Nomifensine amplifies subsecond dopamine signals in the ventral striatum of freely-moving rats

The present experiment examined the effect of the dopamine transporter blocker nomifensine on subsecond fluctuations in dopamine concentrations, or dopamine transients, in the nucleus accumbens and olfactory tubercle. Extracellular dopamine was measured in real time using fast-scan cyclic voltammetry at micron-dimension carbon fibers in freely-moving rats. Dopamine transients occurred spontaneously throughout the ventral striatum in the absence of apparent sensory input or change in behavioral response. The frequency of dopamine transients increased at the presentation of salient stimuli to the rat (food, novel odors and unexpected noises). Administration of 7 mg/kg nomifensine amplified spontaneous dopamine transients by increasing both amplitude and duration, consistent with its known action at the dopamine transporter and emphasizing the dopaminergic origin of the signals. Moreover, nomifensine increased the frequency of detected dopamine transients, both during baseline conditions and at the presentation of stimuli, but more profoundly in the nucleus accumbens than in the olfactory tubercle. This difference was not explained by nomifensine effects on the kinetics of dopamine release and uptake, as its effects on electrically-evoked dopamine signals were similar in both regions. These findings demonstrate the heterogeneity of dopamine transients in the ventral striatum and establish that nomifensine elevates the tone of rapid dopamine signals in the brain.     

Relationship of extracellular dopamine in striatum of newborn piglets to cortical oxygen pressure

The present studies describes the relationship between extracellular dopamine in striatum of newborn piglets and cortical oxygen pressure. The extracellular level of dopamine was measured by in vivo microdialysis and the oxygen pressure in the cortex was measured by phosphorescence lifetime of oxygen probe in the blood. Controlled, graded levels of hypoxic insult to the brain of animals were generated by decreasing of the oxygen fraction in the inspired gas (FiO₂) from 21% to 14%, 11%, and 9%. This resulted in decrease in the cortical oxygen pressure from 31–35 Torr to about 24 Torr, 15 Torr and 4 Torr, respectively. The changes in extracellular level of dopamine, DOPAC and HVA were dependent on changes in cortical oxygen pressure. Stepwise decrease in the cortical oxygen pressure (see above) caused increases in extracellular dopamine of about 80%, 200% and 550%, respectively. The levels of DOPAC and HVA progressively decreased and when cortical oxygen decreased to 4–6 Torr were about 50% and 70% of control. respectively. After return of FiO₂ to control (21%), the cortical oxygen pressure rapidly increased to above normal, then returned to control values. The extracellular levels of dopamine, DOPAC, and HVA recovered more slowly, attaining control values in about 30 minutes. The data show that extracellular levels of dopamine increase with even very small decreases in oxygen pressure. Thus, there is no oxygen reserve which protects dopamine release and metabolism from decrease in oxygen pressure.     

Involvement of the phosphoinositol (PI) system in the mechanism of hormonal imprinting

Certain components of the phosphoinositol (PI) system are present in the unicellular Tetrahymena. Treatment of Tetrahymena with insulin did not alter the relative proportions of the examined six phospholipid components (PIP2, PIP, phosphatidylcholine, phosphatidylethanolamine, PI, PA), but the primary interaction (imprinting) with insulin accounted for an about 75% decrease in the PIP2-level and an about 20% increase in the phosphatidylethanolamine level. The experimental results strongly suggest that hormonal imprinting accounted for adjustment of the second messenger systems of Tetrahymena to an energy saving level.     

Involvement of ryanodine receptor type 3 in dopamine release from the striatum: evidence from mutant mice lacking this receptor

Although it is known that ryanodine receptor type 3 is expressed in the striatum, the function of this receptor has not been elucidated. Therefore, we examined whether caffeine- and ryanodine-induced dopamine release in striatal slices is affected in mice lacking ryanodine receptor type 3. Pretreatment with thapsigargin, an inhibitor of the Ca(2+) ATPase pump of the endoplasmic reticulum, abolished caffeine- or ryanodine-induced dopamine release in slices from normal mice. Dopamine concentration in the striatum and KCl-induced dopamine release were unaffected by a ryanodine receptor type 3 deficiency. Ryanodine-induced dopamine release was significantly attenuated in mice lacking ryanodine receptor type 3, whereas caffeine-induced dopamine release was partially attenuated. Caffeine produced a similar hyper-motor activity in both wild and homozygous mice. The present results suggest the involvement of ryanodine receptor type 3 in dopamine release from the striatum.     

