Basal Dopamine Concentrations Research Articles

Effects of subchronic methamphetamine exposure on basal dopamine and stress-induced dopamine release in the nucleus accumbens shell of rats

Subchronic administration of stimulants reduces basal dopamine (DA) concentrations and blocks stress-induced DA release in the nucleus accumbens (NA) of rats during withdrawal. However, no studies have attempted to relate early withdrawal from chronic drug exposure to stress reactivity and changes in DA transmission. The effects of subchronic low-dose methamphetamine (METH) administration on regional changes in dopamine transporter (DAT) and norepinephrine transporter (NET) immunoreactivity and function during early withdrawal were examined. The effects of subchronic METH on stress responsivity measured by DA release in the nucleus accumbens shell (NA SHELL) and core (NA CORE) during acute restraint stress were also examined. Male rats received single injections of METH (2.0 mg/kg i.p.) or saline (SAL) for 10 days and then were killed 24 h after the last injection. DAT and NET protein in NA, striatum (STR), medial prefrontal cortex (mPFC), and hippocampus were assayed by Western blot analysis. Experiment 2 measured basal extracellular DA concentrations and restraint-stress-induced DA release in vivo in the NA SHELL and CORE of SAL- and METH-pretreated rats after 24-h withdrawal. Experiment 3 examined the in vivo regulation of extracellular DA in the NA SHELL and/or CORE after local administration of GBR12909 (50 microM) or nisoxetine (100 microM; NA SHELL). Subchronic METH increased DAT but not NET immunoreactivity in the NA compared to the STR and mPFC. METH reduced basal extracellular DA and blocked restraint-stress-induced DA release in the NA SHELL. DA uptake blockade increased extracellular DA more in the NA SHELL of METH rats, whereas NE uptake blockade increased basal DA concentrations to a similar extent in METH and SAL rats. These results suggest that subchronic METH exposure selectively increases NA DAT and consequently reduces basal and stress-induced DA release in the NA SHELL during early withdrawal.

Dopaminergic transmission in STOP null mice

Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.

Neonatal depletion of cortical dopamine: Effects on dopamine turnover and motor behavior in juvenile and adult rats

Abnormal development of mesoprefrontal dopamine (DA) neurons may contribute to the pathophysiology of schizophrenia. Consistent with this hypothesis, DA nerve terminal density is decreased in the cortex of schizophrenic subjects [M. Akil, J.N. Pierri, R.E. Whitehead, C.L. Edgar, C. Mohila, A.R. Sampson, and D.A. Lewis, Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects, Am. J. Psychiatry, 156 (1999) 1580–1589]. This abnormality may be present early in development, giving rise to dysfunction as an individual matures. The present studies examined the effects of early partial loss of medial prefrontal cortex (mPFC) DA on DA turnover and locomotor behavior in juvenile, pubertal, and adult rats (30, 45, and 60 days of age, respectively). Local infusions of 6-hydroxydopamine on postnatal day (PN) 12–14 produced persistent decreases in basal tissue DA concentrations and increases in 3,4-dihydroxyphenylacetic acid (DOPAC):DA ratios in the mPFC. In the nucleus accumbens of lesioned rats, basal DA concentrations were decreased and DOPAC:DA ratios were increased on PN30, but not PN45 or 60. Footshock (30 min at 0.6 mA) increased DOPAC and DOPAC:DA ratios in the mPFC of PN30 and 60 control rats. These effects were attenuated in age-matched rats previously sustaining ∼50% loss of mPFC DA on PN12–14. Footshock did not affect DOPAC:DA ratios in the nucleus accumbens of control or lesioned rats. The lesion also failed to alter basal or stress-evoked motor activity. The present data suggest that a decreased density of mPFC DA nerve terminals occurring early in development results in persistent alterations in basal and stress-evoked activity of mesoprefrontal DA neurons, but not mesoaccumbens DA neurons.

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 μg/infusion) and cocaine (30 μg/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc.

Effect of repeated treatment with high doses of selegiline on behaviour, striatal dopaminergic transmission and tyrosine hydroxylase mRNA levels.

