Flunarizine induces a transient loss of tyrosine hydroxylase immunoreactivity in nigrostriatal neurons

Neurotoxic effects of flunarizine (Fz), a selective calcium channel blocker, on the nigrostriatal dopamine system was investigated. Systemic injections of Fz to mice resulted in a transient loss of tyrosine hydroxylase (TH) immunoreactive nigrostriatal neurons without cell loss. TH immunoreactivity in these neurons was greatly reduced as rapidly as one day after drug administration (regardless of dosage used) and thereafter recovered in both dose- and time-dependent manners. Such a novel neurotoxic action of Fz may constitute a morphological substrate for reversible drug-induced parkinsonian signs described in recent clinical case reports.     

Interaction of amfonelic acid with antipsychotic drugs on dopaminergic neurons.

The effects of two inhibitors of dopamine (DA) reuptake, amfonelic acid and GBR 12909, on the clozapine- and haloperidol-induced increases in DA synthesis, release, and metabolism were investigated in the rat. In the striatum, as well as in the nucleus accumbens, the haloperidol-induced increase in tissue concentrations of dihydroxyphenylacetic acid (DOPAC) or the accumulation of dihydroxyphenylalanine (DOPA) was potentiated or unaltered, respectively, in rats treated with amfonelic acid. In contrast, amfonelic acid attenuated the stimulatory effects of clozapine on DOPAC concentrations and DOPA accumulation in both brain regions. GBR 12909 also differentially affected the haloperidol- and clozapine-induced increases in DOPAC concentrations. However, the clozapine-induced increase in DOPA accumulation in the median eminence was not significantly altered by treatment with amfonelic acid. The haloperidol-induced increase in the extracellular concentrations of DA and DOPAC in the striatum also was potentiated by amfonelic acid, whereas the increase elicited by clozapine was suppressed. The increase in extracellular DA produced by the administration of morphine or the coadministration of ritanserin, a 5-HT2 antagonist, and haloperidol also was potentiated by amfonelic acid. The ability of amfonelic acid to distinguish between the actions of clozapine and haloperidol on nigrostriatal and mesocorticolimbic DA neurons does not appear to be related to differences in the effects of the drugs on DA autoreceptors or 5-HT2 receptors. Moreover, the mechanism through which clozapine activates tuberoinfundibular DA neurons may differ from that which is involved in the activation of nigrostriatal or mesocorticolimbic DA neurons.     

Dorsal raphé stimulation modifies striatal-evoked antidromic invasion of nigral dopaminergic neurons in vivo

Summary Extracellular single unit recordings were obtained from antidromically identified nigrostriatal dopaminergic neurons in anesthetized rats to determine the effects of dorsal raphé stimulation on the somatodendritic excitability of substantia nigra dopaminergic neurons. Stimulation of the dorsal raphé with a brief train of pulses delivered 7–2 ms prior to the neostriatal-evoked antidromic response significantly reduced the proportion of neostriatal-evoked antidromic responses that consisted of both initial segment and somatodendritic components without significantly altering the neostriatal-evoked post-stimulus inhibitory period. Raphé stimulation alone facilitated post-stimulus neuronal firing in almost half of the cells examined. The raphé-induced decrease in somatodendritic excitability was blocked by the serotonin antagonist, metergoline (0.5–2.0 mg/kg, i.v.), without significantly affecting the rate or pattern of spontaneous activity. The tryptophan hydroxylase inhibitor, parachlorophenylalanine (400 mg/kg, i.p. for three consecutive days), abolished the decrease in somatodendritic excitability following raphé stimulation which could be re-instated by intravenous administration of 5-HTP. The dopamine antagonists haloperidol (25–100 g/kg, i.v.) and sulpiride (10–30 mg/kg, i.v.) also blocked the effects of dorsal raphé stimulation on somatodendritic invasion. These data suggest that in vivo, serotonin liberated from raphé-nigral terminals facilitates the release of dopamine from nigrostriatal dendrites resulting in a local, autoreceptor-mediated reduction in somatodendritic excitability without affecting the spontaneous firing rate and excitability of the neuron as a whole.     