Stochastic resonance as a possible mechanism of amplification of weak electric signals in living cells

The most important but still unresolved problem in bioelectromagnetics is the interaction of weak electromagnetic fields (EMFs) with living cells. Thermal and other types of noise pose restrictions in cell detection of weak signals. As a consequence, some extant experimental results that indicate low-intensity field effects cannot be accounted for, and this renders the results themselves questionable. One way out of this dead end is to search for possible mechanisms of signal amplification. In this paper, we discuss a general mechanism in which a weak signal is amplified by system noise itself. This mechanism was discovered several years ago in physics and is known, in its simplest form, as a stochastic resonance. It was shown that signal amplification may exceed a factor of 1000, which renders existing estimations of EMF thresholds highly speculative. The applicability of the stochastic resonance concept to cells is discussed particularly with respect to the possible role of the cell membrane in the amplification process. © 1994 Wiley-Liss, Inc.     

5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release

Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)(2A) than dopamine D(2) antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT(1A) agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT(1A) receptor activation, as a result of the blockade of 5-HT(2A) and D(2) receptors. M100907 (0.1 mg/kg), a 5-HT(2A) antagonist, significantly increased the ability of both S:(-)-sulpiride (10 mg/kg), a D(2) antagonist devoid of 5-HT(1A) affinity, and R:(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT(1A) agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT(1A) antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R:(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT(1A) partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT(2A) and D(2) receptor blockade, regardless of intrinsic 5-HT(1A) affinity, may promote the ability of 5-HT(1A) receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT(2A) antagonists and typical APDs, which are D(2) antagonists, may facilitate 5-HT(1A) agonist activity.     

Neuropeptide Y induced modulation of dopamine synthesis in the striatum

The purpose of the present study was to determine whether the activation of NPY receptors alters catecholamines (CA) synthesis in the central nervous system and, if so, to identify the NPY receptor subtype(s) mediating this effect. Tyrosine hydroxylation, the rate-limiting step in CA synthesis, was assessed by measuring the accumulation of 3,4-dihydroxyphenyalanine (DOPA) by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC) in rat striatal dices following incubation of the tissue with the aromatic L-amino acid decarboxylase inhibitor m-hydroxybenzyl hydrazine (NSD 1015). Treatment with NSD 1015 resulted in an increase in DOPA accumulation that was increased even further following depolarization with a high potassium (KCl) buffer. PYY13-36 and NPY13-36 both produced a significant enhancement of the KCl-induced increase in DOPA accumulation. The effect of PYY13-36 was completely attenuated by the selective Y2 antagonist BIIE0246 suggesting that activation of Y2 receptors enhanced the synthesis of dopamine. In contrast to the effects of NPY13-36 and PYY13-36; NPY, PYY and PYY3-36 all produced a significant attenuation of the KCl-induced increase in DOPA accumulation. The Y1 antagonist BIBO3304 and the Y5-antagonist CGP71683A, both prevented the inhibitory effect of NPY converting it to a stimulatory effect. The enhancement of the NPY induced increase in DOPA accumulation observed by BIBO3304 was attenuated when examined in the presence of the Y2 antagonist BIIE0246. These results suggest that activation of NPY receptors can modulate the synthesis of CA in the rat striatum. The Y1 and Y5 receptor appear to be involved in attenuation, while Y2 receptors are involved in the stimulation of synthesis.     

Ghrelin amplifies the nicotine-induced dopamine release in the rat striatum

The orexigenic peptide ghrelin plays a prominent role in the regulation of energy balance and in the mediation of reward mechanisms and reinforcement for addictive drugs, such as nicotine. Nicotine is the principal psychoactive component in tobacco, which is responsible for addiction and relapse of smokers. Nicotine activates the mesencephalic dopaminergic neurons via nicotinic acetylcholine receptors (nAchR). Ghrelin stimulates the dopaminergic neurons via growth hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area and the substantia nigra pars compacta resulting in the release of dopamine in the ventral and dorsal striatum, respectively. In the present study an in vitro superfusion of rat striatal slices was performed, in order to investigate the direct action of ghrelin on the striatal dopamine release and the interaction of ghrelin with nicotine through this neurotransmitter release. Ghrelin increased significantly the dopamine release from the rat striatum following electrical stimulation. This stimulatory effect was reversed by both the selective nAchR antagonist mecamylamine and the selective GHS-R1A antagonist GHRP-6. Nicotine also increased significantly the dopamine release under the same conditions. This stimulatory effect was antagonized by mecamylamine, but not by GHRP-6. Ghrelin further stimulated the nicotine-induced dopamine release and this effect was abolished by mecamylamine and was partially inhibited by GHRP-6. The present results demonstrate that ghrelin stimulates directly the dopamine release and amplifies the nicotine-induced dopamine release in the rat striatum. We presume that striatal cholinergic interneurons also express GHS-R1A, through which ghrelin can amplify the nicotine-induced dopamine release in the striatum. This study provides further evidence of the impact of ghrelin on the mesolimbic and nigrostriatal dopaminergic pathways. It also suggests that ghrelin signaling may serve as a novel pharmacological target for treatment of addictive and neurodegenerative disorders.     

