Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens

The behavioral stimulant effect of peripheral cocaine injection into rats is augmented following daily administration. In vivo dialysis in the nucleus accumbens of conscious rats was used to determine if the increased behavioral response following daily cocaine administration is associated with an increase in extracellular dopamine concentration. Acute injection of cocaine (15 mg/kg, ip) produced an elevation in extracellular dopamine concentration in the nucleus accumbens. Following daily pretreatment with cocaine (15 mg/kg, ip X 4 days), a subsequent acute injection of cocaine (15 mg/kg, ip) significantly elevated the extracellular dopamine levels compared to that produced by a single acute injection. Although the levels of extracellular dopamine metabolites was significantly lowered by both acute cocaine and daily cocaine, no difference between these two groups of animals was measured. The increase in extracellular dopamine following a single acute injection of cocaine was not correlated to the motor stimulant response. However, after daily pretreatment with cocaine the motor stimulant response to acute cocaine was positively correlated with the increased extracellular concentration of dopamine in the nucleus accumbens. These data demonstrate that enhanced dopamine release into the nucleus accumbens may mediate the behavioral sensitization produced by daily injections of cocaine, but that other neural systems are influential in mediating the acute motor stimulant effect of cocaine.     

Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus

The regional brain metabolism of serotonin (5-HT) and dopamine (DA) was studied in rats injected with morphine either systemically or in the nuclei raphe medianus (MR) or dorsalis (DR). A subcutaneous injection of 10 mg/kg morphine significantly raised the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the diencephalon, striatum, nucleus accumbens and cortex with no effect in the hippocampus. Similar changes in 5-HT metabolism were found in animals injected with 5 micrograms/0.5 microliter in the DR whereas morphine injected in the MR raised 5-HIAA levels only in the nucleus accumbens. A subcutaneous or direct injection of morphine in the DR significantly raised the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens, but injection in the MR was ineffective. All the effects of morphine were blocked by naloxone, injected either intraperitoneally (1 mg/kg) or directly in the raphe nuclei (2 micrograms/0.5 microliter). Pretreatment with parachlorophenylalanine, an inhibitor of serotonin synthesis, significantly reduced the effect of morphine injected in the DR on dopamine metabolism in the striatum and nucleus accumbens. The data suggest that a major mechanism by which morphine increases 5-HT metabolism in the rat forebrain is activation of 5-HT cells in the nucleus raphe dorsalis, and this action may contribute to the increased DA metabolism found in the animal injected with morphine in this brain area.     

Differential effects of amfonelic acid on the haloperidol- and clozapine-induced increase in extracellular DOPAC in the nucleus accumbens and the striatum.

This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats. DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes. Amfonelic acid (2.5 mg/kg s.c.) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens. Haloperidol (1 mg/kg s.c.) increased extracellular DOPAC in both regions. When amfonelic acid was injected 5 min before haloperidol, the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum. Clozapine (30 mg/kg i.p.) increased extracellular DOPAC in both regions, an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum. When ritanserin (5 mg/kg i.p.), a serotonergic antagonist (5-HT-2), was co-administered with haloperidol, the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum. The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo. The effects of amfonelic acid on the neuroleptic-induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens. These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms, supporting the view that the regulation of dopamine metabolism differs in the two regions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulatory role of prolactin on the development of tuberoinfundibular dopaminergic neurones in prepubertal female rats: studies with cysteamine and somatostatin

