On the role of serotonin2A/2C receptors in the sensitization to cocaine.

Apart from showing involvement of dopamine, recent studies also indicate a role of serotonin (5-HT) in the behavioral effects of cocaine in rodents. In the present study we investigated the role of 5-HT2A/2C receptors in the development or expression of sensitization to cocaine in rats, using ketanserin, an antagonist at these receptors. Since ketanserin also shows a high affinity for alpha1-adrenoceptors, prazosin, a comparative antagonist at those receptors was also examined. Male Wistar rats were treated repeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either vehicle, or ketanserin (1-3 mg/kg) or prazosin (3 mg/kg); afterwards, on day 10, they received a challenge dose of cocaine (10 mg/kg). In another experiment, the animals were given either with vehicle or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combination with vehicle, or ketanserin (1-3 mg/kg) or prazosin (3 mg/kg) on day 10. Acute administration of cocaine increased the locomotor activity in rats; that hyperactivation was inhibited by ketanserin (3 mg/kg), but not by prazosin. In animals treated repeatedly with cocaine, the locomotor hyperactivity induced by a challenge dose of the psychostimulant was ca. 2-3 times higher than that after its first administration. No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocaine, ketanserin+cocaine, or prazosin+cocaine. In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocaine was dose-dependently decreased when the drug was combined with ketanserin, but not with prazosin. The above findings indicate a role of 5-HT2A/2C receptors (but not alpha1-adrenoceptors) in the acute locomotor hyperactivity, as well as in the expression (but not development) of cocaine sensitization. Since chronic use of cocaine by humans may lead to psychoses or craving for this drug of abuse, our findings also seem to indicate possible importance of 5-HT2A/2C receptor antagonists in the therapy of cocaine addiction.     

Phospholipase A2 activity in the rat uterus: Modulation by steroid hormones

Phospholipase A2 (PLA2), an enzyme which provides free arachidonic acid for the synthesis of prostaglandins (PG), has been studied in the rat uterus under various experimental conditions. Uterine PLA2 activity increased 14 fold in hypophysectomized rats implanted with Silastic capsules containing estradiol-17β as compared to those treated with oil vehicle. Dexamethasone treatment reduced the PLA2 activity induced by estrogen by 78%. Hypophysectomized animals treated with progesterone (2mg/day) for 5 days had low levels of uterine PLA2 activity but a single injection of estradiol (10ug/rat) given 24 h after the last injection of progesterone increased activity 5 fold within 12 h. Administration of the protein synthesis inhibitor cycloheximide in the rats treated with progesterone, before and after injection of estradiol, prevented the stimulating action of the estrogen on PLA2 activity. If the estrogen was given at the time of the last injection of progesterone, PLA2 activity did not increase until 24 h later and the level was much less than when progesterone was absent. The results are consistent with the view that estrogen stimulates uterine prostaglandin production because of its effect upon PLA2; this effect can be greatly reduced by a glucocorticoid. Progesterone may modulate the PLA2 stimulating effect of estrogen in order to direct the production of specific PGs by regulating the amount of arachidonic acid available for PG synthetase.     

Carbamazepine produces nonspecific effects on cocaine self-administration in rats.

Anecdotal evidence in humans suggest that carbamazepine suppresses cocaine-induced rush and craving. Such claims are unsupported in controlled trials using a placebo control. In the present study, rats were trained to self-administer i.v. cocaine in daily 2-hr sessions in which every tenth lever press delivered 1 mg/kg cocaine. After responding was stable, they were injected before each session with the vehicle for 2 days followed by carbamazepine for 2 days. At a 7 mg/kg dose, carbamazepine was without effect, whereas 15 mg/kg suppressed responding for cocaine only on the second (day 4) day of carbamazepine treatment. With 4 consecutive days of treatment, carbamazepine (15 mg/kg) reduced cocaine-maintained responding slightly, but significantly. In another group of animals trained to lever-press for food reinforcement, carbamazepine (15 mg/kg) also significantly decreased the rate of responding, suggesting that the suppression of responding was not specific to cocaine-reinforced behavior.     

PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity

Phosphatidylinositol 3-kinase (PI3K) is an important signaling molecule involved in cell differentiation, proliferation, survival, and phagocytosis, and may participate in various brain functions. To determine whether it is also involved in cocaine sensitization, we measured the p85alpha/p110 PI3K activity in the nuclear accumbens (NAc) shell, NAc core, and prefrontal cortex (PFC) following establishment of cocaine sensitization and its subsequent reversal. Na?ve rats were rank-ordered and split into either daily cocaine or saline pretreatment group based on their locomotor responses to an acute cocaine injection (7.5 mg/kg, i.p.). These two groups were then injected with cocaine (40 mg/kg, s.c.) or saline for 4 consecutive days followed by 9-day withdrawal. Cocaine sensitization was subsequently reversed by 5 daily injections of the D1/D2 agonist pergolide (0.1 mg/kg, s.c.) in combination with the 5-HT3 antagonist ondansetron (0.2 mg/kg, s.c., 3.5h after pergolide injection). After another 9-day withdrawal, behavioral cocaine sensitization and its reversal were confirmed with an acute cocaine challenge (7.5 mg/kg, i.p.), and animals were sacrificed the next day for measurement of p85alpha/p110 PI3K activity. Cocaine-sensitized animals exhibited increased PI3K activity in the NAc shell, and this increase was reversed by combined pergolide/ondansetron treatment, which also reversed behavioral sensitization. In the NAc core and PFC, cocaine sensitization decreased and increased the PI3K activity, respectively. These changes, in contrast to that in the NAc shell, were not normalized following the reversal of cocaine-sensitization. Interestingly, daily injections of pergolide alone in saline-pretreated animals induced PI3K changes that were similar to the cocaine sensitization-associated changes in the NAc core and PFC but not the NAc shell; furthermore, these changes in saline-pretreated animals were prevented by ondansetron given 3.5h after pergolide. The present study suggests that selective enhancement of the PI3K activity in the NAc shell may be one of key alterations underlying the long-term cocaine sensitization. To the extent cocaine sensitization is an important factor in human cocaine abuse, pharmacological interventions targeted toward the NAc shell PI3K alteration may be useful in cocaine abuse treatment.     

Effects of nitric oxide synthesis inhibition with or without nitric oxide inhalation on responses to systemic cocaine administration in rats

The effects of N^ω-nitro-L-arginine methyl ester (L-NAME) i.v. and nitric oxide (NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats. Cocaine (4 mg/kg/min i.v.) produced seizures then isoelectric electrocephalographic (isoEEG) activity as well as an initial increase in systolic blood pressure and heart rate, then progressive cardiovascular system depression culminating in asystole. Pretreatment with L-NAME (2 mg/kg/min i.v.) for 30 min significantly reduced the incidence of seizure as compared to saline treated animals (saline 7/8; L-NAME 3/8). Doses of cocaine that produced arrhythmias, isoEEG and asystole were significantly lower in the L-NAME treated animals as compared to the saline group. L-NAME did not affect peak systolic blood pressure and heart rate responses to cocaine. NO inhalation (80 ppm) did not affect CNS and cardiovascular responses to cocaine in control animals but enhanced the effects of L-NAME on cocaine toxicity. The results show that pretreatment with L-NAME reduces the central nervous system stimulatory effect of cocaine (reduced seizure incidence) and enhances its depressant effect on both the central nervous system (lower does for isoEEG) and the cardiovascular system (lower dose for arrhythmias and asystole), but does not affect the cardiovascular stimulatory action of cocaine. NO inhalation does not protect against any of the systemic effects of cocaine in animals with normal or suppressed NO production.     

L-tryptophan attenuation of the dopaminergic and behavioral responses to cocaine.

This study assessed the effects of acute intravenous L-tryptophan (neutral amino acid precursor for serotonin) administration on cocaine-induced dopaminergic responses. Male Sprague-Dawley rats were surgically implanted with guide cannulas in the nucleus accumbens 5 days prior to the study and with vascular catheters (carotid artery and jugular vein) on the day prior to the study. Using microdialysis, extracellular nucleus accumbens dopamine levels were measured in freely moving rats. Following a 2 h equilibration period, animals were randomized (n=7-8 per group) to receive either a constant intravenous (IV) infusion of L-tryptophan (200 mg/kg/h) or an equal volume (2 ml/h) of saline. Ninety minutes into the infusion, cocaine (20 mg/kg) was injected intra-peritoneally. Cocaine increased nucleus accumbens microdialysate dopamine levels (500% at 30 min). This was associated with marked hyperactivity. Tryptophan infusion elevated plasma tryptophan (8-fold), and blunted the cocaine-induced increase in nucleus accumbens microdialysate dopamine levels by approximately 60%. Furthermore, tryptophan attenuated the cocaine-induced locomotor activity. These neurochemical and behavioral effects of tryptophan were associated with a marked increase in brain tissue serotonin content. The results of these studies demonstrate the feasibility of acute dietary manipulation of neurochemical and behavioral responses to cocaine. The duration, adaptation and tolerance to these effects remain to be elucidated.     

