The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats

It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinsons disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5×1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinsons disease.     

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.     

用在体脑微透析技术研究大鼠纹状体中单胺递质的释放和代谢

采用脑微透析技术与高效液相色谱-电化学检测器联用测定了清醒自由活动大鼠纹状体细胞外液中多巴胺(DA)及其酸性代谢物3,4-二羟苯乙酸(DOPAC)和高香草酸(HVA)以及5-羟色胺代谢物5-羟吲哚乙酸(5-HIAA)的含量.透析液中DA为0.44 pmol/40μl,DOPAC和HVA含量较DA高约80倍.右旋苯丙胺2 mg/kg,ip使纹状体DA释放显著增加,DOPAC和HVA含量明显下降.     

Comparison of the effects of epibatidine and nicotine on the output of dopamine in the dorsal and ventral striatum of freely-moving rats

The effects of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine on the extracellular concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal (caudate-putamen) and the ventral striatum (nucleus accumbens) of freely-moving male Wistar rats were studied by in vivo microdialysis. In the dorsal striatum, epibatidine (3.0 microg/kg s.c.) significantly elevated the extracellular concentrations of DA, DOPAC and HVA. In contrast, epibatidine did not alter the extracellular DA concentration in the ventral striatum, but elevated significantly the concentration of DOPAC and also tended to elevate that of HVA. In parallel experiments, nicotine (0.5 mg/kg s.c.) significantly increased DA output in the ventral striatum whereas only a modest and non-significant increase of extracellular DA concentration was found in the dorsal striatum. Earlier studies have shown that the doses of epibatidine and nicotine used in the present study are about equieffective at least with respect to the analgesia-producing or hypothermic effects of the drugs. Comparison of the effects of epibatidine and nicotine suggests that the responses of the mesolimbic and nigrostriatal dopaminergic systems to the two nicotinic receptor agonists differ. Epibatidine, in contrast to nicotine, preferentially stimulates the nigrostriatal vs. the mesolimbic dopaminergic system. Therefore, novel nicotinic AChR ligands structurally related to epibatidine may have low abuse potential.     

Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition

In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 microM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 microM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.     

5-HT3 receptor agonist induced carrier-mediated release of dopamine in rat striatum in vivo.

1. In vivo microdialysis was used to study the effect of phenylbiguanide (PBG), a 5-hydroxytryptamine3 receptor agonist, on the extracellular output of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the corpus striatum. 2. PBG produced a dose-related (10-500 microM) increase in the release of dopamine (280-2000%). DOPAC and HVA output decreased with the perfusion of PBG. This decrease was similar with 50-500 microM PBG. 5-HIAA output was not affected by any PBG concentration used. 3. When nomifensine (5 microM) was included in the Ringer solution, the effect of PBG on the release of dopamine was ameliorated or inhibited. However, the effect of PBG (50-500 microM) on the extracellular output of DOPAC and HVA was similar in the absence and in the presence of nomifensine (5 microM). 4. Perfusion of MDL 72222, a 5-hydroxytryptamine3 receptor antagonist, at doses of 50 and 100 microM produced similar decreases (50% of controls) and increases (120% of controls) in the extracellular output of dopamine and DOPAC, respectively. HVA and 5-HIAA output levels were not affected by either concentration of MDL 72222. MDL 72222 (10 microM) produced a slight and transient increase in the release of dopamine and a decrease in the extracellular output of DOPAC. HVA and 5-HIAA extracellular output was not affected by MDL 72222 (10 microM) perfusion. 5. Co-perfusion of MDL 72222 (10 and 100 microM) or tetrodotoxin (1 microM) with PBG (50 microM) did not modify the effect produced by PBG (50 microM) alone on the release of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Deamination of norepinephrine, dopamine, and serotonin by type A monoamine oxidase in discrete regions of the rat brain and inhibition by RS-8359

