Compensatory increase in extracellular dopamine in the nucleus accumbens of adult rats with neonatal 6-hydroxydopamine treatment.

To characterize a compensatory function of the dopaminergic system of residual dopamine (DA) neurons in the mesolimbic pathway with DA-depleting lesions, we compared tissue and extracellular concentrations of DA and its metabolites in the nucleus accumbens (NACC) of adult rats with neonatal 6-hydroxydopamine (6-OHDA) treatment with those of control rats with neonatal vehicle treatment using high-performance liquid chromatography. The tissue concentration of DA for 6-OHDA-treated rats was 26.9% of that for the control rats, whereas the extracellular DA was not significantly different from the controls. Furthermore, the extracellular DA concentration in the NACC of 6-OHDA-treated rats was significantly increased compared to the controls following neurotensin (NT) microinjection into the ventral tegmental area (VTA). These results suggest that the extracellular DA of the adult rat brain following neonatal 6-OHDA treatment was compensated for by increasing the release of DA from terminals in the NACC of remaining DA neurons through increased mesolimbic pathway afferents (increased demand), as well as by decreasing the synaptic DA reuptake sites and/or D4 receptors. This study supports our hypothesis that the compensatory mechanism(s) of remaining DA neurons in the mesolimbic system are underlying in behavioral characteristics of adult rats with neonatal depletion of brain DA.     

Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism.

The effect of various doses of tianeptine on the extracellular concentrations of dopamine was studied in the striatum and nucleus accumbens of the rat. At 5 (but not 2.5) mg/kg intraperitoneally, tianeptine increased the extracellular dopamine only in the nucleus accumbens. At 10 mg/kg, the effect was also seen in the striatum but it was less marked and shorter-lasting. At 10 mg/kg (i.p.), tianeptine significantly raised the extracellular concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in both regions. The effect of 10 mg/kg tianeptine on dopamine and its metabolites was not significantly changed in animals which had received this dose twice daily for 15 days. Intracerebroventricular administration of 150 micrograms/20 microliters 5,7-dihydroxytryptamine, which markedly depleted serotonin in the brain, did not modify the effect of 10 mg/kg tianeptine on the extracellular concentrations of dopamine and HVA in the nucleus accumbens but reduced the effect on DOPAC. Various doses of tianeptine (1, 3 and 10 mg/kg i.p.) did not change the synthesis of serotonin and dopamine in the striatum and nucleus accumbens. The results show that tianeptine increased the extracellular concentrations of dopamine more in the nucleus accumbens than in striatum. The effect on the output of DA in the nucleus accumbens could be involved in the antidepressant activity of tianeptine.     

Brain concentrations of tricyclic antidepressants: Single-dose kinetics and relationship to plasma concentrations in chronically dosed rats

A previously reported method of measuring tricyclic antidepressant concentrations in brain tissue and plasma was used to measure amitriptyline (AMI) in rats following drug administration using different routes, doses, and time intervals. In rats given AMI intraperitoneally (IP), brain concentrations increased during the first 30 min after drug adminstration and then declined. Brain concentrations increased linearly with changes in IP dosage and increased logarithmically with changes in intravenous dosage. No simple relationship existed between brain and plasma concentrations in acutely dosed rats. However, a linear relationship existed between plasma and brain concentrations in chronically treated animals (r=0.96, P<0.001). The brain: plasma drug ratios observed in chronically treated rats corresponded to ratios reported in man. Thus, conclusions drawn from these studies can probably be extrapolated to the clinical situation. Based on our data, the molar concentration of drug achieved on therapeutic doses is 10^-5–10^-6 M. This information may aid in understanding the clinical relevance of in vitro drug: receptor binding studies which are typically reported in molar concentrations.     

Locomotor activity stimulation in rats produced by dopamine in the nucleus accumbens: potentiation by caffeine.

The increased motor activity of reserpine-nialamide pretreated rats given dopamine into the nucleus accumbens was potentiated in a dose-dependent manner by systemically administered caffeine. Similarly, the increase in motor activity seen when the endogenous dopamine was released by intraperitoneally administered amphetamine was potentiated by systemically given caffeine. These effects might be due to an increase in the dopamine-induced accumulation of cyclic AMP in the nucleus accumbens after inhibition of the phosphodiesterase by caffeine.     

