Subcortical DA Research Articles

P.6.c.002 Blockade of central serotonin 2B receptors reduces cocaine-induced hyperlocomotion independently of subcortical DA outflow

Diabetic retinopathy (DR) is characterized by the development of intraretinal microvascular abnormalities. Endoplasmic reticulum (ER) stress is known to play a pathogenic role in vascular impairment in DR. The present study demonstrated that the treatment of human retinal endothelial cells with ER stress inducers such as thapsigargin (Tg) and tunicamycin (Tm) significantly increased the permeability of exogenously added FITC–dextran, accompanied by a decrease of transendothelial electrical resistance (TEER). The expression of claudin-5 among tight junction proteins was significantly decreased by the treatment with Tg or Tm. A p38 MAPK inhibitor, SB203580, and an NF-κB inhibitor, dexamethasone, significantly suppressed the Tg-induced down-regulation of claudin-5, decrease of TEER and leakage of added FITC–dextran. The translocation of NF-κB p65 subunit to the nucleus was also inhibited by the addition of SB203580 or dexamethasone. The effects of dexamethasone are thought to be due to the transrepression of the above signaling and direct regulation of claudin-5 gene.

Cannabinoid transmission in the prefrontal cortex bi-phasically controls emotional memory formation via functional interactions with the ventral tegmental area.

Disturbances in cortical cannabinoid CB1 receptor signaling are well established correlates of various neuropsychiatric disorders, including depression and schizophrenia. Importantly, the ability of cannabinoid transmission to modulate emotional processing is functionally linked to interactions with subcortical DA systems. While considerable evidence demonstrates that CB1 receptor-mediated modulation of emotional processing and related behaviors follows a biphasic functional curve, little is known regarding how CB1 signaling within cortical networks may interact with subcortical DAergic systems involved in emotional behavior regulation. Using a combination of in vivo electrophysiological recordings and behavioral pharmacology in rats, we investigated the relationship between mPFC cannabinoid transmission, fear memory formation, and subcortical DA neuron activity patterns. We report that direct intra-mPFC CB1 activation biphasically modulates spontaneous, subcortical VTA DA neuron activity in a dose-dependent fashion; while lower doses of a CB1 receptor agonist, WIN 55,212-2, significantly increased spontaneous firing and bursting rates of VTA DA neurons, higher doses strongly inhibited spontaneous DA neuron activity. Remarkably, this same dose-related functional difference was observed with the regulation of fear-related emotional memory formation. Thus, lower levels of CB1 activation potentiated the emotional salience of normally subthreshold fear memory, whereas higher levels completely blocked fear memory acquisition. Furthermore, while the potentiation of subthreshold fear memory salience was blocked by DA receptor antagonism, CB1-mediated blunting of suprathreshold fear memory was rescued by intra-VTA administration of a GABAB receptor antagonist, demonstrating that reversal of GABAergic inhibitory mechanisms in the VTA can reverse the inhibitory influence of intra-PFC CB1 transmission on mesolimbic DA activity.

EPA-0164 – Animal modeling of dual diagnosis: schizophrenia and alcoholism

Alcoholism prevalence is three times higher in patients with schizophrenia than in general population. The aim of this study was to create two experimental models of dual disorders: schizophrenia and alcoholism. The study was carried out on 90 male Wistar rats. The first dopaminergic model of schizophrenia was conducted by means levodopa-carbidopa (LC) introduction: 300 mg/kg for 5 days every month of the experiment. The second model was rat earlier isolation from 21 till 56 day after birth. During 4 month all experimental animals had 15% ethanol solution intermittent half-voluntary drinking. Alcohol preference was evaluated in the ‘two-bottle-test’. Behavior parameters and anxiety level was estimated in the ‘open field’ test, Porsolt test and auditory stimulus reactions. LC rats have shown significantly higher alcohol intake in earlier experimental period, compared to water controls. Alcohol preference was higher exactly after LC administration (‘acute psychosis’) than in three weeks (‘remission’). The LC rats have shown the reduced threshold sensitivity to auditory stimuli and no differences in locomotor and exploratory activity. Compared to control animals the early isolated rats have shown higher alcohol preference as well. After isolation rats have demonstrated the increased motor activity and anxiety in the open field. After the end of alcoholization the isolated rats have shown significantly less swimming time than controls in Porsolt test. Different mechanisms of alcoholism origin in different schizophrenia models are discussed: common sub-cortical DA transmission changes in schizophrenia and alcoholism in LC model and self-medication mechanisms in early isolation model.