Levels of monoamines and their metabolites were determined in the cortex, hippocampus, and striatum of rats killed by microwave irradiation. Moclobemide (20 mg/kg, p.o.) and clorgyline (10 mg/kg, p.o.), type A monoamine oxidase (MAO-A) inhibitors, increased the levels of normetanephrine (NM) and 3-methoxytyramine (3MT) and decreased those of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) in almost all three regions. Deprenyl (10 mg/kg, p.o.), a type B monoamine oxidase inhibitor, however, little affected monoamine and metabolite levels in all regions. The maximum effects of RS-8359 (10 mg/kg, p.o.) were obtained at 2 to 6 hr after administration, when the levels of norepinephrine (NE), NM, 3MT, and serotonin (5HT) in all regions and dopamine (DA) in the striatum increased, while DOPAC and HVA levels decreased. The levels of monoamines and metabolites had returned to normal by 20 hr after administration. Dose-dependency of the effects of RS-8359 on monoamine metabolites was observed at doses up to 30 mg/kg (p.o.) at 1 and 6 hr after administration. In conclusion, NE, DA, and 5HT are exclusively or preferentially deaminated by MAO-A in the cortex, hippocampus, and striatum of rats, and RS-8359 exhibits a reversible MAO-A inhibitory action in all three regions tested in vivo.     

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.     

松果菊苷对6-羟基多巴胺急性损伤大鼠纹状体细胞外液中单胺类递质的影响

目的研究松果菊苷(ECH)对6-羟基多巴胺(6-OH-DA)急性损伤大鼠纹状体细胞外液中单胺类递质的影响,以探讨ECH对脑神经保护作用的可能机制。方法30只大鼠随机分为对照组、模型组、ECH高、低剂量组和美多芭(MD)组。除对照组纹状体内注射等量生理盐水外,其余各组注射6-OHDA4μl(3g·L-1)制作大鼠多巴胺(DA)能神经元损伤的急性模型,术后给予各组动物相应药物或生理盐水腹腔注射,每天1次,于d7进行微透析试验,将透析液注入高效液相—电化学检测器(HPLC-ECD)测定各组纹状体细胞外液中DA、3,4-二羟基苯乙酸(DOPAC)和高香草酸(HVA)的含量。结果与对照组相比,模型组动物纹状体细胞外液中DA、DOPAC和HVA含量均明显降低(P<0.01);而ECH高、低剂量组(3.5、7mg.kg-1)和美多芭(MD)组3种物质的含量则高于模型组,两两相比差异具有统计学意义(P<0.05,P<0.01)。结论ECH对6-OHDA急性损伤所致大鼠纹状体细胞外液中的DA及其代谢产物含量减少具有较好的预防作用。     

The metabolism of systemically-administered L-dihydroxyphenylalanine, by intact and dopamine-denervated striata, as revealed by brain microdialysis

Idiopathic Parkinson's Disease arises from the progressive loss of dopamine (DA)-utilizing neurons of the nigrostriatum and responds to the replacement of DA with L-dihydroxyphenylalanine (L-DOPA). In awake rats, with unilateral lesions induced with 6-hydroxydopamine (6-OHDA) of the DA-utilizing nigrostriatal pathway, treatment with L-DOPA causes the rapid onset of brisk contralateral turning behaviour. In urethane-anesthetized rats with identical unilateral lesions of the nigrostriatum, dialysis of the striatum, performed before and after the systemic administration of L-DOPA (25 mg/kg i.p.), did not demonstrate any alteration in extracellular DA in the striatum which was DA-deprived compared to intact striata. After treatment with L-DOPA extracellular levels of the metabolites of DA. DOPAC and HVA increased several fold. These results suggest: (a) DA neurons surviving after extensive lesions with 6-OHDA can compensate for loss of DA in the striatum and maintain extracellular fluid (and presumably synaptic) concentrations of DA; (b) in striata with extensive depletion of DA L-DOPA undergoes rapid decarboxylation to DA, followed by catabolism to DOPAC and HVA; and (c) in urethane-anesthetized animals, DA formed from DOPA does not appear to enter a releasable pool.     