Anxiogenic drugs beta-CCE and FG 7142 increase extracellular dopamine levels in nucleus accumbens

Two experiments were conducted to study the effects of anxiogenic drugs on dopamine release and metabolism in nucleus accumbens. Microdialysis probes were implanted into the nucleus accumbens, and rats were tested the day after implantation. In the first experiment, groups of rats received injections of saline, 1.25 or 2.5 mg/kg beta-CCE. In the second experiment, groups of rats received injections of saline, 10.0, 20.0 or 30.0 mg/kg FG-7142. Both drugs produced significant increases in dopamine release and metabolism in nucleus accumbens. Neither drug had significant effects on locomotor activity. These experimeriments indicate that exposure to anxiogenic drugs increases accumbens dopamine activity, an effect that is consistent with other studies showing that the mesolimbic dopamine system is responsive to stressful stimuli. In addition, these results demonstrate that drug-induced increases in accumbens dopamine release are not unique to drugs of abuse.     

Benzodiazepine-induced decreases in extracellular concentrations of dopamine in the nucleus accumbens after acute and repeated administration

In vivo microdialysis was used to assess the effects of acute and repeated injections of the benzodiazepine midazolam on extracellular dopamine (DA) concentrations in the nucleus accumbens. Acute administration of midazolam (5 mg/kg, SC) elicited a 22% decrease in extracellular DA in the nucleus accumbens but failed to affect DA concentrations in the striatum. Similarly, six spaced intravenous infusions of midazolam, at a dose that has previously been found to support self-administration (0.05 mg per infusion), produced a 50% decrease in extracellular DA in the nucleus accumbens. In order to assess the effects of subchronic midazolam injections, two groups of rats were given injections of saline or midazolam (5 mg/kg, SC) for 14 days (two injections per day). A subsequent challenge injection of midazolam (5 mg/kg) decreased extracellular DA in the nucleus accumbens by 25% in both groups, indicating that neither tolerance nor sensitization occurred during the repeated drug administration. These experiments indicate (1) that midazolam differentially affects meso-accumbens and nigrostriatal DA neurons, and (2) that the midazolam-induced decrease in extracellular DA in the nucleus accumbens is not affected by repeated drug administration. The data further suggest that the rewarding effects of midazolam are not associated with increased release of DA in the nucleus accumbens.     

Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus

Recently, we have shown that acamprosate is able to modulate extracellular dopamine (DA) levels in the nucleus accumbens (NAc) and may act as an antagonist of N-methyl-D-aspartate (NMDA) receptors. Neurochemical studies show that chemical stimulation (using NMDA) of the ventral subiculum (vSub) of the hippocampus produces robust and sustained increases in extracellular DA levels in the NAc, an effect mediated through ionotropic glutamate (iGlu) receptors. The present study examines whether acamprosate locally infused in the NAc of rats could block or attenuate the increase in NAc extracellular DA elicited by chemical stimulation (with 5 mM NMDA) of the ventral subiculum of the hippocampus. The stimulation of the vSub during perfusion of artificial cerebrospinal fluid in NAc induced a significant and persistent increase in NAc DA levels. Reverse dialysis of 0.05 mM acamprosate in NAc blocked the increase in DA evoked by the chemical stimulation of the vSub. These data support the possibility that the antagonism at the NMDA receptors in NAc can explain, at least in part, the mechanism of action of this drug.     

Release of dopamine is reduced by diazepam more in the nucleus accumbens than in the caudate nucleus of conscious rats

The effects of 1-20 mg/kg diazepam were studied on the extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and striatum of conscious rats, using intracerebral microdialysis. Five, but not 1 mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the nucleus accumbens. Twenty mg/kg diazepam significantly reduced extracellular DA, DOPAC and HVA in the striatum. A significant effect on striatal DOPAC, but not on DA and HVA, was seen with 10 mg/kg diazepam, while no changes were found with 5 mg/kg diazepam. The results suggest that diazepam reduces the release and metabolism of DA in the nucleus accumbens more than in the striatum.     

Two simultaneously working storage pools of dopamine in mouse caudate and nucleus accumbens.

