Contribution of noradrenergic neurons to 3,4-dihydroxyphenylacetic acid concentrations in the regions of the rat brain containing incertohypothalamic dopaminergic neurons

The purpose of this study was to determine the source of 3,4-dihydroxyphenylacetic acid (DOPAC) in medial zona incerta (MZI) and dorsomedial nucleus (DMN), with the overall aim of ascertaining whether alterations in the concentration of this dopamine (DA) metabolite reflect the activity of incertohypothalamic dopaminergic neurons. In both the MZI and DMN, the concentration of norepinephrine (NE) exceeds that of DA, reflecting a higher density of noradrenergic vs. dopaminergic neurons in these brain regions. The ratio of DOPAC to DA was greater than the ratio of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) to NE indicating that the activity of dopaminergic neurons in the MZI and DMN is greater than that of noradrenergic neurons. Destruction of noradrenergic neuronal axons in the ventral bundle following bilateral injections of the neurotoxin 5-amino-2,4-dihydroxy-alpha-methylphenylethylamine (5-ADMP) decreased NE concentrations in the MZI and DMN, but had no effect on the concentrations of DA or DOPAC, revealing that under basal conditions noradrenergic neurons contribute little to DOPAC concentrations in these brain regions. The DA receptor antagonist haloperidol increased, while the DA receptor agonist apomorphine decreased DOPAC concentrations in the MZI and DMN, indicating that alterations in the activity of incertohypothalamic dopaminergic neurons are accompanied by corresponding changes in the concentration of this DA metabolite. On the other hand, activation of noradrenergic neurons following administration of the alpha 2-adrenergic receptor antagonist idazoxan increased DOPAC concentrations in both the MZI and DMN in intact, but not in ventral bundle-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genotype-dependent effects of chronic stress on apomorphine-induced alterations of striatal and mesolimbic dopamine metabolism

After 10 daily consecutive restraint experiences, DBA/2 (DBA) mice showed an increase of climbing behavior after injection of 0.25 mg/kg of the dopamine (DA) agonist apomorphine (APO), while no changes were observed following vehicle or 1 mg/kg of APO. By contrast, chronically stressed C57BL/6 (C57) mice showed a clear-cut decrease of climbing behavior at the dose of 0.25 mg/kg of APO and a similar, although less pronounced, effect of stress on the behavior of mice injected either with vehicle or with 1 mg/kg APO. The DA agonist at these same doses decreased 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) concentrations in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of both strains. Higher DOPAC, HVA and 3-MT concentrations were evident in stressed DBA mice receiving 0.25 mg/kg but not 1 mg/kg of APO, in both CP and NAS. Concerning C57 mice, lower concentrations of the 3 metabolites were present at both doses of APO in the NAS of stressed mice in comparison with non-stressed animals, while no significant stress-related effects were evident in the CP. Non-significant differences between control and stressed mice of both strains were evident as regards DA concentrations in CP and NAS. These results suggest that repeated stressful experiences lead to a hyposensitivity of DA presynaptic receptors in DBA mice while they produce a sensitization of mesolimbic DA presynaptic receptors possibly accompanied by down-regulation of postsynaptic DA receptors in the C57 strain.     

Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex

Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-

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-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.     

Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions withd-amphetamine

Systemic administration of ibogaine (40 mg/kg, i.p.) has been reported to induce both acute (1–3 h) and persistent (19–20 h) changes in extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum. In the present study, local administration of ibogaine to the striatum and nucleus accumbens produced effects that mimicked both the acute and persistent effects of systemic administration: perfusion with high concentrations (200 and 400 μM) of ibogaine mimicked the acute effects (decreased extracellular dopamine levels and increased extracellular metabolite levels) whereas perfusion with a low concentration (10 μM) of ibogaine mimicked the persistent effects (decreased extracellular levels of DOPAC). These results indicate that ibogaine acts directly in brain regions containing dopaminergic nerve terminals and that long-lasting effects of systematically administered ibogaine might be mediated by persisting low levels of ibogaine. Locally administered ibogaine (10 μM) was also found to enhance the effects of systematically administeredd-amphetamine (1.25 mg/kg, i.p.) on extracellular dopamine levels, and conversely, systemically administered ibogaine (40 mg/kg, i.p.: 19 h pretreatment) enhanced the effects of locally administeredd-amphetamine (1–10 μM). These results indicate that, in addition to a metabolic mechanism implicated previously, a pharmacodynamic mechanism contributes to the interaction between ibogaine andd-amphetamine. The relevance of such mechanisms to claims regarding ibogaine's anti-addictive properties is unclear.     