Effects of neurotransmitters or drugs on the in vivo release of dopamine and its metabolites

The effects of neurotransmitters or drugs on the release of endogenous dopamine (DA) and extracellular levels of its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were examined in vivo by intracerebral dialysis. A dialysis tube was implanted stereotaxically through bilateral caudate nuclei of rats and perfused with the Ringer solution. Amounts of DA, DOPAC and HVA in the perfusates were measured by high performance liquid chromatography (HPLC) with electrochemical detection. The basal level of DA was 2.76 +/- 0.64 pg/min, whereas the levels of DOPAC and HVA were 218.7 +/- 20.7 and 142.4 +/- 10.6 pg/min, respectively. Apomorphine (4 mg/kg, i.v.) reduced the efflux of DA and its metabolites. Haloperidol (0.4 mg/kg, i.v.) did not change DA release and produced only a minor increase of its metabolites. This increase of metabolites was inhibited by pargyline. Met-enkephalin (10(-4) M), substance P (10(-4) M) and acetylcholine chloride (10(-4) M) added to the perfusing medium increased the release of DA. Met-enkephalin also increased the release of DOPAC. gamma-Amino-n-butyric acid (GABA, 10(-4) M) reduced the release of DOPAC and HVA when added to the perfusing medium. Thyrotropin releasing hormone (TRH, 5 mg/kg, i.v.) increased the release of HVA. These findings indicated that different mechanisms mediated effects of neurotransmitters or drugs on the release and metabolism of DA in the rat striatum.     

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.     

Involvement of opioid mu1-receptors in opioid-induced acceleration of striatal and limbic dopaminergic transmission.

The role of mu1-opioid receptors in the acceleration of cerebral dopaminergic transmission induced by morphine and the putative mu1-opioid agonist, etonitazene, was studied in rats by measuring the tissue levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal striatum and nucleus accumbens. The striatal extracellular concentrations of DA and its metabolites in freely moving rats were estimated as well. Morphine (3 mg/kg) and etonitazene (2.5 microg/kg) increased the striatal and accumbal dopamine metabolism as measured by the tissue ratios of DOPAC/DA and HVA/DA. The mu1-opioid receptor antagonist, naloxonazine (15 mg/kg), significantly antagonized these elevations except the morphine-induced elevation of striatal HVA/DA ratio. Both morphine (3 mg/kg) and etonitazene (1, 2.5, and 5 microg/kg) elevated the striatal extracellular DA, DOPAC, and HVA. Naloxonazine antagonized the effects of morphine and etonitazene on striatal extracellular DA concentration as well as etonitazene's effects on DOPAC and HVA, but not morphine's effects on DOPAC and HVA. As we previously showed concerning morphine, the conditioned place preference induced by etonitazene was inhibited by naloxonazine. These findings emphasize the role of mu1-opioid receptors in opioid reward, in which the mesolimbic dopaminergic system is considered to be importantly involved. Our results clearly show that in addition to the mesolimbic dopaminergic system the mu1-opioid receptors are also involved in the control of nigrostriatal DA release and metabolism. However, the effects of etonitazene on the striatal DA differ from those of morphine, suggesting that the opioid mechanisms regulating these two DA systems differ.     