LH syndrome and brain catecholamine levels after lesions of the nigrostriatal bundle

Lesions of the nigrostriatal bundle (NSB), whose fibers pass through the medial portions of the internal capsule and the immediately adjacent lateral hypothalamus (LH), produced a more severe aphagia, adipsia, and disturbance of water regulation than did lesions of the medial forebrain bundle (MFB). When deprived of food, animals with NSB lesions drank significantly less than controls and animals with MFB lesions. NSB lesions also produced greater decreases in telencephalic content of the catecholamines than MFB lesions, while the reverse was true for serotonin. Water intake during food deprivation was highly correlated with telencephalic catecholamine levels in animals with NSB lesions. Thus, the inability to regulate water intake in the absence of food, one of the characteristic and long lasting effects of the LH syndrome, appears to be due to destruction of the NSB and the consequent decline in telencephalic content of catecholamines.     

Estrogen reduces acute striatal dopamine responses in vivo to the neurotoxin MPP+ in female, but not male rats

The effects of in vivo estrogen treatment upon MPP⁺-induced dopamine (DA) release were determined using in vivo microdialysis in female and male rats. Ovariectomized female rats were implanted or not with an estrogen pellet (0.1 mg, 17β estradiol) and subjected to microdialysis 6 days later. After baseline DA release was determined, 5 mM MPP⁺ was infused through the microdialysis probe for one 20-min interval. Perfusion resumed with normal medium for the duration of the experiment. A significant attenuation of MPP⁺-induced DA release was obtained in estrogen-treated females. One week later, striatal DA and dihydroxyphenylacetic acid (DOPAC) concentrations were determined for the lesioned and non-lesioned striata of each animal. MPP⁺ infusion significantly decreased striatal DA concentrations, however, there was no effect of estrogen treatment on striatal DA depletion. This experiment was repeated using orchidectomized male rats treated with 0, 0.1, or 5 mg estradiol. In contrast to the females, no differences in MPP⁺-induced DA release were seen among these males, and there was no significant effect of the varying estrogen treatments on striatal DA or DOPAC concentrations. These results demonstrate that in vivo estrogen treatment attenuates MPP⁺-induced striatal DA release in gonadectomized female, but not male, rats.     

Amelioratory effects of testosterone propionate supplement on behavioral, biochemical and morphological parameters in aged rats

Testosterone has been shown to affect motor behavior and nigrostriatal dopaminergic (NSDA) system in young and adult male rats. However, it is not known whether exogenous testosterone intervention to aged male rats can ameliorate age-related motor impairment. Thus, in the present study, the open field motor behavior and adhesive tape removal motor performance as well as the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) of NSDA system were examined in aged male rats following chronic subcutaneous injections of testosterone propionate (TP). Aged rats showed significantly reduced open field motor behavior and adhesive tape removal motor performance compared to adult rats. Chronic TP supplement significantly ameliorated the age-related motor deficits. The expression of TH and DAT of NSDA system was significantly enhanced in TP-treated aged rats revealed by RT-PCR, Western blot and immunohistochemistry analysis respectively. The results imply that chronic TP treatment may favorably improve the declined motor behavior and motor performance with aging. Testosterone propionate supplement that facilitated NSDA system may influence the maintenance of motor behavior and performance in aged rats.     

Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of Parkinson's disease

The effects of intranigral iron injection on dopamine (DA) release and content in the caudate putamen (CPu) and their relationship to DA-related behavioral response were investigated in rats. Different concentrations of FeCl(3) (10, 20, and 40 microg) and saline were injected separately into the left substantia nigra. In some experiments, rats were pretreated with desferrioxamine or saline before iron injection. After 3 weeks, changes in behavioral response, DA release, and DA content in the CPu were determined. In all iron injection groups (10, 20, and 40 microg), DA content in the lesioned side of the brain was significantly decreased, showing a significant linear correlation (R(2) = 0.981, P = 0.01), and DA turnover ratio significantly increased (both P = 0.01, 0.01 and 0.001 vs unlesioned sides, respectively). However, injection dosages of 10 or 20 microg of iron did not lead to significant changes in DA release in the CPu or in behavioral response. At the 40-microg dosage, it was found that DA release in the lesioned side and rearing activity both were significantly reduced (all P = 0.01 vs unlesioned side or control) and apomorphine-induced rotation was observed. Pretreatment with desferrioxamine significantly inhibited the effect of iron on DA release and content. These results demonstrate that iron injection can damage dopaminergic neurons and suggest that DA release, rather than DA content, in the CPu is associated with DA-related behavioral changes in this PD model.     