Effect of systemically administered caerulein on dopamine metabolism in rat brain

The effect of caerulein, a cholecystokinin-like peptide, on the dopamine (DA) system was examined in rat brain. Caerulein, when tested in vitro, had no significant influence on either D-1 or D-2 DA receptors. A single injection of caerulein (400 μg/kg, i.p.) reduced both homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. No significant change in DA metabolites was found in the other 7 areas (polar and medial fields of prefrontal cortex, anterior cingulate cortex, nucleus accumbens, tuberculum olfactorium, septum and amygdala). After repeated injections of caerulein (200 μg/kg, i.p., daily for 5 days), the decreases in striatal HVA and DOPAC had disappeared, while the amount of HVA had increased in the nucleus accumbens. These results suggest that peripherally administered caerulein modulates the nigrostriatal and mesolimbic DA neuron systems in the different modes of action.     

Comparative analysis of the effects of iontophoretically applied dopamine in different regions of the rat brain, with special reference to the cingulate cortex.

A systematic comparison of the effects of iontophoresed dopamine (DA) was carried out in the neostriatum (NS), nucleus accumbens (Acb) and anterior cingulate (ACg), prefrontal (PF) and parietal (Par) cortex of urethane-anesthetized rats, before and after treatment with the specific DA uptake blockers GBR 12909 and Bupropion. Similar experiments were also conducted after DA denervation with 6-hydroxydopamine and after DA depletion with alpha-methyl-p-tyrosine. The average rate of spontaneous neuronal firing was comparable in all regions, except in the NS after DA depletion. A majority of the units were inhibited by DA in every region and condition tested. As assessed with the IT50 index, the responsiveness to DA was not markedly different between regions, indicating that the postsynaptic sensitivity to this amine is independent of the density of DA receptors and of DA innervation. In contrast, the average duration of DA inhibitions (RT90) was considerably longer (5-fold) in the intact ACg than in the PF, Par, NS, or Acb. Moreover, treatment with both DA uptake blockers reduced the duration of DA inhibitions in ACg (4- to 9-fold); while lengthening it in PF, NS and Acb; and having no apparent effect in Par. DA depletion and DA denervation also reduced the duration of the DA inhibitions in ACg without effect in Par. Taken together, these results provide further evidence for the existence of a presynaptic, positive-feedback mechanism in ACg, triggered by DA, and favouring the further release of this transmitter upon its reuptake in DA nerve terminals.     

Androgen inhibits neurotransmitter turnover in the medial prefrontal cortex of the rat following exposure to a novel environment

Previous studies have demonstrated that gonadal steroid hormones affect the neuroendocrine response to a novel environment and other stressors. Introduction to a novel environment also increases neurotransmitter turnover in the medial prefrontal cortex (MPFC). In this study, we examined the possibility that gonadal steroid hormones could similarly modulate the neurotransmitter response to a novel environment in the MPFC of the male rat. Male Fischer 344 rats at 3 months of age were gonadectomized (GDX'd) and implanted with Silastic capsules containing dihydrotestosterone propionate (DHTP, a non-aromatizable form of androgen), 17 β-estradiol (E), or placebo. Control animals were left intact. Each of these groups was further divided into a group introduced to a novel environment or a home cage control group. Animals exposed to a novel environment were killed after spending 20 min in a novel open field, whereas control animals were killed immediately upon removal from their home cage. Using high performance liquid chromatography, the MPFC was assayed for tissue levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA); norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG); or serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA). The introduction to a novel environment caused significant increases in turnover of all three neurochemicals examined as estimated by metabolite/precursor ratios. These increases were characterized by increases in DOPAC, HVA, MHPG and 5-HIAA coupled with decreases in DA, NE and 5-HT. There was no effect of GDX on neurotransmitter turnover, however, treatment of GDX animals with DHTP prevented the open field induced increase in DOPAC/DA, MHPG/NE, and 5-HIAA/5-HT ratio. Treatment of GDX animals with estrogen had the opposite effect of DHTP, DOPAC/DA and MHPG/NE ratios increased to a greater level following the introduction to a novel environment than in GDX or intact animals. Examination of behavior in the open field showed significant decreases in activity in the DHTP-treated group but not in any other behavioral parameter (rears, nose pokes). Since the non-aromatizable androgen, DHTP, is presumably acting via androgen receptors, and E is presumably acting via estrogen receptors, these data suggest that, in the MPFC of male rats, androgen and estrogen receptors act in an opposing fashion to modify neurotransmitter turnover. This suggests that local changes in the relative levels of androgen and estrogen can have profound effects on the neurobiological response of the medial prefrontal cortex to stimuli.© 1997 Elsevier Science B.V. All rights reserved.     

Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats

It has been hypothesized that striatal dopamine (DA) terminals undergo compensatory changes in response to partial damage of the mesostriatal DA system, which results in higher concentrations of DA in the extracellular space than would be predicted by DA concentrations in post-mortem tissue. But, this hypothesis has never been tested directly in vivo, and therefore, the present study was designed to do so. Microdialysis was used in freely moving rats to estimate the concentrations of DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in striatal extracellular fluid; simultaneously from the hemisphere with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra and from the intact hemisphere. It was found that following recovery from a 6-OHDA lesion, and during the resting state, the extracellular concentrations of DA were normal on the lesion side, even after that side was depleted of up to 99.0% of the DA measured in post-mortem tissue. Furthermore, the extracellular concentrations of DA were elevated in the intact hemisphere of animals with a >95% DA depletion. In rats with a <95% DA depletion amphetamine (1.5 mg/kg) caused a large increase in the extracellular concentration of DA in both the lesion and intact hemispheres (intact > lesion), but in rats with a > 95% tissue DA depletion amphetamine only enhanced extracellular DA on the intact side; on the lesion side amphetamine produced a progressive decrease in extracellular DA to nondetectable levels. Animals rotated towards the lesion side. Unlike DA, the extracellular concentrations of DOPAC and HVA were greatly reduced on the lesion side, and the extent of the depletion was highly correlated with lesion size. It is concluded that following partial unilateral damage to mesostriatal DA projections there are massive changes in the remaining DA terminals that are sufficient to normalize the extracellular (and presumably synaptic) concentrations of DA. The normalization of extracellular DA concentrations seen after extensive (but incomplete) damage to the mesostriatal system must play a major role in the sparing and recovery of behavioral function that is so characteristic of this system. After extensive damage the capacity of the remaining DA neurons to respond to increased demand is limited, however, and this may explain why behavioral deficits can be reinstated by stimuli that challenge the system.     

The role of brain dopamine in response initiation: effects of haloperidol and regionally specific dopamine depletions on the local rate of instrumental responding

Two experiments were undertaken to investigate dopaminergic involvement in the local rate of responding on a fixed ratio 5 (FR5) instrumental lever pressing schedule. Rats were trained to press for food reinforcement on a FR5 schedule, and a computer program was used to record the interresponse time (IRT) for each response. The IRT is the time between each lever pressing response, which is equal to the reciprocal of the local response rate. After several weeks of training, rats received i.p. injections of the dopamine antagonist haloperidol (HP; 0.1, 0.2 and 0.4 mg/kg). HP produced a dose-related decline in overall response number. In addition, HP dramatically alteref the IRT distribution. HP-treated rats showed a dose-related reduction in the proportion of IRTs with low time values (high local rates of responding), and a corresponding corresponding increase in the relative of IRTs with high time values (low local rates of responding). In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial neostriatum or ventrolateral neostriatum in order to determine the effects of DA depletion on lever pressing performance. Dopamine depletion in all regions significantly reduced lever pressing, and dopamine-depleted rats had substantial changes in their IRT distributions. Rats with dopamine depletions showed significant reductions in the proprtion of IRTs with low time values, and increased in the relative number of IRTs with high time values. The greatest reductions in response number and the most pronounced alterations of the IRT distribution were shown by rats with ventrolateral neostriatal dopamine depletions. In addition, dopamine levels in the ventrolateral neostriatum were correlated with the total number of responses in the first week of postsurgical testing (r = 0.71, P < 0.05). These results demonstrate that interference with dopamine transmission by pharmacological antagonism or neurotoxic depletion produces a slowing of local response rate. Moreover, these results indicate that dopamine in the ventrolateral neostriatum is particularly necessary for maintaining very high rates of instrumental responding.     