Effect of conditioning with d-amphetamine on the extracellular concentration of dopamine and its metabolites in the striatum of behaving rats

The effect of classical conditioning with d-amphetamine on the extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving rats was studied using microdialysis. This was done in order to test, whether there occurred alterations in DA release as conditioned responses in the striatum. The first series of experiments studied the acute effects of d-amphetamine on the concentration of DA and its metabolites DOPAC and HVA. d-Amphetamine (2 mg/kg, s.c.) increased extracellular DA and decreased DOPAC and HVA. Behaviorally, it led to stereotyped locomotor activation and sniffing. In principle, these observations confirmed earlier findings. In a second series, conditioned responses to d-amphetamine were studied. Rats were implanted with guide cannulas prior conditioning experiments started. For conditioning experiments, the rats were divided into three groups: conditioned group, pseudoconditioned group and a drug-naive control group. After 7 daily training sessions with d-amphetamine (2 mg/kg), on the 8th day, the test day, rats were injected with saline and exposed to the conditional stimuli, while they were observed for their stereotyped, conditioned response. Additionally, microdialysis was performed in order to observe possible changes in the extracellular transmitter or metabolite concentrations. Conditioning with amphetamine led to conditioned stereotypic behavior. In comparison with the pseudoconditioned rats, there was an increase in DA release as conditioned response to amphetamine. In pseudoconditioned rats. DOPAC and HVA were slightly higher than in both other groups. DOPAC and HVA were lower in rats conditioned to d-amphetamine when compared with the pseudoconditioned ones. The results suggest that with regard to DA release, the conditioned responses to d-amphetamine mimicked the acute pharmacological responses. The same is valid for the DA metabolites, although in the opposite direction — they mimicked decreases. Furthermore, the conditioned DA responses to d-amphetamine might contribute to conditioned behavioral responses observed in these experiments. Correspondence to: K. Kuschinsky at the above address     

Nitric oxide-independent cGMP efflux in the striatum of rats exposed to carbon monoxide as determined by microdialysis

Extracellular cGMP in the striatum of rats exposed to 3000 ppm carbon monoxide (CO) or 8% O2 was decreased during the early period of exposure. Thereafter, extracellular cGMP in rats exposed to CO, but not 8% O2, was transiently increased. A nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine, strongly reduced the steady-state level of extracellular cGMP in the striatum, indicating a primary role of NO in cGMP production. However, it failed to suppress the CO-induced increase in extracellular cGMP in the striatum. These findings suggest that CO may stimulate cGMP production in rat striatum independently of NO and hypoxia.     

Effects of phencyclidine on extracellular levels of dopamine, dihydroxyphenylacetic acid and homovanillic acid in conscious and anesthetized rats

Dose-dependent effects of phencyclidine on extracellular levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum were studied in both urethane-anesthetized and conscious rats. In vivo microdialysis was used to collect 10 min samples that were analyzed for levels of DA, DOPAC and HVA, using high-performance liquid chromatography with electrochemical detection (HPLC-EC). In both the anesthetized and conscious preparations, 20 mg/kg of phencyclidine produced an increase in extracellular levels of DA, 10 mg/kg resulted in no change, while 1 mg/kg produced a slow decrease. In the anesthetized animals phencyclidine did not have a significant effect on levels of DOPAC or HVA, but in the conscious animals phencyclidine produced a dose-dependent decrease in levels of DOPAC and HVA. The increase in levels of DA could be the result of increased release of DA or inhibition of the uptake of DA. The decrease in levels of DOPAC and HVA, at the 1 mg/kg dose, could result from a decrease in the synthesis of DA that is offset at the 10 and 20 mg/kg doses by opposing mechanisms.     

Further evaluation of the mechanism by which amphetamine reduces striatal dopamine metabolism: a brain dialysis study

An intracerebral dialysis method was used in the halothane-anaesthetized rat to further clarify the site which mediates the amphetamine-induced decrease of the striatal dopamine (DA) metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Following subcutaneous injection of amphetamine (0.1-5.0 mg/kg), DOPAC and HVA in striatal perfusates decreased over the 2 h time course, with 0.5 mg/kg of the drug having maximal effect. In comparison, amphetamine (0.1-5.0 mg/kg) caused a strictly dose-dependent increase of DA in striatal perfusates. Following low (0.1-5.0 mg/kg) but not high (2.0-5.0 mg/kg) doses of amphetamine there was a negative correlation between the increase of DA and decrease of DOPAC in the striatum. Amphetamine (0.5 mg/kg) caused a reduction in DA metabolism in the ibotenic acid-lesioned striatum. Intranigral injection of 10 micrograms, but not of 1 microgram amphetamine, decreased DOPAC (-27%) in the striatal perfusates. However, injection of 1 microgram amphetamine into the striatum caused a strong decrease in striatal DOPAC (-46%) and HVA (-22%). The possible mechanisms of action of amphetamine are discussed in the light of these data.     