1. The dynamics of the decline of evoked dopamine overflow after repeated electrical stimulation (2 or 4 s train duration, 50 Hz) of the median forebrain bundle were investigated by means of in vivo voltammetry in mouse caudate and nucleus accumbens. An unexpected effect-slowing of the rate of dopamine decline after repeated stimulation at short (10 s or less) between-stimulation intervals, and an increase in the absolute amount of dopamine released at the beginning of the repeated stimulation-was found. 2. After the evoked dopamine overflow had been reduced by alpha-methyl-p-tyrosine (AMPT), repeated stimulation at intervals of 5 s increased dopamine release to each subsequent stimulation applied. 3. It is proposed that there are two compartments involved in dopamine storage. Both contribute to the release of dopamine, however, they may be separated artificially by either applying stimulation at short intervals or by depletion of intracellular dopamine. 4. The first releasable pool (newly synthesized, AMPT-sensitive) provides dopamine for the release after a single stimulation or repeated stimulation, being independent of whether the first stimulation is succeeded quickly by a second. It is also independent of between-stimulation interval. 5. The second pool (AMPT-insensitive storage pool) is progressively activated after repeated stimulation. The duration of the between-stimulation intervals is the crucial factor for the activation of this pool.     

Systemic morphine simultaneously decreases extracellular acetylcholine and increases dopamine in the nucleus accumbens of freely moving rats.

Microdialysis was used to measure extracellular levels of acetylcholine (ACh) and dopamine (DA) simultaneously in the nucleus accumbens (NAC) of freely moving rats. Systemic injection of morphine (20 mg/kg) significantly decreased ACh (30%, p less than .01) while it increased DA (55%, p less than .01). The effects of morphine were eliminated by naloxone. The results confirm that morphine increases DA and in addition, demonstrate an inhibitory influence of this opiate on extracellular levels of ACh in the NAC.     

Acute effects of bupropion on extracellular dopamine concentrations in rat striatum and nucleus accumbens studied by in vivo microdialysis

This study examined the acute effects of the novel antidepressant drug, bupropion, on extracellular concentrations of dopamine (DA), its metabolites, and the serotonin metabolite 5-HIAA in the striatum and nucleus accumbens using on-line microdialysis in freely moving rats. Bupropion HCl (10, 25, and 100 mg/kg intraperitoneally) increased extracellular striatal DA in a dose- and time-dependent manner; 1 mg/kg did not affect extracellular DA. The maximal response occurred within the first 20 minutes (+76%, +164%, and +443% for each dose, respectively) followed by a gradual decrease to a stable but elevated level for the next 2 hours. This neurochemical response was strongly associated with bupropion-induced stereotyped behavior during the first hour but not during the subsequent 2 hours. Bupropion decreased DOPAC concentrations, increased 5-HIAA, and had variable effects on homovanillic acid (HVA) (decreases with 10 mg/kg and increases with 25 and 100 mg/kg). The increase in extracellular DA after bupropion (25 mg/kg) was blocked by tetrodotoxin and was therefore action-potential-dependent. Bupropion produced similar neurochemical responses in the striatum and the nucleus accumbens. These results suggest that increases in DA transmission contribute to the behavioral effects of bupropion and are consistent with a role for DA in the antidepressant effects of this drug. The partial dissociation between DA release and stereotyped behavior suggests that the relationship between neurotransmitter release and behavior may be complex.     

Athetoid and choreiform hyperkinesias produced by caudate application of dopamine in cats

Behavioral changes resembling human athetoid and choreiform hyperkinesias were produced by unilateral injections of l-3,4-dihydroxyphenylalanine (l-DOPA), dopamine, 3-methoxy-tyramine and dexamphetamine into the rostromedial part of the caput caudati of cats; saline, noradrenaline and 3,4-dihydroxyphenylacetic acid were ineffective. Pretreatment with the tyrosine hydroxylase inhibitor, -methyl-para-tyrosine, blocked the effects induced by l-DOPA, dopamine and dexamphetamine in a competitive way; the 3-methoxy-tyramine effect was blocked in a non-competitive way. Applications of the active compounds into the anteroventral part of the caput caudati were ineffective.The hypothesis is put forward that normally dopamine-sensitive sites are involved in the manifestation of choreo-athetoid movements. The implications of these findings are considered in view of the efficacy of l-DOPA and -methyl-DOPA in Parkinson's disease and Huntington's chorea, respectively. In addition, our data are discussed in the light of the recent finding that lesions restricted to the anteroventral part of the caput caudati also result in these hyperkinesias.     