Hepatoprotective effects of saponarin, isolated from Gypsophila trichotoma Wend. on cocaine-induced oxidative stress in rats

The antioxidant effect of saponarin, which is the main flavone isolated from Gypsophila trichotoma Wend., and its protection against cocaine hepatotoxicity were investigated in male Wistar rats. The animals were treated with cocaine (40 mg/kg i.p.) alone and also after 3 consecutive days of pretreatment with saponarin (80 mg/kg p.o.). After 18 hours the rats were sacrificed by decapitation. The production of thiobarbituric acid reactive substances, reduced glutathione (GSH) and the activity of the following antioxidant enzymes: catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were assessed in liver homogenate. Administered alone, cocaine induced significant hepatotoxicity manifested with GSH depletion and reduced antioxidant defences. Saponarin pretreatment, however, decreased cocaine toxicity both by increasing GSH levels and antioxidant enzyme activities. The results of this study proved the antioxidant activity of saponarin and its protective effect against cocaine-induced oxidative stress and hepatotoxicity.     

Site and mechanism of behavioral tolerance to cocaine: A study of dopamine release in Wistar-Kyoto and spontaneously hypertensive rats

Wistar-Kyoto and spontaneously hypertensive rats received i.v. infusions of cocaine hydrochloride (60 mg/kg per day) for 3, 7, and 14 days, or saline for 7 days. Acute cocaine challenge (40 mg/kg, s.c.) was given to treated and control rats 24 hr after the termination of each infusion period. There were no strain differences in brain levels of cocaine during cocaine infusion, nor after cocaine challenges. There were no strain differences in resting levels of [³H]dopamine release. Release of [³H]dopamine decreased in nuclei accumbens of 7- and 14-day cocaine-infused animals. Release of [³H]dopamine was maximal in both brain regions 2 hr after acute cocaine challenge. After 14 days of cocaine infusion, cocaine challenge in both strains reduced [³H]dopamine release in the nucleus accumbens, but not in the striatum; the reduction being greater in Wistar-Kyoto rats. The behavioral tolerance which accompanies similar cocaine infusion regimens may be related to striatal tolerance to cocaine-induced dopamine release.     

Effect of experimenter-delivered and self-administered cocaine on extracellular beta-endorphin levels in the nucleus accumbens

Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be involved in the behavioral effects of drugs of abuse including psychostimulants. Using microdialysis, we studied the effect of cocaine on extracellular levels of beta-endorphin in the nucleus accumbens, a brain region involved in the reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2 mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.). The effect of cocaine on beta-endorphin release in the nucleus accumbens was mimicked by a local perfusion of dopamine (5 microm) and was blocked by coadministration of SCH-23390 (10 microm). Self-administered cocaine (1 mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the nucleus accumbens. In addition, using functional magnetic resonance imaging, we found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta-endorphin release in the nucleus accumbens following experimenter-delivered and self-administered cocaine mediated by the local dopaminergic system. These findings suggest that activation of the beta-endorphin neurons within the arcuate nucleus-nucleus accumbens pathway may be important in the neurobiological mechanisms underlying the behavioral effects of cocaine.     

Inhibition of neuronal nitric oxide synthase suppresses the maintenance but not the induction of psychomotor sensitization to MDMA ('Ecstasy') and p-chloroamphetamine in mice.