A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD

The hyperfunctioning dopamine hypothesis in the mesocorticolimbic (MCL) system has been addressed by a neurogenetic approach in model systems. Thus, a morphometric analysis was carried out on neurons of origin of Substantia Nigra (SN) and Ventral Tegmental Area (VTA) dopamine systems of the Naples High-Excitability (NHE), Low-Excitability (NLE) and control lines. Male adult rats were tested in a spatial novelty for indices of activity and non-selective attention. Mesencephalic coronal sections were processed for tyrosine hydroxylase (TH) immunohistochemistry and cytochromoxidase (C.O.) histochemistry. Image analysis in the rostro-caudal plane showed (i) a higher neuron size of TH+ elements in the VTA of NHE and NLE, across the entire structure in the NHE, and only in the middle portion in the NLE; (ii) a higher expression of TH in the neuropil of the VTA in NHE; (iii) a lower C.O. activity in both NLE and NHE; (iv) no differences in the SN. The larger neuron size in both NHE and NLE rats as compared with control rats, along with higher TH expression mainly in the NHE, in absence of any relevant alteration in the SN, reveals an unbalance between the two dopamine systems and a subsequent alteration in limbic (reward, motivation, sustained attention) functions. The decreased C.O. activity might be due to reduced feedback inhibition by striatal GABA neurons and interneurons leading to increased DA neuron firing. In conclusion, the increased behavioral activity and impaired attention observed in the NHE rats are associated to hyperfunctioning MCL system in this genetic model of Attention-Deficit Hyperactivity Disorder (ADHD).     

Neuroleptic-induced changes in the firing pattern of guinea pig nigrostriatal neurons

Summary It is well established that neuroleptics increase the firing rate of nigrostriatal neurons. However, the action of these drugs on firing pattern has received scant attention. The effect of local administration of neuroleptic agents was investigated on the firing pattern, and also firing rate, of nigro-striatal neurons. Chlorpromazine or haloperidol was microinjected into the substantia nigra of the urethane-anaesthetized guinea pig during extracellular recordings from identified nigrostriatal cells. Both neuroleptics induced the familiar increase in firing rate of nigrostriatal neurons. More significantly, however, these drugs also caused a dose-dependent change in firing pattern, specific to neuroleptic action. This change consisted of a drug-induced transition from slow irregular single or double spikes with a short interspike interval (beat firing) to irregular bursts of spikes with a longer interspike interval (burst firing). Furthermore, the transition from beat to burst firing occurred sharply and sometimes continued to switch in a regular cyclical fashion between the two modes for up to three hours following infusion of the neuroleptic. Administration of neuroleptics may thus provide a useful tool for studying the physiology of the firing pattern of nigrostriatal neurons.     

3,4-Dihydroxyphenylacetic acid and homovanillic acid in rat plasma: possible indicators of central dopaminergic activity.

The concentrations of dopamine (DA) metabolites (free and conjugated) was measured in plasma and brain regions of rats by the mass spectrometric method of selected ion monitoring. Experimental treatments which altered the function of central dopamine neurons also induced concomitant changes in plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Stimulation of the nigrostriatal pathway increased plasma DOPAC and HVA whereas lesion of the pathway decreased plasma metabolites. Several drug treatments induced parallel changes in brain and plasma concentrations of DA metabolites. It is suggested that changes in the concentration of DOPAC and HVA in rat brain are reflected by parallel changes in plasma. No conjugated forms of DOPAC and HVA were found in plasma and brain tissue of vervet monkeys (Cercopithecus aethiops).