The D1 agonist SKF 38393 increases dopamine release in the developing rat striatum

Changes in extracellular levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) following systemic injection of the D1 agonist SKF 38393, 10 mg/kg, the D1 antagonist SCH 23390, 0.5 mg/kg, or the mixed D1/ /D2 agonist apomorphine, 0.05 mg/kg, were monitored in the striatum of developing rats implanted with a dialysis probe. There was a significant age-related increase in DA in perfusates from adult and 35-36-day-old rats injected with SKF 38393 compared to 10-11- and 21-22-day-old rats. Also, SKF 38393 significantly decreased DOPAC and HVA in perfusates from 10-11-day-old rats when compared to the older aged rats. Pretreatment with SCH 23390 completely blocked the SKF 38393-induced increase in DA but not the SKF 38393-induced decrease in DOPAC and HVA. In contrast, there were no significant differences between ages in the response to DA to SCH 23390. However, SCH 23390 did produce a small, but significant, decrease in DOPAC and HVA at 10-11 days of age compared to the other ages. Forty minutes after injecting apomorphine, DA levels were decreased by 45% and remained near this level for the duration of the experiment. These results indicate that stimulation of DA D1, receptors can increase striatal DA release and that this ability is acquired between 21 and 35 days of age. This finding is consistent with the idea of opposing roles for DA D1 and D2 receptor subtypes.     

Effects of cocaine on release and uptake of dopamine in vivo: differentiation by mathematical modeling

Although considerable effort has been invested trying to distinguish between the effects of cocaine on dopamine (DA) uptake and release in both in vitro and in vivo experiments, disagreement over the specific actions of cocaine remains. The results obtained by combining experimental extracellular DA data with a mathematical model of the dopaminergic neuron allow examination of the cocaine uptake inhibition/release question. The extracellular DA concentration profile observed following a 30 mg/kg IP cocaine injection can be modeled if both pre- and postsynaptic uptake are competitively inhibited by cocaine with or without an enhanced DA release effect. However, if cocaine elicits enhanced DA release, modeling predicts a 40% increase over basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and a 30% increase in homovanillic acid (HVA) at 60 minutes following a 30 mg/kg IP cocaine injection. Reported DOPAC and HVA data for similar cocaine doses indicate little change in either DOPAC or HVA. These data agree best with modeled metabolite predictions for little or no cocaine-enhanced DA release.     

Differential effects of acute and subacute HA-966 treatment on storage and release of striatal dopamine

Acute injections of HA-966 (100 mg/kg) into rats caused a rapid elevation of dopamine (DA) content in the striatum. 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels increased after a latency period of 0.5 h and 1 h respectively. Repeated ("subacute") HA-966 treatment produced a smaller DA increase than did single administration, while DOPAC and HVA rose at the same rate after both treatments. In HA-966-pretreated rats no tolerance for DA increase followed a lesion of the dopaminergic fibres. Acute as well as subacute HA-966 prevented the disappearance of DA after alpha-methyl-p-tyrosine for about 3 h. In both cases DOPAC and HVA levels dropped sharply after HA-966. HA-966 had no influence on the decline of DOPAC and HVA levels after monoamine oxidase inhibition. It is concluded that the rises of DOPAC and HVA after HA-966 did not occur because the capacity of the vesicular DA stores was exceeded. Instead, HA-966 affects the storage mechanism for newly formed DA. Possible explanations for the observed tolerance to DA accumulation after HA-966 are discussed.