted only, trained only, minimum response rate, 50% maximum response rate and maximum response rate. Following a 50 min test session, a comparison of either DA, or DOPAC concentrations across the different ICSS conditions revealed no change for the caudate nucleus, nucleus accumbens or olfactory tubercles. Likewise, there was no change between the stimulated and unstimulated sides within each ICSS group. When a comparison was made between implanted only and maximal ICSS response rate groups for changes in DA or DOPAC concentrations in the frontal cortex, no differences were found. Apparently, chronic electrode implantation abolished the ability to electrically stimulate nigro-striatal dopaminergic neurons under non-contingent conditions, and the relationship between dopaminergic neurons and ICSS appears to be indirect in nature.