Involvement of ceramide in the mechanism of Cr(VI)-induced apoptosis of CHO cells

Mitochondria reduce Cr(VI) to Cr(V) with concomitant generation of reactive oxygen species, thereby exhibiting cytotoxic effects leading to apoptosis in various types of cells. To clarify the mechanism by which Cr(VI) induces apoptosis, we examined the effect of Cr(VI) on Chinese hamster ovary (CHO) cells. Cr(VI) increased cellular levels of ceramide by activating acid sphingomyelinase (ASMase) and inhibiting the phosphorylation of pleckstrin homology domain-containing protein kinase B (Akt). Cr(VI) also induced cyclosporin A- and trifluoperazine-sensitive depolarization of mitochondria and activated caspase-3, 8 and 9, thereby causing fragmentation of cellular DNA. The presence of desipramine, an inhibitor of ASMase, and membrane permeable pCPT-cAMP suppressed the Cr(VI)-induced activation of caspases and DNA fragmentation. These results suggested that accumulation of ceramide play an important role in the Cr(VI)-induced apoptosis of CHO cells through activation of mitochondrial membrane permeability transition.     

Nomifensine attenuates d-amphetamine-induced dopamine terminal neurotoxicity in the striatum of rats

Long-term or high dose administration of d-amphetamine (AMPH) in the rat has been shown to result in dopamine terminal neurotoxicity in the striatum of rats. This phenomenon includes depletion of dopamine content, decreased activity of tyrosine hydroxylase and diminish in the number of dopamine reuptake transporter. Recent studies implicate a role of oxidative stress induced by dopamine in the AMPH-induced neurotoxicity. However, the primary source of dopamine responsible for radical formation during AMPH challenge has remained elusive. To elucidate this issue, the study was designed to examine the effects of nomifensine, a dopamine transporter blocker, and deprenyl, a monoamine oxidase B (MAO-B) inhibitor, on the prevention of striatal dopamine neurotoxicity in AMPH-treated rats. The results showed that nomifensine but not deprenyl protected against AMPH-induced long-term dopamine depletion. Correspondingly, the hydroxyl radical formation caused by AMPH in the striatum was attenuated by nomifensine, whereas its formation was not abolished by deprenyl. In conclusion, this study suggests that intracellular oxidative stress is more likely involved in the AMPH-induced dopamine terminal toxicity in the rat striatum, while this phenomenon is not mediated by MAO-B pathway.     

Involvement of striatum serotonergic system in the expression of genetically defined catalepsy

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, and specific binding of [3H]ketanserin to 5-HT2A receptors and [3H]8-OH-DPAT to 5-HT1A receptors in the striatum of genetically predisposed to catalepsy rats and mice have been studied. The activity of tryptophan hydroxylase in the striatum of rats bred for many generations for predisposition to catalepsy was higher than in nonselected rats. Mice of highly susceptible to pinch-induced catalepsy CBA strain also differed from noncataleptic AKR and C57BL mouse strains by higher activity of tryptophan hydroxylase in striatum. Inhibition of tryptophan hydroxylase with p-chlorophenylalanine or p-chloromethamphetamine significantly decreased immobility time in genetically predisposed to catalepsy rats and mice. A decrease in the [3H]ketanserin specific binding in the striatum of cataleptic rats and CBA mice was found indicating a decrease in 5-HT2A receptor density. A decrease in [3H]8-OH-DPAT binding in striatum of cataleptic rats but not in CBA mice was shown. These results indicate that serotonergic system of striatum is involved in the expression of hereditary catalepsy and suggest that hereditary catalepsy may result from genetic changes in the regulation of serotonin metabolism and reception in striatum.     

Correlation between (3H)dopamine specific uptake and (3H)GBR 12783 specific binding during the maturation of rat striatum

The development of the specific uptake of dopamine in the rat striatum during the early postnatal period is compared with the ontogenetic changes of the specific binding of (3H)GBR 12783 to the site of uptake inhibition. During maturation, the increase in the specific binding of (3H)GBR 12783 parallels the increase in the specific uptake of dopamine. (3H)GBR 12783 specific binding sites increase in number from day 1 postpartum until 40 days, when they reach the adult level. In 40 day-old rats, the weight of the striatum represents 80% of adult values. The affinity of (3H)GBR 12783 for the inhibition site is similar in membrane preparations obtained from 6 day-old pups and adults; this results in a same ability of the inhibitor to block the specific uptake of dopamine into synaptosomes obtained from pups or adult rats. These data support the hypothesis of the existence of a single molecular entity including both the inhibition site and the carrier itself.     