The anti-parkinsonian drug selegiline is a monoamine oxidase B (MAO-B) inhibitor and a potential neuroprotective agent which facilitates dopaminergic transmission. Its metabolites (-)-amphetamine and (-)-metamphetamine might contribute to the pharmacological effects as they are also able to increase dopaminergic transmission and in addition might lead to behavioural sensitization after repeated administration. We investigated the effects of acute and repeated treatment with a high dose of selegiline on dopamine overflow in the striatum as well as on behaviour and on tyrosine hydroxylase (TH) mRNA levels in midbrain. Two experiments were performed. In the first one, rats were implanted with microdialysis probes into the striatum and received daily injections of selegiline (10 mg/kg, i.p.) for 1 or 8 days or a single dose of saline. In vivo microdialysis was carried out on days 1, 8 or 17 (after withdrawal of 9 days) to measure dopamine overflow. Motility was measured at the same time. In the second experiment, rats were injected daily with selegiline (10 mg/kg, i.p.) or saline over a time period of 6 weeks or only once before the brains were processed for in situ hybridization with a (35)S-radiolabelled probe for TH. Repeated treatment led to higher levels in motility scores than acute administration after administration of the same dose, indicating behavioural sensitization, which was still manifest after an interruption of 9 days in the supply of selegiline. In contrast, acute administration of selegiline increased dopamine levels to a similar degree as the same dose after subchronic treatment, with or without interruption of 9 days. The dopamine metabolite DOPAC was reduced by more than 50% after acute administration of selegiline and even more so on day 8 by the same dose, after repeated administration. The basal concentrations of dopamine (before challenge with selegiline) were not altered by the repeated administration, whereas the basal concentrations of DOPAC were decreased by more than 80% by the repeated administration of selegiline, suggesting a decrease in dopamine turnover. Acute administration did not have any influence on TH mRNA levels, whereas chronic treatment significantly reduced TH mRNA levels in substantia nigra and ventral tegmental area. In conclusion, repeated administration of selegiline leads to behavioural sensitization independent of altered dopamine levels. In addition, it leads to a decrease, probably due to a down-regulation, of dopamine turnover and tyrosine hydroxylase.

Chronic desipramine treatment selectively potentiates somatostatin-induced dopamine release in the nucleus accumbens.

Dopamine and somatostatin have been implicated in the pathophysiology of depression. We have employed in vivo microdialysis to investigate the regulation of dopamine release by somatostatin in the nucleus accumbens and the striatum of awake, freely moving rats, and to ascertain how this regulation may be affected by desipramine treatment. Somatostatin-14 (10(-4) M) infusion induced an increase in the release of dopamine and a decrease in the release of its metabolites in both the nucleus accumbens (568% of basal) and the striatum (546% of basal). Chronic desipramine treatment resulted in an exaggerated somatostatin-induced increase of dopamine levels, specifically in the nucleus accumbens (3542% compared with 564% of basal in the striatum), whereas acute desipramine treatment had no effect (582% of basal) compared with saline treated rats. Basal concentrations of dopamine and metabolites were not influenced by either chronic or acute treatment of desipramine in either brain area. These results demonstrate that somatostatin regulates dopamine release in the nucleus accumbens and the striatum. Chronic antidepressant treatment influences somatostatin's actions on dopamine function selectively in the nucleus accumbens.

Stimulation of P2 receptors in the ventral tegmental area enhances dopaminergic mechanisms in vivo

It has been shown that endogenous adenosine 5′-triphosphate (ATP) as well as its exogenously applied structural analogue, 2-methylthio ATP (2-MeSATP), facilitate the release of dopamine from axon terminals in the rat nucleus accumbens (NAc) by activating ATP-sensitive P2 receptors. In the present study, reversed microdialysis of 2-MeSATP (10 μM, 100 μM and 1 mM), or its microinjection (0.5, 5.0 and 50 pmol) into the ventral tegmental area (VTA), dose-dependently increased the local extracellular level of dopamine and the locomotion in the open field, respectively. These effects were abolished by the P2-receptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS). When applied alone, the antagonist decreased the basal dopamine concentration, indicating that endogenous ATP controls the somatodendritic release of dopamine. Repeated microinjections of 2-MeSATP (5 pmol) once daily for 4 days led to a reproducible locomotor stimulation in the open field. Conditioned locomotion was induced by re-exposure to the novel environment on the seventh day. A challenge with amphetamine (1 mg/kg intraperitoneally) on the eighth day enhanced the locomotor activity in the 2-MeSATP-treated group in the sense of a cross-sensitisation, but failed to do so in the control group. Neurons in the VTA were heavily stained with antibodies developed against the P2Y 1 subtype of P2 receptors. Taken together, our data suggest that P2 receptors (probably of the P2Y 1 subtype) are involved in the initiation of somatodendritic dopamine release in the VTA and thereby may have a profound influence on sensitisation and reward-motivated behaviour.