Repeated exposure to psychostimulants such as cocaine and amphetamines results in behavioral sensitization, a paradigm thought to be relevant to drug craving and addiction in humans. We have previously shown that the induction, expression, and maintenance of psychomotor sensitization to cocaine, methamphetamine, and methylphenidate (indirect dopamine agonists) are blocked by co-administration of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI). In the present study, we investigated the effects of 7-NI on the induction, expression, and maintenance of psychomotor sensitization to 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') and p-chloroamphetamine (PCA). The following observations are reported: (a) Repeated administration of MDMA (10 mg/kg) and PCA (5 mg/kg) to Swiss Webster mice for six consecutive days caused a 3-fold increase in the psychomotor stimulating effect of the drugs on day 6 compared to day 1. (b) Pretreatment with 7-NI (25 mg/kg) did not affect the induction and expression of sensitization to MDMA and PCA. (c) Pretreatment with 7-NI did, however, suppress the enduring sensitized response to challenge injections of MDMA and PCA which was observed in mice pretreated with vehicle instead of 7-NI. (d) Unlike other psychostimulants, MDMA and PCA treatment did not produce conditioned (context-dependent) hyperlocomotion. These findings, coupled with our previous studies, suggest the following: (a) The induction and expression of psychomotor sensitization to MDMA and PCA are independent of nNOS activity and involve primarily serotonergic transmission. (b) The maintenance of psychomotor sensitization is dependent on intact nNOS activity and involves primarily dopaminergic transmission.     

Dextromethorphan affects cocaine-mediated behavioral pattern in parallel with a long-lasting Fos-related antigen-immunoreactivity

In order to understand the underlying mechanisms responsible for the behaviors mediated by dextromethorphan (DM), we examined the effects of DM on locomotor activity and locomotor patterns in mice, and Fos-related antigen immunoreactivity (FRA-IR) of mouse brain following repeated administration of cocaine. Combined treatments (30 min prior to each cocaine administration) with DM dose-dependently decreased locomotor activity for high doses of cocaine (20 mg/kg, i.p./day x 7). DM combinations did not significantly affect hyperactivity for 10 mg cocaine/kg, i.p./day x 7. In contrast, combined treatments with DM increased the locomotor activity for 5 mg cocaine/kg, i.p./day x 7. These results were consistent with alterations in marginal activity. Repeated administration with cocaine or DM increased FRA-IR in the nucleus accumbens (NAc) and striatum which lasted for at least 7 days. Our results suggest that DM exhibits biphasic effects on the locomotor stimulation induced by cocaine, and that locomotor activities are in parallel with FRA-IR of the striatal complex. However, the role of FRA-IR regulated by DM or/and cocaine remains to be further determined.     

Effects of prenatal cocaine, morphine, or both on postnatal opioid (mu) receptor development

We studied the effects of prenatal cocaine and morphine given separately and in combination on the (1) postnatal brain mu-opioid receptor development and (2) interaction of dopamine with mu receptors. Pregnant rats received single daily intraperitoneal (I.P.) injections of saline, cocaine (20 mg/kg), morphine (2 mg/kg), or the combination of both drugs from day 13 to day 20 of gestation. Postnatal days (P) 1, 7, 14, and 28, whole brains were analyzed for opioid receptor binding and mu mRNA. Prenatal cocaine administered by itself had no significant effect on the ontogeny of brain mu receptors on all the days studied when compared to controls. The morphine-treated group showed a significant increase in mu receptor binding on P1 and P7. Exposure to both cocaine and morphine showed a significant increase in mu receptor density on P1 and P7. In addition, there was also a significant increase in MOR mRNA in both the morphine alone and combination groups. Pretreatment with dopamine D2 receptor antagonist (sulpiride, 20 mg/kg) prior to drug administration showed decreased mu receptor binding on P1 and P7. These results suggest that prenatal exposure to morphine or a combination of cocaine and morphine significantly increases mu receptor density. By P14, mu-opioid receptor binding was no longer different than the control. This may suggest that the effect on receptor may be short-lived and that other key intracellular events may be activated to mediate the long-term effects. Also, the data show that dopaminergic mechanisms are (or opioid-dopamine interaction is) involved in the effects of morphine alone or morphine in combination with cocaine on mu receptor regulation.     

Effect of Cocaine on the Histaminergic Neuron System in the Rat Brain

Abstract: To examine the effect of cocaine on the brain histamine neuron system, histamine levels and histamine N -methyl-transferase activity in the rat brain were measured after the administration of cocaine. Moreover, we examined the effect of l -histidine on cocaine-induced wheel-running behavior. The administration of cocaine (20 mg/kg) increased histamine levels and histamine N -methyltransferase activity in the striatum, nucleus accumbens, and amygdala 1 h later. The pretreatment with l -histidine (350 and 700 mg/kg) inhibited the cocaine (20 mg/kg)-induced increase of wheel-running activity in a dose-dependent manner. These findings suggest that cocaine activates the brain histamine neuron system, which may play the role of inhibiting the cocaine-induced wheel-running behavior.     