Effect of intra-amygdala dopaminergic grafts on methamphetamine-induced locomotor activity, extracellular dopamine and dopamine metabolite overflow: a comparison with the effect of intra-accumbens grafts

The effects of 6-hydroxydopamine lesions of the ventral tegmental area and following intra-amygdala or intra-accumbens dopaminergic (DAergic) grafts on methamphetamine (MAP)-induced locomotor activity were investigated in rats. Intra-accumbens DAergic grafts from rat embryos restored the locomotor hyperactivity response to MAP 5 weeks after grafting, while intra-amygdala grafts did not restore responses by 10 weeks after grafting. Biochemical measurements of extracellular DAergic activity in the amygdala (AMY) by in vivo microdialysis after grafting showed no significant change in the basal levels of dopamine (DA) and partial restoration of metabolite levels. MAP induced an increase of DA efflux and a decrease in dihydroxyphenylacetic acid without a significant change in homovanillic acid, which is the same pattern of response seen in control animals. These biochemical changes are similar to those seen previously after intra-accumbens grafts. The results show that restoration of DAergic activity in the AMY in the presence of DAergic denervation of accumbens does not have an effect on MAP-induced locomotion.     

Comparison of the effects of the dopamine D2 agonist quinelorane on tuberoinfundibular dopaminergic neuronal activity in male and female rats

The purpose of the present study was to examine the effects of quinelorane (LY163502), a potent and selective D₂ dopaminergic (DA) receptor agonist, on the activity of tuberoinfundibular DA neurons in male and female rats as estimated by determining the concentration of the primary metabolite of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), in terminals of these neurons in the median eminence (ME). In males, quinelorane produced dose- and time-related increases in the concentration of DOPAC in the ME which was blocked by the D₂ receptor antagonist raclopride. The activity of tuberoinfundibular neurons in female rats is higher than it is in males because circulating levels of prolactin tonically stimulate these neurons in the female. In female rats, quinelorane markedly lowered plasma concentrations of prolactin but failed to alter DOPAC concentrations in the ME. Pretreatment of female rats with prolactin antiserum induced hypoprolactinemia and reduced DOPAC concentrations in the ME; in these animals quinelorane increased ME DOPAC concentrations. These results indicate that by acting on D₂ receptors quinelorane is able to stimulate tuberoinfundibular DA neurons in both male and female rats, but in female rats the ability of quinelorane to reduce circulating levels of prolactin indirectly reduces the activity of tuberoinfundibular DA neurons and thereby masks the stimulatory action of this drug on these neurons.     

Chronic propranolol treatment in developing rats: Acute and lasting effects on monoamines and beta-adrenergic receptors in the rat brain

During early postnatal development rat pups were treated twice daily with the beta-adrenergic antagonist propranolol (15 mg/kg) in order to study the acute and long-lasting effects of early blockade of noradrenergic beta-mediated neurotransmission. Treatments from postnatal days 1-10 or days 11-20 did not induce alterations in the number of beta-adrenergic receptors as measured three days after the last injection, nor could lasting effects be shown at 60 days of age. The day 1-10 treatment, however, had a significant effect on the regional brain levels of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), measured 90 min after the last injection. The metabolite had increased by 40% in all brain regions examined. On day 60, the MHPG concentrations were still increased when compared to postnatally saline-treated animals. Propranolol treatment from day 11-20 only marginally increased MHPG on day 20 and induced no lasting differences. These results suggest that propranolol treatment during the first ten days of life produces a long-lasting increase in NA metabolism, possibly reflecting an increased neuronal NA turnover.     