Effects of prenatal cocaine exposure on amphetamine-induced dopamine release in the caudate nucleus of the adult rabbit

Acute amphetamine (AMPH) challenge has been used to probe the neurochemical and behavioral integrity of dopaminergic neurons under various conditions including prenatal cocaine exposure. In this study, we employed in vivo microdialysis to examine the effects of prenatal cocaine exposure on AMPH-induced dopamine (DA) release in the caudate nucleus of the awake adult rabbit. Pregnant rabbits were given intravenous injections of either saline or cocaine (4 mg/kg) twice a day from gestational day 8 (G8) through G29. Microdialysis was performed in adult saline and cocaine progeny at approximately postnatal day 70 (P70). There were no significant differences between cocaine and saline progeny in their basal concentrations of DA or its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). AMPH (5 mg/kg, i.v.) significantly increased extracellular DA in the caudate of both groups. However, AMPH-induced DA release was 2 to 3-fold greater in cocaine progeny than in the saline controls. Although, DOPAC decreased in both groups following AMPH injection, there was no significant group effect. In addition, there were no significant changes in concentrations of HVA. AMPH is known to release DA by a mechanism of exchange diffusion via the presynaptic DA transporter (DAT). Therefore, we examined the binding of [ 3 H ]WIN 35,428 to membrane fractions prepared from fresh caudate tissue to determine whether prenatal exposure to cocaine had altered the density ( B max) or affinity ( K d) of the DAT. While the B max for [ 3 H ]WIN 35,428 binding increased 3-fold between P3 and P120, there were no significant differences between saline and cocaine progeny at any age examined. The K d for [ 3 H ]WIN 35,428 binding did not change with postnatal age and did not differ between cocaine and saline progeny. These findings suggest that prenatal exposure to cocaine produces a long-term increase in the size of the presynaptic, AMPH releasable, cytoplasmic pool of DA.

Recovery of high potassium-evoked dopamine release after depolarization challenge in the striatum of young and old male rats

The aim of this study was to assess the recovery of high potassium-evoked dopamine (DA) release after depolarization challenge in young (3–4 months) and old (21–25 months) male Wistar rats. Recovery of DA release was evaluated by comparison of the peak responses of DA release induced by two serial high potassium stimulations. Concentric microdialysis probes were stereotaxically implanted in the lateral striatum of rats, and microdialysis was commenced 24 h after surgery. Using a low flow rate of perfusion (1 μl/min), all rats received 2×20 min infusions of 100 mM potassium solution separated by either 60 or 140 min. No difference in the basal DA concentration or the potassium-evoked DA release or its recovery was seen between the two groups. Our results suggest that the vesicular DA store recovers rapidly after high potassium challenge in both young and old rats.

PHARMACOKINETICS OF DOPAMINE IN HEALTHY MALE VOLUNTEERS

Introduction: Dopamine is an endogenous catecholamine with dose dependent pharmacologic effects. No one to date has been able to correlate these effects with plasma concentrations. The purpose of this study is to define the pharmacokinetics of dopamine in healthy male volunteers and to develop a pharmacokinetic model to help predict plasma concentrations for given dosages of the drug. Methods: Nine healthy male volunteers were recruited for the study. An intravenous and intraarterial catheter were used for drug delivery and blood sampling, respectively. An infusion of dopamine was used in the following manner: 10 [micro sign]g/kg/min for 10 min followed by a 30 min washout; 3 [micro sign]g/kg/min for 90 min followed by another 30 min washout, with arterial blood samples collected. BP and HR were recorded before, during and after the infusions. Assay data from each subject was fit to both one and two compartment disposition models using nonlinear mixed effects regression (NONMEM software, UCSF). The Schwartz-Bayesian criterion was used to determine whether the one or two compartment model best fit the data. To date we have completed the dopamine assays in four of the nine volunteers. Results: Baseline plasma dopamine concentrations ranged from 22 to 367 pg/mL; peak plasma concentrations reached as high as 201.5 ng/mL. The one compartment model best fits the data, with a median volume of distribution (Vd) of 5.2L and median clearance of 1.90 L/min (Table 1).Table 1Discussion: Institution of a dopamine infusion results in huge increases in plasma concentrations, reaching as much as a 10,000-fold increase over basal dopamine concentrations. Dopamine appears to fit a one-compartment model best, with a volume of distribution approximately equal to circulating blood volume, and a clearance of 1.9 L/min. Infusion of "renal dose" dopamine (3 [micro sign]g/kg/min) resulted in sustained plasma levels nearly equivalent to those obtained with a 10 min infusion of 10 [micro sign]g/kg/min. (Figure 1)Figure 1Support: Southern Medical Association Research Project Grant; General Clinical Research Center of Wake Forest University Medical Center #M01-RR07122