Cysteamine, a potent depletor of prolactin and somatostatin, was used to determine the role of prolactin and somatostatin in the control of central dopamine neurones in prepubertal rats. Cysteamine (100 mg/kg, i.p., twice daily) was injected for 7, 14 or 21 days in 28-day-old Sprague-Dawley female rats in one study and for 3 days in 35-day-old rats in another. In control rats, the 3, 4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence increased threefold from day 35 to day 49, and serum prolactin concentration increased about 50%. Cysteamine lowered serum prolactin concentrations to 20%, and median eminence DOPAC and dopamine levels to 32-50% of control levels in both studies. The DOPAC levels in the nucleus accumbens and striatum were also lowered, while both DOPAC and dopamine in the paraventricular nucleus and periventricular nucleus (A14) were increased by cysteamine. A single injection of rat prolactin (0.01, 0.1 or 1 mg/kg) significantly increased DOPAC or DOPA levels in the median eminence, nucleus accumbens and striatum, but not in the paraventricular nucleus or A14 at 14 h later in 28-day old female rats or in 40-day-old rats pretreated with cysteamine. In contrast, central injection of somatostatin dose (0.001-1 microg/rat) and time (30-90 min) dependently decreased the DOPAC levels in the median eminence, paraventricular nucleus and A14 and increased those in the nucleus accumbens and striatum of adult female rats. These results indicate that serum prolactin is important for the maturation and maintenance of dopamine systems in the median eminence, nucleus accumbens and striatum, while somatostatin exhibits inhibitory and stimulatory effects on hypothalamic and midbrain dopamine systems, respectively.     

Infusions of 6-hydroxydopamine into the nucleus accumbens abolish the analgesic effect of amphetamine but not of morphine in the formalin test

The effects of bilateral infusions of 6-hydroxydopamine into the nucleus accumbens on analgesia produced by d-amphetamine and morphine were examined, in separate experiments, in the formalin test in rats. The lesions in the two experiments were not significantly different and dopamine in the nucleus accumbens, olfactory tubercle and striatum was depleted to 21.1%, 40.3% and 65.0% of control values, respectively.d-Amphetamine (0.75 and 2.0 mg/kg) and morphine (3.0 and 6.0 mg/kg) attenuated the response to formalin in unlesioned control rats. The analgesic effect of amphetamine was severely reduced by 6-hydroxydopamine lesions, and the residual analgesia was correlated with the amount of dopamine in the nucleus accumbens, but not with dopamine levels in the olfactory tubercle or striatum. Lesions also attenuated the locomotor stimulant effect of amphetamine. The analgesic effect of morphine was not altered by 6-hydroxydopamine infusions, nor was there any correlation between the analgesic effect of morphine and dopamine concentration in the nucleus accumbens, olfactory tubercle or striatum. The results indicate that the dopamine innervation of the nucleus accumbens is not critical for the analgesic effect of morphine but plays a major role in the analgesic effect of amphetamine.     

Acute effects of morphine on neurochemical estimates of activity of incertohypothalamic dopaminergic neurons in the male rat

The effects of an acute injection of morphine on the activities of mesotelencephalic, tuberoinfundibular and incertohypothalamic dopamine (DA) neurons was estimated by measuring: the rate of turnover of DA (decline after alpha-methyltyrosine); and the concentration of the DA metabolite, dihydroxyphenylacetic acid (DOPAC), in brain regions containing cell bodies or terminals of these neurons (i.e. nucleus accumbens, striatum, median eminence and various hypothalamic nuclei). The rate of turnover of DA and the concentration of DOPAC were increased in nucleus accumbens and striatum and decreased in the median eminence 60 min after the administration of morphine (10 mg/kg, s.c.). Morphine increased the rate of turnover of DA and the concentration of DOPAC in brain regions containing both cell bodies (periventricular nucleus and medial zona incerta) and terminals (medial preoptic, preopticosuprachiasmatic and dorsomedial nuclei) of incertohypothalamic DA neurons. The effects of morphine in all brain regions were blocked by pretreatment with naltrexone. These results indicate that incertohypothalamic DA neurons are stimulated by the acute administration of morphine, and in this respect they resemble the extrahypothalamic mesotelencephalic DA neurons rather than hypothalamic tuberoinfundibular DA neurons.     

The potential anti-addictive agent, 18-methoxycoronaridine, blocks the sensitized locomotor and dopamine responses produced by repeated morphine treatment