Effect of reserpine on 3-methoxy-4-hydroxyphenylethyleneglycol and 3,4-dihydroxyphenylacetic acid in the hippocampus of depression-model rats: An in vivo microdialysis study

Using in vivo microdialysis, we examined the effect of intraperitoneal injection of reserpine (2 mg/kg) on hippocampal 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 3,4-dihydroxy-phenylacetic acid (DOPAC), two major metabolites of catecholamine. Responses were examined serially for 12 h in the hippocampus of walking-stress-induced depression-model rats, recovery rats and control rats. Control rats showed a rapid rise followed by a gradual fall of free and total MHPG and a delayed increase of DOPAC in response to reserpine. Depression-model rats showed a significantly blunted biphasic response of free and total MHPG as well as blunted monophasic response of DOPAC compared with control rats. Recovery rats also exhibited a blunted fall response of MHPG. Our findings suggest that the vesicle membrane in the central noradrenaline (NA) neurons could be hyposensitive to reserpine in the depression-model rats.     

Cobalt injections into the substantia nigra of the rat: effects on behavior and dopamine metabolism in the striatum

Small amounts of cobalt unilaterally injected into the substantia nigra of rats caused a strong, spontaneous contralateral turning which was suppressed by haloperidol. One to 2 days after intranigral cobalt microinjection, d-amphetamine decreased the intensity of the contralateral turning; 5 days after cobalt application, d-amphetamine changed the direction of the turning to the ipsilateral side. Intranigral cobalt microinjection initially caused a significant increase in the concentration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the ipsilateral striatum. Thereafter, dopamine and its metabolites declined progressively to values significantly below control values. Similar biochemical changes in the striatum were also seen after partial electrolytic lesions of the substantia nigra. However, such lesions produced only mild contralateral turning. Frontal hemisection did not result in any increase of striatal metabolite values, and produced mild ipsilateral turning. Thus, there was no parallelism between the intensity and time course of the turning behavior induced by the different techniques and the changes in dopamine metabolism in the striatum. Within the cobalt-injected substantia nigra, γ-aminobutyric acid (GABA) and glutamic acid decarboxylase were decreased to less than 60% of the contralateral control values. The possibility is considered that the depression of a GABA-mediated inhibitory influence on the nigrostriatal or mesolimbic dopamine neurons may play a role in the cobalt-induced contralateral turning and altered striatal dopamine metabolism.     

Substantia nigra and pentylenetetrazol threshold in rats: correlation with striatal dopamine metabolism.

The time course of the metrazol threshold in rats with electrolytic lesions of the substantia nigra presents variations inversely proportional to the changes in dopamine and its metabolites in the neostriatum. Thus initially dopamine is increased and the threshold lowered, then a progressive decrease in dopamine and its metabolite is accompanied by a progressive increase in metrazol threshold. This supports the hypothesis that changes in functional activity of the caudate nucleus are reflected in variations of the brain's susceptibility to generalized seizures. When cobalt chloride was injected into the substantia nigra there were biochemical changes in the neostriatum similar to those observed with electrolytic lesions, but the pentylenetetrazol threshold steadily decreased. This is probably due to the fact that cobalt induces a lesion which changes in extent with time to involve adjacent brain stem nuclei sensitive to its epileptogenic action.     

Differential effects of α-, β- and γ-endorphins on dopamine metabolism in the mouse brain

The effects of intracerebral injection of α-, β- and γ-endorphins on the mouse brain dopamine (DA) metabolism were contrasted in relation to the previously identified patterns of behavior. α-Endorphin (20 μg) decreased the content of homovanillic acid (HVA) in the striatum, while γ-endorphin (10 μg) the contents of DA, 3,4-dihydroxyphenylacetic acid and HVA. β-Endorphin (1 and 2 μg) had no effects on the mouse DA metabolism in the brain. The changes in the DA metabolism induced by α- and γ-endorphins were readily reversed by the pretreatment with naloxone (1 mg/kg). Results suggested: (1) the patterns of behavior in mice treated with endorphins are mediated by these differences in DA metabolism; (2) changes in DA metabolism induced by α- and γ-endorphins occur via opiate receptors in the mouse brain.     