PHARMACOKINETICS OF DOPAMINE IN HEALTHY MALE VOLUNTEERS

Introduction: Dopamine is an endogenous catecholamine with dose dependent pharmacologic effects. No one to date has been able to correlate these effects with plasma concentrations. The purpose of this study is to define the pharmacokinetics of dopamine in healthy male volunteers and to develop a pharmacokinetic model to help predict plasma concentrations for given dosages of the drug. Methods: Nine healthy male volunteers were recruited for the study. An intravenous and intraarterial catheter were used for drug delivery and blood sampling, respectively. An infusion of dopamine was used in the following manner: 10 [micro sign]g/kg/min for 10 min followed by a 30 min washout; 3 [micro sign]g/kg/min for 90 min followed by another 30 min washout, with arterial blood samples collected. BP and HR were recorded before, during and after the infusions. Assay data from each subject was fit to both one and two compartment disposition models using nonlinear mixed effects regression (NONMEM software, UCSF). The Schwartz-Bayesian criterion was used to determine whether the one or two compartment model best fit the data. To date we have completed the dopamine assays in four of the nine volunteers. Results: Baseline plasma dopamine concentrations ranged from 22 to 367 pg/mL; peak plasma concentrations reached as high as 201.5 ng/mL. The one compartment model best fits the data, with a median volume of distribution (Vd) of 5.2L and median clearance of 1.90 L/min (Table 1).Table 1Discussion: Institution of a dopamine infusion results in huge increases in plasma concentrations, reaching as much as a 10,000-fold increase over basal dopamine concentrations. Dopamine appears to fit a one-compartment model best, with a volume of distribution approximately equal to circulating blood volume, and a clearance of 1.9 L/min. Infusion of "renal dose" dopamine (3 [micro sign]g/kg/min) resulted in sustained plasma levels nearly equivalent to those obtained with a 10 min infusion of 10 [micro sign]g/kg/min. (Figure 1)Figure 1Support: Southern Medical Association Research Project Grant; General Clinical Research Center of Wake Forest University Medical Center #M01-RR07122

Effects of different perfusion medium on the extracellular basal concentration of dopamine in striatum and medial prefrontal cortex: a zero-net flux microdialysis study

The zero-net flux microdialysis method was used to determine (1) the basal concentration of dopamine (DA) in the extracellular space, and (2) the in vivo recovery of DA in the striatum and the medial prefrontal cortex by using three different kinds of perfusion medium. They were, (a) commercial Ringer's solution, (b) low Ca2+ Ringer's solution, and (c) artificial cerebrospinal fluid (aCSF). Our results not only support previous findings that the high Ca2+ concentration in the perfusion medium could increase the baseline concentration of DA in the dialysate, which was collected from extracellular space through dialysis probe; but also provides evidence that this baseline increase was primarily due to an increase of basal DA concentration, and not from the increase of the in vivo recovery. Additionally, there was no significant difference in the basal DA concentration by using either commercial Ringer's solution or aCSF. This indicates that both commercial Ringer's solution and aCSF are suitable as good perfusion medium to determine the basal DA in the rat's brain.

Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat

Cerebellar syndrome has been described after acute lithium intoxication in human. Neuropathological studies have demonstrated neuronal loss and spongiosis in the cerebellum. We describe an animal model of acute lithium-induced cerebellar degeneration. Five hours following administration of lithium chloride (250 mg/kg, i.p.), the cerebellar white matter of seven rats out 14 exhibited extensive spongiform changes. Microdialysis study in the rat cerebellar cortex demonstrated basal concentrations of dopamine (DA), hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA). These metabolites were unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of dopaminergic or serotoninergic neurotransmission.