Interactions of glutamate and dopamine in a computational model of the striatum

A network model of simplified striatal principal neurons with mutual inhibition was used to investigate possible interactions between cortical glutamatergic and nigral dopaminergic afferents in the neostriatum. Glutamatergic and dopaminergic inputs were represented by an excitatory synaptic conductance and a slow membrane potassium conductance, respectively. Neuronal activity in the model was characterized by episodes of increased action potential firing rates of variable duration and frequency. Autocorrelation histograms constructed from the action potential activity of striatal model neurons showed that reducing peak excitatory conductance had the effect of increasing interspike intervals. On the other hand, the maximum value of the dopamine-sensitive potassium conductance was inversely related to the duration of firing episodes and the maximal firing rates. A smaller potassium conductance restored normal firing rates in the most active neurons at the expense of a larger proportion of neurons showing reduced activity. Thus, a homogeneous network with mutual inhibition can produce equally complex dynamics as have been proposed to occur in a striatal network with two neuron populations that are oppositely regulated by dopamine. Even without mutual inhibition it appears that increased dopamine concentrations could partially compensate for the effects of reduced glutamatergic input in individual neurons.     

Involvement of hypothalamic dopamine in the regulation of prolactin secretion

The neuroendocrine control of prolactin (PRL) secretion is known to be a multifactorial process, but dopamine (DA) secreted by the tuberoinfundibular dopaminergic (TIDA) neurons of the hypothalamus is believed to exert a predominant inhibitory control on the secretion of PRL. The secretory activity of the TIDA neurons, including the rate of biosynthesis of DA and the rate of release of the neurohormone into hypophysial portal blood, can be readily evaluated in the rat. In most conditions in which an altered secretion of PRL has been documented, an altered secretory activity of the TIDA neurons has been found. When an acute reduction in the secretion of DA is observed, an increased secretion of PRL is associated, with an inverse relationship between DA and PRL concentrations in hypophysial portal and systemic blood, respectively. However, the secretion of PRL can be regulated by PRL itself through stimulation of the secretory activity of the TIDA neurons, and consequently hyperprolactinemia can be observed concomitantly with a sustained high secretion of DA, as seen after treatment with estrogen. The short loop feedback of PRL secretion seems to be impaired in the aging rat, since a sustained reduced hypothalamic secretion of DA is observed in spite of long-term hyperprolactinemia.     

Controlled cortical impact injury affects dopaminergic transmission in the rat striatum

The therapeutic benefits of dopamine (DA) agonists after traumatic brain injury (TBI) imply a role for DA systems in mediating functional deficits post‐TBI. We investigated how experimental TBI affects striatal dopamine systems using fast scan cyclic voltammetry (FSCV), western blot, and d‐amphetamine‐induced rotational behavior. Adult male Sprague–Dawley rats were injured by a controlled cortical impact (CCI) delivered unilaterally to the parietal cortex, or were naïve controls. Amphetamine‐induced rotational behavior was assessed 10 days post‐CCI. Fourteen days post‐CCI, animals were anesthetized and underwent FSCV with bilateral striatal carbon fiber microelectrode placement and stimulating electrode placement in the medial forebrain bundle (MFB). Evoked DA overflow was assessed in the striatum as the MFB was electrically stimulated at 60 Hz for 10 s. In 23% of injured animals, but no naïve animals, rotation was observed with amphetamine administration. Compared with naïves, striatal evoked DA overflow was lower for injured animals in the striatum ipsilateral to injury (p < 0.05). Injured animals exhibited a decrease in V_max (52% of naïve, p < 0.05) for DA clearance in the hemisphere ipsilateral to injury compared with naïves. Dopamine transporter (DAT) expression was proportionally decreased in the striatum ipsilateral to injury compared with naïve animals (60% of naïve, p < 0.05), despite no injury‐related changes in vesicular monoamine transporter or D₂ receptor expression (DRD₂) in this region. Collectively, these data appear to confirm that the clinical efficacy of dopamine agonists in the treatment of TBI may be related to disruptions in the activity of subcortical dopamine systems.     

Cholinergic effect on the dopamine turnover in the rat corpus striatum]

The peripheral administration of oxotremorine caused a significant increase in dihydroxyphenylacetic acid (DOPAC) in the striatum of rats, dopamine (DA) level was unaffected. Injection of oxotremorine into the substantia nigra failed to change the content of dopamine and its acid metabolites homovanillic acid (HVA) and DOPAC in striatum. Injection of oxotremorine or carbachol into the substantia nigra or into the caudate nucleus did not significantly influence the DA-turnover. The partly inconsistent results are discussed in connection with literature data in regard to the existence of excitatory as well as inhibitory cholinergic systems, which are located differently and are involved in the regulation of DA-turnover.