18-Methoxycoronaridine (18-MC), a novel synthetic iboga congener, attenuates the reinforcing efficacy of morphine, disrupts some signs of morphine withdrawal in physically dependent rats and attenuates the dopamine response in the nucleus accumbens to acute morphine. The present study further investigated the interactions between 18-MC and morphine by examining the effects of 18-MC (40 mg/kg, i.p., 19 h earlier) on the expression of dopamine sensitization in the nucleus accumbens in response to morphine (20 mg/kg, i.p.) and on the dose-effect curves for morphine-induced locomotion (0-30 mg/kg, i.p.) in rats treated either acutely or repeatedly (five, once daily, injections of 20 mg/kg, i.p.) with morphine. Compared to vehicle pretreated controls, 18-MC increased the potency of morphine, shifting the dose-response curve to the left, in acute morphine treated rats; however, 18-MC did not alter the potency of morphine in rats treated repeatedly with morphine. Repeated morphine administration induced locomotor sensitization in approximately 50% of the rats tested; in vehicle pretreated rats, the morphine dose-response curve was shifted to the left in sensitized as compared to non-sensitized rats. In 18-MC pretreated rats, sensitized and non-sensitized rats responded similarly to morphine, revealing a blockade of sensitization by 18-MC. Consistent with this behavioural finding, 18-MC pretreatment completely abolished the sensitized dopamine response in the nucleus accumbens expressed by rats repeatedly treated with morphine. It is suggested that the potential anti-addictive efficacy of 18-MC might be related to an ability to restore normal functioning to a hypersensitive mesolimbic dopamine system produced by previous repeated morphine administration.     

Acute changes in dopamine release and turnover in rat caudate nucleus following a single dose of methamphetamine

Summary. Acute changes in dopamine (DA) turnover were studied in the caudate nucleus (CN) of adult male rats between 0–24 h after a single injection of Methamphetamine (20 mg/kg, ip). A single dose of METH-induced an increase in DA turnover [(DOPAC + HVA)/DA] concomitant with an acute DA release followed by transient DA and DOPAC depletion in the rat CN. Received February 15, 2002; accepted May 1, 2002 Published online June 28, 2002     

Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats.

Ibogaine, an indolalkylamine, proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic system acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopamine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at several time points, between 1 h and 1 month post-injection. One hour after ibogaine-administration (40 mg/kg i.p.) a 50% decrease in DA along with a 37-100% increase in HVA were observed in all 3 brain regions studied: striatum, nucleus accumbens and prefrontal cortex. Nineteen hours after ibogaine-administration a decrease in DOPAC was seen in the nucleus accumbens and in the striatum. A week after administration of ibogaine striatal DOPAC levels were still reduced. A month after ibogaine injection there were no significant neurochemical changes in any region. We also investigated the effects of ibogaine pretreatment on morphine-induced locomotor activity, which is thought to depend on DA release. Using photocell activity cages we found that ibogaine pretreatment decreased the stimulatory motor effects induced by a wide range of morphine doses (0.5-20 mg/kg, i.p.) administered 19 h later; a similar effect was observed when morphine (5 mg/kg) was administered a week after ibogaine pretreatment. No significant changes in morphine-induced locomotion were seen a month after ibogaine pretreatment. The present findings indicate that ibogaine produces both acute and delayed effects on the tissue content of DA and its metabolites, and these changes coincide with a sustained depression of morphine-induced locomotor activity.     

In heterozygous GDNF knockout mice the response of striatal dopaminergic system to acute morphine is altered

Glial cell line-derived neurotrophic factor (GDNF) regulates striatal dopaminergic neurons. To study whether reduced endogenous GDNF affect morphine's effects on striatal dopamine transmission, we estimated extracellular concentrations of dopamine and its metabolites by microdialysis in vivo and tissue concentrations post mortem in mice lacking one GDNF allele (GDNF+/- mice). In the wild-type mice, acute morphine (5 and 10 mg/kg s.c.) increased accumbal dopamine output dose-dependently (maximally by 30 and 80%, respectively). In the GDNF+/- mice, 5 mg/kg of morphine enhanced the accumbal dopamine output maximally by 110%, and significantly more than morphine 10 mg/kg (maximally by 60%). Also, the response of extracellular accumbal DOPAC to acute morphine was significantly altered in the GDNF+/- mice. In mice of both genotypes, the responses to morphine in the caudate putamen were similar to but much less intense than those in the nucleus accumbens. Morphine at the doses 5, 10, and 30 mg/kg dose-dependently elevated the striatal tissue concentrations of DOPAC and HVA, but the effect of 30 mg/kg was significantly smaller in the GDNF+/- mice than in their wild-type littermates. The binding of [(3)H]DAMGO to striatal membrane homogenates was similar between the genotypes. However, morphine induced antinociception in the GDNF+/- mice at a smaller dose than in the controls. The finding that reduced GDNF level alters the effects of morphine on striatal dopamine and our previous findings of elevated extracellular striatal dopamine concentrations and FosB/DeltaFosB expression in the GDNF+/- mice show the importance of GDNF in the regulation of striatal dopaminergic system.     