Does monoamine oxidase inhibition by pargyline increase extracellular dopamine concentrations in the striatum?

The present study examined the possibility that pargyline-induced stimulation of dopamine neurotransmission in the striatum measured by intracerebral microdialysis may be related to alterations in the function of dopamine nerve terminals in close proximity to the implanted microdialysis probe. Changes in extracellular concentrations of dopamine were determined bilaterally in the striata of awake rats by microdialysis with concentric dialysis probes and by chronoamperometry with electrochemical (stearate–graphite paste) recording electrodes, after inhibition of monoamine oxidase by pargyline and subsequent blockade of dopamine uptake by nomifensine. Pargyline (75mg/kg, i.p.) increased dopamine overflow by 14nM from a mean basal value of 9nM as determined from dialysis probes implanted in the right striatum. Pargyline failed, however, to increase basal concentrations of dopamine measured by electrochemical electrodes implanted alone in the contralateral striatum. In contrast, 3h following pargyline, administration of nomifensine (10mg/kg, i.p.) increased extracellular dopamine concentrations to a similar magnitude above baseline levels in both right and left striata (135 and 127nM, respectively). In a separate group of rats, electrochemical electrodes were implanted in the left striatum with the tip of the electrode placed directly adjacent to the lumen of a dialysis probe. In contrast to pargyline's inability to increase basal extracellular dopamine measured at individually implanted electrochemical electrodes in the striatum, pargyline administration increased dopamine concentrations measured at electrodes implanted adjacent to non-perfused dialysis probes to an extent similar to that observed by dialysis alone (25 vs 14nM, respectively).The present study indicates that pargyline increases dopamine concentrations in the region of striatal tissue immediately adjacent to the shaft of a permanently implanted dialysis probe, but not at the tip of an electrochemical electrode. The former affect appears to reflect an interaction between monoamine oxidase inhibition and those elicited by the physical presence of the dialysis probe in tissue.

U-69593 prevents cocaine sensitization by normalizing basal accumbens dopamine.

Repeated intermittent administration of cocaine (20 mg kg-1, i.p.) for 3 days dramatically increased basal dopamine (DA) overflow in the nucleus accumbens (ACB) 48 h after the final daily injection. This cocaine pretreatment also produced a significant increase in stereotypy in response to a subsequent cocaine challenge. However, when the selective kappa-opioid receptor agonist U-69593 was administered in combination with cocaine for 3 days, these cocaine-induced biochemical and behavioral effects were abolished. It is suggested that the responsiveness of mesolimbic DA neurons to cocaine is intimately related to basal DA concentrations within the ACB and that U-69593, by normalizing cocaine-induced increases in basal DA overflow, may prevent the development of behavioral sensitization to cocaine.

Withdrawal from morphine or amphetamine: different effects on dopamine in the ventral-medial striatum studied with microdialysis

The effect of withdrawal from chronic morphine or amphetamine treatment on dopamine (DA) neurotransmission in the ventral-medial striatum was studied by use of in vivo microdialysis. There was no effect of 24 h of amphetamine withdrawal on the basal concentration of DA in the ventral-medial striatum. Spontaneous morphine withdrawal (24 h) was associated with a significant decrease in the basal concentration of DA in dialysate, but following morphine replacement and naloxone-precipitated withdrawal variations in withdrawal symptoms were not related to variations in the concentration of DA in dialysate. It is suggested that: (1) the correlation between the extracellular concentration of DA in the ventral-medial striatum and the symptoms of morphine withdrawal may not be indicative of a necessary, causal relationship; and (2) a decrease in the extracellular concentration of DA in the ventral-medial striatum is not a common feature of drug withdrawal syndromes.

Dopamine release and metabolism in nucleus accumbens and striatum of morphine-tolerant and nontolerant rats

Morphine administered at high doses produces a biphasic locomotor effect, characterized by an initial locomotor depression, followed a short time later by hyperlocomotion. Prior exposure to morphine produces tolerance to the motor-depressive effects and sensitization to the motor-activating effects of morphine. Little is known of the neurochemical changes that occur to produce tolerance and sensitization to morphine. In the present study, we developed a morphine pretreatment regimen in rats that produced both tolerance and sensitization to a high (30 mg/kg) dose of morphine. Using in vivo microdialysis, we then measured dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) release in the nucleus accumbens (NAC) and striatum (STR) in morphine- and saline-pretreated rats after acute morphine administration. In morphine-tolerant/sensitized rats, basal DA concentrations in the NAC were higher and levels of DOPAC and HVA in the NAC after acute morphine injection were greater compared to controls. These results suggest that the NAC, but not the STR, may be important in mediating tolerance and sensitization to opiates.

Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya

Cocaine was administered daily (15 mg/kg, i.p. x 1 d followed by 30 mg/kg, i.p. x 5 d) to produce behavioral sensitization. Using microdialysis in the ventral tegmental area and medial substantia nigra, the effect of repeated cocaine was examined on the extracellular levels of dopamine. One day after discontinuing repeated cocaine injections, an acute challenge with cocaine (15 mg/kg, i.p.) produced a significant elevation in extracellular dopamine compared to rats pretreated with daily saline (x6 d). The augmentation in extracellular dopamine persisted longer than the sensitized behavioral response. In contrast, 14 d after discontinuing daily cocaine, the increase in extracellular dopamine produced by an acute cocaine challenge was not augmented, although behavioral sensitization was present. In separate animals, the basal concentration of dopamine in the ventral tegmental area/medial substantia nigra was measured by determining the concentration of dopamine at which no net flux occurred across the dialysis membrane in vivo. One day after discontinuing daily treatments, the basal level of extracellular dopamine in the cocaine pretreated rats was significantly elevated over the level in saline-pretreated animals (1.3 nM vs. 0.8 nM). By 14 d after the last daily injection, the basal levels of dopamine were equivalent in cocaine- and saline-pretreated animals. It is concluded that daily cocaine injections produce a transient alteration in the regulation of somatodendritic dopamine release. While such changes are not responsible for the long-term behavioral sensitization produced by repeated cocaine administration, they may be involved in the initiation of behavioral sensitization.

Individual differences in basal and cocaine-stimulated extracellular dopamine in the nucleus accumbens using quantitative microdialysis

The current experiment examined the role of nucleus accumbens (NACC) dopamine in individual differences. Subjects were divided into high responders (HR) and low responders (LR) based on their locomotor response to a novel environment. HR rats were subjects which had a locomotor response to novelty in the upper third of the population sscreened and LR rats in the bottom third of the population. A new method of microdialysis was then used that allowed determination of the extracellular dopamine concentration. This was accomplished by adding various dopamine concentrations (0.0.5.0 and 20.0 nM) to the perfusate. The concentration of dopamine in the dialysate was subsequently determined. The difference in the dialysate and perfusate dopamine was regressed on the perfusate dopamine. The regression yielded the in vivo recovery and the extracellular concentration. HR rats exhibit a 250% higher basal dopamine concentration (6.45 ± 1.01 nM, n = 6) than LR rats (2.58 ± 0.16 nM, n = 7). The in vivo microdialysis recovery was used to estimate the extracellular dopamine followin cocaine challenge (15mg/kg) in the two groups. Following i.p. cocaine administration. HR rats had both a greater locomotor response and increase in absolute dopamine concentration compared to LR rats. The maximum dopamine concentration in the HR group was 2.3 ± 2.9 nM, while that in the LR group was only 8.6 ± 1.1 nM. The maximum on the LR group is comparable to the basal level in the HR group. However, there were no difference in percent change in dopamine following cocaine. These result provide further evidence in support of a role for variation in NACC dopamine in individual differences in vulnerability to psychomotor stimulants.

The effects of four days of continuous striatal microdialysis on indices of dopamine and serotonin neurotransmission in rats

The effects of 4 days of continuous microdialysis with a small-diameter concentric-style probe on indices of striatal dopamine (DA) and serotonin neurotransmission were assessed. It was found that over 4 days of dialysis, there was a marked time-dependent decrease in the basal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in dialysate and in amphetamine-stimulated DA release. In contrast, there was no decrease in basal DA or in the ability of cocaine to elevate the concentration of DA in dialysate over the same period of time. There were only very modest changes in dialysate levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), relative to the marked changes in DA metabolites. It is suggested that 4 days of continuous dialysis does not result in a non-specific decrease in diffusibility of these compounds into the dialysis probe, but that the changes are more likely due to probe-induced damage to the nigrostriatal DA system. It is also suggested that a “stable” basal concentration of DA in dialysate is an especially poor indicator of the integrity of the dopaminergic input to the striatum. The implications of these findings for within-subjects design microdialysis experiments are discussed.