Schizotypal Personality Disorder

Early phenomenological descriptions of schizophrenia have acknowledged the existence of milder schizophrenia spectrum disorders characterized by the presence of attenuated symptoms typically present in chronic schizophrenia. The investigation of the schizophrenia spectrum disorders offers an opportunity to elucidate the pathophysiological mechanisms giving rise to schizophrenia. Differences and similarities between subjects with schizotypal personality disorder (SPD), the prototypical schizophrenia personality disorder, and chronic schizophrenia have been investigated with genetic, neurochemical, imaging, and pharmacological techniques. Patients with SPD and the more severely ill patients with chronic schizophrenia share cognitive, social, and attentional deficits hypothesized to result from common neurodevelopmentally based cortical temporal and prefrontal pathology. However, these deficits are milder in SPD patients due to their capacity to recruit other related brain regions to compensate for dysfunctional areas. Individuals with SPD are also less vulnerable to psychosis due to the presence of protective factors mitigating subcortical DA hyperactivity. Given the documented close relationship to other schizophrenic disorders, SPD will be included in the psychosis section of DSM-5 as a schizophrenia spectrum disorder as well as in the personality disorder section.

Expression of AMPA Receptor Flip and Flop mRNAs in the Nucleus Accumbens and Prefrontal Cortex after Neonatal Ventral Hippocampal Lesions

Many lines of evidence implicate dysfunctional excitatory amino acid (EAA) transmission in schizophrenia. The present study examined α-amino-3-hydroxy-5-methylisoxazole- 4-priopionate (AMPA) receptor expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using a rat model of schizophrenia in which excitotoxic lesions of ventral hippocampus (VH) on postnatal day (PD) 7 lead to the postpubertal emergence of behavioral abnormalities that resemble schizophrenic symptoms. In situ hybridization histochemistry with 35S-labeled oligonucleotide probes was used to quantify mRNA levels for GluR1-3 flip and flop variants at prepubertal and postpubertal time-points (PD 35 and 60, respectively). Comparisons of PD 35 and PD 60 groups suggested that there may be changes in the relative expression of flip and flop isoforms during normal development. The most pronounced change was an apparent increase in the flip/flop ratio for GluR1 from PD 35 to PD 60 in both the PFC and the NAc. Neonatal VH lesions did not significantly alter GluR1-3 flip and flop mRNA levels in the NAc at either time-point. However, in the PFC, GluR3 flop mRNA levels were significantly decreased in lesioned rats at PD 60. AMPA receptors incorporating flop variants exhibit faster desensitization, so a shift towards flip incorporation might lead to increased neuronal excitability in the PFC, thereby influencing subcortical DA systems regulated by PFC efferents. In summary, an early developmental injury can predispose rats to abnormal development of EAA transmission in the PFC. This may contribute to the postpubertal onset of symptoms after neonatal VH lesions. [Neuropshychopharmacology 24:253–266, 2001]

Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors

Background: Phencycline (PCP, “angel dust”) and other noncompetitive antagonists of N-methyl- d-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. Methods: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. Results: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. Conclusions: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.