Serotonin and Dopamine Sensitization in the Nucleus Accumbens, Ventral Tegmental Area, and Dorsal Raphe Nucleus Following Repeated Cocaine Administration

Abstract— The present study was designed to examine the effects of chronic cocaine administration on the extracellular response of serotonin (5-HT) and dopamine (DA) to a peripheral cocaine injection using in vivo brain microdialysis in awake rats. Two different dual probe preparations were used: One group of animals had guide cannulae aimed at the ventral tegmental area (VTA) and nucleus accumbens (N ACC) and a second group of animals had guide cannulae aimed at the dorsal raphe nucleus (DRN) and N ACC. Rats from both groups were given daily injections of either cocaine (20 mg/kg i.p.) or saline (0.9%; 0.05 ml/kg i.p.) for 10 consecutive days. On day 11, baseline dialysate levels of DA, 5-HT, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were obtained from either the N ACC and VTA or the N ACC and DRN, followed by a 10 mg/kg i.p. cocaine injection and an additional 150 min of dialysate sampling. The percent baseline increases of both 5-HT and DA were significantly higher in the N ACC, VTA, and DRN of animals that received daily injections of cocaine compared with saline controls ( p < 0.05, in each region). Maximum dialysate 5-HT concentrations after cocaine challenge were significantly higher in the N ACC and VTA ( p < 0.05) and DRN ( p < 0.01) of chronically treated animals compared with saline controls. Maximum dialysate DA concentrations were significantly higher in the N ACC and DRN ( p < 0.05) of chronically treated animals compared with saline controls. There was no significant difference between acute and chronic animals in the maximum dialysate DA concentration from the VTA after cocaine challenge. 5-HT was significantly more sensitized in the 5-HT cell body region (DRN) than the N ACC terminal field ( p < 0.05), whereas DA was significantly more sensitized in the N ACC terminal field than the DA cell bodies of the VTA ( p < 0.05).     

Cocaine regulates protein kinase B and glycogen synthase kinase-3 activity in selective regions of rat brain

Protein kinase B (also known as Akt) signaling regulates dopamine-mediated locomotor behaviors. Here the ability of cocaine to regulate Akt and glycogen synthase kinase 3 (GSK3) was studied. Rats were injected with cocaine or saline in a binge-pattern, which consisted of three daily injections of 15 mg/kg cocaine or 1 mL/kg saline spaced 1 h apart for 1, 3, or 14 days. Amygdala, nucleus accumbens, caudate putamen, and hippocampus tissues were dissected 30 min following the last injection and analyzed for phosphorylated and total Akt and GSK3(alpha and beta) protein levels using western blot analysis. Phosphorylation of Akt on the threonine-308 (Thr308) residue was significantly reduced in the nucleus accumbens and increased in the amygdala after 1 day of cocaine treatment; however, these effects were not accompanied by a significant decrease in GSK3 phosphorylation. Phosphorylation of Akt and GSK3 was significantly reduced after 14 days of cocaine administration, an effect that was only observed in the amygdala. Cocaine did not alter Akt or GSK3 phosphorylation in the caudate putamen or hippocampus. The findings in nucleus accumbens may reflect dopaminergic motor-stimulant activity caused by acute cocaine, whereas the effects in amygdala may be associated with changes in emotional state that occur after acute and chronic cocaine exposure.     

Potential neuroprotective effect of t-butylhydroquinone against neurotoxicity-induced by 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) in mice