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.     

Sex differences in methamphetamine toxicity in mice: effect on brain dopamine signaling pathways

Male mice were reported to display greater methamphetamine-induced neurotoxicity than females. The present study evaluated the involvement of phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways in this sex-dependent methamphetamine toxicity. Intact female and male mice were administered methamphetamine (20 or 40mg/kg) and euthanized a week later. Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) autoradiography in the lateral striatum showed a greater sensitivity in male mice treated with 20mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40mg/kg methamphetamine compared to female mice. Mice administered 40mg/kg methamphetamine showed no sex difference in striatal VMAT2 autoradiography. In the substantia nigra, DAT specific binding was decreased only in male mice treated with 40mg/kg methamphetamine and DAT mRNA levels decreased in methamphetamine-treated female and male mice. Methamphetamine-treated male mice presented a dose-dependent decrease of VMAT2 mRNA levels. Methamphetamine reduced insulin-like growth factor 1 receptor levels in females at both methamphetamine doses tested whereas it elevated G protein-coupled estrogen receptor 1 (GPER1) only in male mice. Phosphorylated Akt levels decreased only in male mice treated with 40mg/kg methamphetamine. Glycogen synthase kinase 3β levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40mg/kg. Bcl-2 levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged. These results implicate some of the signaling pathways associated with the sex differences in methamphetamine-induced toxicity.     

Antidepressant-like effects of liquiritin and isoliquiritin from Glycyrrhiza uralensis in the forced swimming test and tail suspension test in mice

Two classic animal behavior despair tests--the Forced Swimming Test (FST) and the Tail Suspension Test (TST) were used to evaluate the antidepressant activity of liquiritin and isoliquiritin from Glycyrrhiza uralensis in mice. It was observed that both liquiritin and isoliquiritin at doses of 10, 20 and 40 mg/kg significantly reduced the immobility time in the FST and TST in mice 30 min after treatment. Measurement of locomotor activity indicated that liquiritin and isoliquiritin had no central nervous system (CNS)-stimulating effects. The main monoamine neurotransmitters and their metabolites in mouse brain regions were also simultaneously determined by HPLC-ECD. It was found that these two compounds significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus and cortex. Liquiritin and isoliquiritin also significantly reduced the ratio of 5-HIAA/5-HT in the hippocampus, hypothalamus and cortex, slowing down 5-HT metabolism compared with mice treated with vehicle+stress. In conclusion, liquiritin and isoliquiritin produced significant antidepressant-like effects, and their mechanism of action may be due to increased 5-HT and NE in the mouse hippocampus, hypothalamus and cortex.     

Effects of d- and l-amphetamine on dopamine metabolism and ascorbic acid levels in nucleus accumbens and olfactory tubercle as studied by in vivo differential pulse voltammetry

Differential pulse voltammetry used together with electrochemically pretreated carbon fibre microelectrodes allowed us to detect in vivo two well-separated peaks in nucleus accumbens and olfactory tubercle. The two peaks situated at −50 mV (peak 1) and +100 mV (peak 2) correspond, respectively, to the oxidation current of the ascorbic acid and to the oxidation current of the 3,4-dihydroxyphenylacetic acid (DOPAC). The experiments were carried out on anesthetized rats. Voltammograms were recorded in nucleus accumbens and olfactory tubercle every minute alternately in each structure. In control conditions, peak 1 height was greater in olfactory tubercle than in nucleus accumbens and peak 2 height was greater in nucleus accumbens than in olfactory tubercle. Both isomers of amphetamine induced a decrease of the peak 2 height in the two structures. The decrease was greater in olfactory tubercle. Higher doses of l-amphetamine were required to induce peak 2 height decrease of the same extent. Both isomers induced a marked increase of the peak 1 height in nucleus accumbens whereas peak 1 height in olfactory tubercle was slightly augmented. d-amphetamine was more effective than l-amphetamine in increasing peak 1 height.