Morphine acutely and persistently attenuates nonvesicular GABA release in rat nucleus accumbens

Withdrawal from repeated exposure to morphine causes a long-lasting increase in the reactivity of nucleus accumbens nerve terminals towards excitation. The resulting increase in action potential-induced exocytotic release of neurotransmitters, associated with behavioral sensitization, is thought to contribute to its addictive properties. We recently showed that activation of N-methyl-D-aspartate (NMDA) as well as dopamine (DA) D1 receptors in rat striatum causes tetrodotoxin-insensitive transporter-dependent GABA release. Since sustained changes in extracellular GABA levels may play a role in drug-induced neuronal hyperresponsiveness, we examined the acute and long-lasting effect of morphine on this nonvesicular GABA release in rat nucleus accumbens slices. The present study shows that morphine, through activation of mu-opioid receptors, reduces nonvesicular NMDA-induced [(3)H]GABA release in superfused nucleus accumbens slices. Moreover, prior repeated morphine treatment of rats (10 mg/kg, sc, 14 days) caused a reduction in NMDA-stimulated [(3)H]GABA release in vitro until at least 3 weeks after morphine withdrawal. This persistent neuroadaptive effect was not observed studying dopamine D1 receptor-mediated [(3)H]GABA release in nucleus accumbens slices. Moreover, this phenomenon appeared to be absent in slices of the caudate putamen. Interestingly, even a single exposure of rats to morphine (>2 mg/kg) caused a long-lasting inhibition of NMDA-induced release of GABA in nucleus accumbens slices. These data suggest that a reduction in nonvesicular GABA release within the nucleus accumbens, by enhancing the excitability of input and output neurons of this brain region, may contribute to the acute and persistently enhanced exocytotic release of neurotransmitters from nucleus accumbens neurons in morphine-exposed rats.     

Selective psychostimulant sensitization by food restriction: differential changes in accumbens shell and core dopamine

We have recently reported that behavioural sensitization to morphine, amphetamine, cocaine and nicotine is associated with an increased response of dialysate dopamine to the same drugs in the nucleus accumbens core and/or a reduced response in the shell. Prolonged exposure to stressful stimuli also induces behavioural sensitization to drugs of abuse. We therefore investigated the effect of different drugs of abuse on behaviour and on dopamine transmission in the nucleus accumbens shell and core of rats stressed by 1 week schedule of food restriction. Food-restricted rats (80% of their initial body weight) were implanted with microdialysis probes in the nucleus accumbens shell and core and challenged with cocaine (5 and 10 mg/kg i.p.), amphetamine (0.25 and 0.5 mg/kg s.c.), morphine (1 and 2 mg/kg s.c.), nicotine (0.2 and 0.4 mg/kg s.c.) and the changes in dialysate dopamine transmission were monitored together with the behaviour. Food restricted rats showed strong behavioural sensitization to cocaine and amphetamine but not to morphine or nicotine as compared to ad libitum fed controls. Behavioural sensitization to psychostimulants was associated with an increased response of dialysate dopamine in the core and with an unchanged or even reduced response in the shell. No significant differences were observed between controls and food-restricted animals in the ability of morphine and nicotine to stimulate dopamine transmission in the shell and core. The present results indicate that a sensitized dopamine response in the nucleus accumbens core is a general feature of the expression of behavioural sensitization.     