Enhancement of prolactin-secreting effect produced by repeated administration of haloperidol in the avoidance situation and dopamine neurons in rats

Male Wistar strain rats subcutaneously administered haloperidol at the dose of 0.035 mg/kg at 3-4 days interval, 10 times, in the avoidance situation. Enhancement of the prolactin-secreting effect of haloperidol was observed when it was given in the home cages at the 10th day after termination of the repeated administration. In these animals, 3H-spiperone binding sites in the pituitary significantly increased, while the DOPAC/DA ratio in the hypothalamus significantly decreased. The enhancement phenomenon may be produced by a decrease in the activity of dopamine neurons in the hypothalamus.     

Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat

 Studies indicate that nucleus accumbens (NAcc) dopamine neurotransmission is involved in the reinforcing and direct effects of cocaine. The present study was initiated to explore further the relationship of NAcc extracellular dopamine concentrations ([DA]_e) and cocaine self-administration using a yoked littermate design. In the first experiment, one rat from each litter was trained to self-administer cocaine IV (SA; 0.33 mg/inf) under a fixed ratio 2 schedule, while a second rat received simultaneous infusions of cocaine yoked to the infusions of the SA (YC). NAcc [DA]_e and cocaine concentrations ([COC]) were assessed during the test sessions using in vivo microdialysis combined with microbore HPLC procedures. [DA]_e and [COC] were significantly elevated in the SA and YC groups during the self-administration session; however, [DA]_e were greater in the SA group compared to the YC group in the first hour of the session, even though [COC] were not significantly different. On the following day, the rats previously allowed to self-administer cocaine were administered response-independent cocaine infusions yoked to the infusion pattern from the previous day. [DA]_e were significantly elevated above baseline levels during the session but were significantly less than concentrations obtained when cocaine was self-administered by these subjects. [COC] during the sessions were not significantly different between the two days. Baseline [DA]_e were not significantly different between the SA and YC groups or between Day 1 and Day 2. Furthermore, there was no significant difference in the in vitro probe recovery between one and two days following probe implantation. These results suggest that the context in which cocaine was administered significantly altered the neurochemical response to equivalent brain concentrations of cocaine. NAcc [DA]_e was significantly increased when the delivery of cocaine infusions was contingent on the behavior of the rat, indicative of a role in the neural processes underlying cocaine reinforcement. Received: 23 May 1996 / Final version: 11 April 1997     

Microinjections of dopamine agonists in the nucleus accumbens increase ethanol-reinforced responding.

Long-Evans rats (N = 3) were trained to lever press on a fixed-ratio 4 (FR 4) schedule with ethanol (10% v/v) presented as the reinforcer. Each rat received a total of six bilateral nucleus accumbens microinjections, one per week. They were tested with one physiological saline control, three 20.0-microgram/brain d-amphetamine, and two 6.0-microgram/brain quinpirole injections given 10 min prior to operant sessions. Ethanol-reinforced responding terminated after approximately 10 min during control sessions. Microinjections of the D2 agonist quinpirole and the nonspecific dopamine (DA) agonist d-amphetamine increased total responding but produced slowed response rates that continued for 45-60 min. The slowed response rate produced by d-amphetamine resulted in a peak increase in interresponse times (IRTs) between 8-10 s, whereas quinpirole increased IRTs in the 14- to 16-s range, indicating that nonspecific DA activation resulted in higher rates of ethanol-reinforced responding than specific D2 activation although both drugs decreased local response rates. These data indicate that the amount and temporal extent of ethanol-reinforced responding are increased by microinjections of DA agonists in the nucleus accumbens and support the hypothesis that DA activity in this region is involved in the regulation of ethanol-reinforced responding.     

Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous self-administration of cocaine or d-amphetamine