Dopaminergic damage inducing Parkinson's disease (PD) is ubiquitous neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathways. The etiology and pathogenic factors implicated in dopaminergic damage are still unexplored to develop causal therapeutic strategies aimed to halt its progressive loss. The neurotoxicity induced by 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), which is more potent neurotoxic than MPTP in mice, is one of the most valuable models for analyzing pathological feature of dopaminergic damage. Herein, we investigated the neuroprotective effect of the potent antioxidant tertiary butylhydroquinone (TBHQ) against 2'CH3-MPTP-induced neurotoxicity in mice as well as the possible mechanism underlying such neurotoxicity. Male albino mice were injected with two doses of 2'CH3-MPTP (20 mg/kg, i.p.) for two consecutive days. Animals were killed after 2 weeks from the last dose of 2'CH3-MPTP. Control animals received 10 mL/kg body weight i.p. of distilled water. In both groups, brain stems containing the nigrostriatal pathways were dissected and reduced glutathione (GSH), malonyldialdehyde (MDA) contents, and superoxide dismutase (SOD) activity were estimated. Also, brain stem histopathological and histochemical changes were examined. The results of this study revealed that i.p. injection of 2'CH3-MPTP caused decrease in the brain stem content of GSH. On the other hand, the content of MDA and SOD activity was increased as compared with control groups. Also, 2'CH3-MPTP showed severe histopathological changes including swelling of cytoplasm, interstitial edema, and complete loss of the neurons with reactive microglial proliferation and gliosis. Furthermore, histochemical examination of brain stem qualitatively showed depletion of dopaminergic neurons of nigrostriatum. Oral administration of TBHQ (100 mg/kg) prior to 2'CH3-MPTP for 7 days caused normalization of GSH content and SOD activity and ameliorated the MDA content but still above the control value. Pretreatment with TBHQ slightly mitigated the histopathological and histochemical changes observed in 2'CH3-MPTP-treated mice. Based on these observations, it can be concluded that the antioxidant TBHQ has the ability to reverse the oxidative stress caused by 2'CH3-MPTP in mice while failed to challenge the histopathological and histochemical changes induced by that toxicant.     

Chronic Carbamazepine Administration Attenuates Dopamine D<Subscript>2</Subscript>-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

Observations that dopaminergic antagonists are beneficial in bipolar disorder and that dopaminergic agonists can produce mania suggest that bipolar disorder involves excessive dopaminergic transmission. Thus, mood stabilizers used to treat the disease might act in part by downregulating dopaminergic transmission. In agreement, we reported that dopamine D2-like receptor mediated signaling involving arachidonic acid (AA, 20:4n-6) was downregulated in rats chronically treated with lithium. To see whether chronic carbamazepine, another mood stabilizer, did this as well, we injected i.p. saline or the D2-like receptor agonist, quinpirole (1 mg/kg), into unanesthetized rats that had been pretreated for 30 days with i.p. carbamazepine (25 mg/kg/day) or vehicle, and used quantitative autoradiography to measure regional brain incorporation coefficients (k*) for AA, markers of signaling. We also measured brain prostaglandin E2 (PGE2), an AA metabolite. In vehicle-treated rats, quinpirole compared with saline significantly increased k* for AA in 35 of 82 brain regions examined, as well as brain PGE2 concentration. Affected regions belong to dopaminergic circuits and have high D2-like receptor densities. Chronic carbamazepine pretreatment prevented the quinpirole-induced increments in k* and in PGE2. These findings are consistent with the hypothesis that effective mood stabilizers generally downregulate brain AA signaling via D2-like receptors, and that this signaling is upregulated in bipolar disorder.     

Similar Time Course Changes in Striatal Levels of Glutamic Acid Decarboxylase and Proenkephalin mRNA Following Dopaminergic Deafferentation in the Rat

An immunoblot procedure was developed to quantify the amount of tyrosine hydroxylase protein in homogenate of small brain regions. With the use of this method we have studied the variations in tyrosine hydroxylase activity and protein levels in some catecholaminergic neurons at different times following a single reserpine injection (10 mg/kg s.c.) and reevaluated the anatomical specificity of tyrosine hydroxylase induction by this drug. Reserpine administration provoked a long-lasting increase in both tyrosine hydroxylase activity and protein levels within locus ceruleus neurons. This effect culminated at day 4 after injection. At this time, the enzyme activity and protein levels in treated animals were respectively 2.7 and 2.6 times that measured in vehicle-treated animals. Both parameters varied in parallel so that tyrosine hydroxylase specific activity did not change over time. In contrast, reserpine did not cause any changes in tyrosine hydroxylase activity in the dopaminergic neurons of the substantia nigra, but provoked a moderate increase in tyrosine hydroxylase protein level. This latter effect was maximal (1.5 times) 4 days after treatment. In the adjacent dopaminergic area, i.e., the ventral tegmental area, a small decrease in the enzyme activity was recorded at day 2 without any significant change in the level of the protein. In conclusion, first, our data show the capacity of our method to assay tyrosine hydroxylase protein amounts in small brain catecholaminergic nuclei. Second, our results confirm and extend previous studies on the effect of reserpine on the regulation of tyrosine hydroxylase level within brain noradrenergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)