Effects of acute and chronic clozapine on dopaminergic function in medial prefrontal cortex of awake, freely moving rats

We previously showed that chronic administration of the clinically atypical and clinically superior antipsychotic drug clozapine selectively reduces dopamine (DA) release in the nucleus accumbens but not neostriatum, and that this effect appears mediated by anatomically selective mesolimbic DA depolarization blockade. The present study extends that research to another mesocorticolimbic DA locus, the medial prefrontal cortex. Acute clozapine challenge (5-40 mg/kg i.p.) produced dose-dependent increased extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the medial prefrontal cortex of awake, free-moving rats as measured by in vivo brain microdialysis. Chronic clozapine treatment (20 mg/kg/day for 21 days) did not significantly change basal extracellular levels of DA, DOPAC or HVA. Acute clozapine challenge on day 22 in the chronic clozapine-treated animals produced no significant differences in medial prefrontal cortex DA, DOPAC or HVA as compared to chronic vehicle-treated animals, indicating that tolerance to clozapine does not develop in the mesocortical DA system, in contrast to the mesolimbic system. The DA agonist apomorphine (100 micrograms/kg) produced decreased basal extracellular levels of DA, DOPAC and HVA in medial prefrontal cortex of both chronic clozapine-treated and chronic vehicle-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of oxidative stress mechanisms using a morphine / ascorbate animal model and novel N-stearoyl cerebroside and laurate sensors

Summary. The field of oxidative stress, free radicals, cellular defense and antioxidants is a burgeoning field of research. An important biomarker of oxidative stress is ascorbate and alterations in ascorbate have been shown to be a reliable measure of oxidative stress mechanisms. The purpose of this pharmacological study was to assess changes in ascorbate in a morphine/ascorbate animal model using novel sensors which selectively detect electrochemical signals for ascorbate, dopamine (DA) and serotonin (5-HT). Studies were also performed to show reversal of morphine-induced effects by the opioid antagonist, naloxone. In vivo studies were modeled after (Enrico et al. 1997, 1998) in which the oxidative biomarker, ascorbate, was reported to compensate for free radicals produced by morphine-induced increases in DA and 5-HT. In vivo studies consisted of inserting the Laurate sensor in ventrolateral nucleus accumbens (vlNAcc), in anesthetized male, Sprague-Dawley rats. In separate studies, laboratory rats were injected with (1) ascorbate, (5–35 mg/kg, ip) or (2) dehydroascorbate (DHA) (20–100 mg/kg, ip). In another study, (3) morphine sulfate (10–20 mg/kg, sc) was injected followed by a single injection of naloxone (5 mg/kg, ip) in the same animal. Results showed that in vlNAcc, (1) neither ascorbate nor DHA injections produced ascorbate release, (2) morphine significantly increased DA and 5-HT release, but did not alter ascorbate release, and (3) naloxone significantly reversed the increased DA and 5-HT release produced by morphine. Moreover, the sensors, N-stearoyl cerebroside and laurate were studied in vitro, in separate studies, in order to assess selective and separate electrochemical detection of ascorbate, DA and 5-HT, neuromolecules involved in oxidative stress mechanisms. In vitro studies consisted of pretreatment of each sensor with a solution of phosphotidylethanolamine (PEA) and bovine serum albumin (BSA) which simulates the lipid/protein composition of brain. Each new sensor was tested for stability, sensitivity and selectivity by pipetting graduated increases in concentration of ascorbate, DA and 5-HT into an electrochemical cell containing saline/phosphate buffer. Multiple and repetitive images of electrochemical signals from ascorbate, DA and 5-HT were recorded. Results showed that both sensors produced three well-defined cathodic, selective and separate electrochemical signals for ascorbate, DA and 5-HT at characteristic oxidation potentials. Dopamine and 5-HT were detected at nM concentrations while ascorbate was detected at μM concentrations. In summary, the data show that very low concentrations of ascorbate occurred in vlNAcc since novel sensors detected ascorbate at high concentrations in vitro. The data indicate that little or no change in oxidative stress mechanisms occurred in vlNAcc after morphine or naloxone administration since the oxidative biomarker, ascorbate, was not signifi cantly altered. Thus, oxidative stress mechanisms and novel N-stearoyl cerebroside and laurate sensors, which selectively detect and separate neuromolecules involved in these mechanisms, may be potentially clinically relevant. Correspondence: Patricia A. Broderick, Department of Physiology and Pharmacology, The City University of New York Medical School, Convent Ave. & West 138th St., (Office: Suite 310F; MailRoom: Harris 01), NY 10031, USA     

Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment.