Changes in extracellular concentrations of dopamine (DA) were measured in vivo in the nucleus accumbens of the rat during intravenous self-administration of either cocaine (0.25, 0.5, 1.0mg/infusion) or d-amphetamine (0.05, 0.1, 0.2mg/infusion). Drug intake was limited to 12 self-administered infusions per session for each drug/dose combination. Changes in extra-cellular DA concentrations were measured by two different techniques: chronoamperometry in conjunction with chronically-implanted stearate-modified carbon paste electrodes, or intracerebral microdialysis with off-line analyses using high performance liquid chromatography with electrochemical detection (HPLC-ED). Significant increases in extracellular DA concentrations were observed with both in vivo techniques during self-administration of each dose of cocaine or d-amphetamine. For each drug, the magnitude of change during the first hour of the test session was comparable across doses. However, the change observed over the first 2h period, as measured by microdialysis and HPLC-ED, revealed a dose effect for cocaine, but no dose-response effect for d-amphetamine. The duration of the drug-induced elevation was increased significantly as a function of dose with both cocaine and d-amphetamine. Data from the microdialysis experiments indicated that the high dose of d-amphetamine (0.2mg/infusion) produced a significantly greater increase in extracellular DA concentrations in the nucleus accumbens than did the high dose of cocaine (1.0mg/infusion), but that comparable changes were induced by doses of 0.1mg/infusion of d-amphetamine and 1.0mg/infusion of cocaine, respectively. Each dose of both psychostimulant drugs also produced a significant decrease in dihydroxyphenylacetic acid (DOPAC) levels. The latter finding indicated that the electrochemical signal measured in these studies was not due to the oxidation of DOPAC. These results confirm that self-administration of cocaine or d-amphetamine by the rat is accompanied by a significant increase in extracellular DA concentrations in the nucleus accumbens. The fact that two different psychomotor stimulant drugs of abuse have qualitatively similar neurochemical correlates when self-administered, adds credence to the hypothesis that their reinforcing properties are related to dynamic changes in DA concentrations in the ventral striatal region of the brain.     

The associative type of sensitization to d-amphetamine is expressed as an NO-dependent dramatic increase in extracellular dopamine in the nucleus accumbens

After repeated administration of psychomotor-stimulant drugs such as d-amphetamine, a sensitization to its stimulant effects such as locomotor activity and stereotyped behaviour can be observed depending on the treatment schedule. It was the aim of the present study to test whether (1) associative (conditioning) and non-associative (pseudoconditioning) types of sensitization differ in the corresponding alterations in extracellular dopamine in the nucleus accumbens, and (2) the inhibitor of nitric oxide synthase (NOS), N(G)-nitro-L-arginine methyl ester (L-NAME), influences the two types of sensitization in a different way. Rats were treated with d-amphetamine (1 mg/kg i.p.) on days 1, 3, 5 and 7 and alternatively with saline on days 2, 4 and 6 under associative or non-associative conditions, respectively. A third (saline control) group was treated with saline daily for 7 days. Subsequently, probes for microdialysis were implanted into the nucleus accumbens. After a drug-free period of 10 days, on day 17, the increase in extracellular dopamine produced by 1 mg/kg d-amphetamine was much more pronounced in associative (conditioned) than in non-associative (pseudoconditioned) or naive rats. Pretreatment with L-NAME (100 mg/kg i.p.) on day 17 did not significantly alter the baseline concentrations of dopamine, but it inhibited the dopamine increase much more in associative than in naive rats and did not significantly affect it in non-associative rats. The results suggest that (1) associative sensitization to d-amphetamine leads to the most pronounced increase in extracellular dopamine in the nucleus accumbens, and (2) NO is very much involved in the expression of the associative increase in extracellular dopamine in the nucleus accumbens.     

Passive avoidance in rats: Disruption by dopamine applied to the nucleus accumbens

The acquisition of a one-trial step-through passive avoidance task was examined in rats following the administration of nialamide IP and dopamine (DA) or saline into the nucleus accumbens. DA-treated rats displayed impaired learning of the task as evidenced by their lower step-through latencies on a retest trial 7 days later. The specificity of this impairment was studied in a 2×2 design involving intracerebral injections prior to both training and testing trials. It was found that DA treatment prior to the training trial disrupted learning or memorization of the task but that DA did not affect performance or retrieval and did not induce state-dependent learning. These findings suggest that DA applied to the nucleus accumbens does not facilitate learning per se.     

Effects of substance P on extracellular dopamine in neostriatum and nucleus accumbens.

Microdialysis was used to monitor changes in dopamine release in the neostriatum and nucleus accumbens after peripheral administration of substance P in freely moving rats. Substance P in a dose of 50 micrograms/kg produced a steady moderate increase in dopamine levels in the neostriatum, which persisted for at least 5 h. In contrast, a dose of 250 micrograms/kg caused an acute increase in dopamine levels in the nucleus accumbens, which lasted about 2 h. These data suggest that the peripheral administration of substance P can influence dopamine release in mesolimbic and mesostriatal terminals.