This study shows the effect of opiate withdrawal on dopamine (DA) in the nucleus accumbens (NAC). Microdialysis was used to detect variations in extracellular DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC of freely moving rats during acute and chronic morphine treatment followed by naloxone-precipitated withdrawal with and without clonidine. Basal levels of extracellular DA did not change between sessions, but morphine (20 mg/kg, i.p.) caused a significant and identical increase in extracellular DA and metabolites in both the acute phase (day 1) and the chronic phase (day 7). On day 8, naloxone (20 mg/kg i.p.) caused a significant decrease in DA levels accompanied by typical withdrawal symptoms such as wet dog shakes and teeth-chattering. Clonidine pretreatment (200 micrograms/kg, i.p.) eliminated both the withdrawal symptoms and the DA decrease. These results support the view that morphine increases extracellular DA at times when the drug is rewarding and also suggest that the converse may be true; morphine withdrawal decreases DA release in association with the aversive state.     

Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats

Summary The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here.     

Tail-pinch stress increases extracellular DOPAC levels (as measured by in vivo voltammetry) in the rat nucleus accumbens but not frontal cortex: antagonism by diazepam and zolpidem

The effect of a tail-pinch stress on dopamine metabolism in the nucleus accumbens and frontal cortex was investigated in the awake unrestrained rat by measuring extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) levels through the use of in vivo differential pulse voltammetry. Mild tail pressure for 8 min caused a large (maximal effect + 70%) and sustained (more than 2 h) increase in the amplitude of the DOPAC oxidation peak in the nucleus accumbens but not in the prefrontal cortex. A similar increase in DOPAC levels was observed in the nucleus accumbens postmortem 1 h after tail-pinch stress. The tail-pinch induced increase in extracellular DOPAC levels in the nucleus accumbens was antagonized by pretreatment with diazepam (5 mg/kg i.p.) or zolpidem (5 mg/kg i.p.), a novel non-benzodiazepine hypnotic possesing anxiolytic properties. These results suggest that in contrast to other stressors, tail-pinch selectively activates dopaminergic systems projecting to the nucleus accumbens.     

Differential regional and kinetics effects of piribedil and bromocriptine on dopamine metabolites: a brain microdialysis study in freely moving rats

Summary Brain microdialysis coupled to HPLC was applied to freely moving rats to investigate the regional kinetics of piribedil and bromocriptine on the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in striatum, nucleus accumbens, and frontal cortex. Both D2 agonists (20 mg/kg i.p.) decreased DOPAC and HVA in the three brain regions. The responsiveness of frontal cortex to both compounds was greater than those previously reported with other dopaminergic drugs. Regional and temporal differences were observed under piribedil: DOPAC and HVA levels decreased more in the nucleus accumbens than in striatum or frontal cortex but increased over basal values from the 5th hour in the frontal cortex suggesting a late stimulatory effect of piribedil on dopamine synthesis in this area. Such regional effects differentiate piribedil from most other D2 agonists and could explain some behavioural and therapeutic actions possibly related to involvement of nucleus accumbens or/and frontal cortex.     

Invariance of the density of dopamine uptake sites and dopamine metabolism in the rat brain after a chronic treatment with the dopamine uptake inhibitor GBR 12783

Summary A chronic treatment (10 mg/kg, twice daily during 9 days) with the dopamine uptake inhibitor GBR 12783 was performed in rats at a dose increasing their locomotor activity.Forty-eight hours after the last administration, animals were sacrificed and³H mazindol binding was performed on brain slices. Autoradiographic analysis revealed no change in this binding relatively to control animals in regions with high dopamine contents: striatum, nucleus accumbens, olfactory tubercle, substantia nigra and ventral tegmentum area. The treatment did not either modify the levels of dopamine (DA) and metabolites (HVA, DOPAC) both in the striatum and the nucleus accumbens. Thus, early after the end of the treatment, the chronic blockade of the dopamine uptake complex regulates neither the dopamine uptake complex nor the dopamine metabolism.     

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was perfomed through microdialysis probes into the rat ventral pallidum (10 μ1 of 0 2.6 4.0, 13.0, and 26.0 mM) or globus pallidus (10 μ1 of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.