Selective effects on prefrontal cortex serotonin by dopamine D3 receptor agonism: Interaction with low-dose haloperidol

1. 1. Negative symptoms of schizophrenia are characterized by amotivation, anhedonia and anergia. These aspects of the symptom profile can be modeled by D3 agonism in animal behavioral models. 2. 2. Serotonergic systems have been implicated in pathophysiologic substrates for this disorder; most notably, in deficit state schizophrenia, as newer ‘atypical’ neuroleptics which are especially efficacious for treating this syndrome antagonize central 5-HT2 receptors. 3. 3. FC regions may also be important in chronic negative symptoms, as hypofrontality has been associated with these schizophrenic features. 4. 4. The author examined effects of a behaviorally-active dose of the D3 agonist, 7OH, on 5-HT metabolism in FC, and the ability of a low-dose neuroleptic treatment to antagonize this biochemical effect. 5. 5. Acute administration of 7OH induced a selective decrease of 5-HT turnover in the FC without affecting metabolism of this transmitter in more subcortical DA regions. 6. 6. Hal, which has previously been demonstrated to antagonize electrophysiologic, biochemical and behavioral effects of 7OH, was without effect on agonist-induced decreases in 5-HT turnover. 7. 7. The biochemical association between D3 agonism and reductions of FC 5-HT may be significant for pathophysiologic mechanisms of negative symptoms, and antagonism of this effect may differ for neuroleptics with varying efficacy in alleviating these symptoms.

Effects of Acute and Chronic Morphine on DOPAC and Glutamate at Subcortical DA Terminals in Awake Rats

Effects of morphine and naloxone on the levels of 3,4-dihydroxy-phenylacetic acid (DOPAC) and glutamate in the striatum and nucleus accumbens of awake rats were studied with in vivo microdialysis. Acute morphine (50 mg/kg, IP) treatment increased the levels of DOPAC and glutamate in the striatum and nucleus accumbens, but both decreased from the elevated levels when naloxone (10 mg/kg, IP) was given 2 h later. Chronic morphine treatment, twice daily for 5 days in incremental doses (5, 10, 20, 40 and 50 mg/kg, IP), increased the level of DOPAC but decreased that of glutamate in the striatum and nucleus accumbens. When naloxone was given 2 h later, the reverse of the above phenomena are found. After given repeated morphine treatment and experiencing naloxone-precipitated withdrawal, the rats with an intact cortex and the rats with ibotenic acid (5 μg/0.5 μl/2.5 min) lesions on the medial prefrontal cortex and sulcal cortex have similar alternations in the levels of DOPAC and glutamate in the striatum. However, in the nucleus accumbens, the level of DOPAC dropped more and the level of glutamate increased more in the intact rats than the lesioned rats during the withdrawal stage. These data suggested that the intact cortex ordinarily exerted an inhibitory role to influence the level of DOPAC in the striatum and nucleus accumbens during chronic morphine treatment. In conclusion, morphine seems to activate different pathways in dependent and non-dependent rats.

Microinjection of apomorphine into the prefrontal cortex of the rat reduces dopamine metabolite concentrations in microdialysate from the caudate nucleus

The effects of dopamine fDA) depletion within the medical prefrontal cortex (MPFC) suggest that mesocortical DA projections influence subcortical DA systems (Pycock et al 1980). This hypothesis has been weakened by negative reports (Joyce et al 1983) and by problems inherent to lesion studies. In vivo neurochemical techniques offer a more direct approach. In vivo voltammetry studies have shown that enhancement of DA release in the MPFC is followed by a reduction in DA turnover in the nucleus accumbens (Louilot et al 1989)o Using intracerebral microdialysis we have tested the analogous hypothesis, that stimulation of MPFC DA

Schizophrenic postmortem studies: Alterations in the distribution of trh receptors in the temporal lobe

125 ineglect (p = .003). These findings suggest that in humans as in rodents, ischemic insults to antero-lateral cortex may be a not uncommon antecedent of striatal DA hyperactivity. We hypothesize that penetrance of some common psychosis genes may be variable because these genes merely predispose carriers to responding to minor cortical ischemia with a marked subcortical DA supersensitivity. Other data in support of this hypothesis will be reviewed. (Supported by the VA and R29-MH43530-01)

Effect of excitotoxin lesions in the medical prefrontal cortex on cortical and subcortical catecholamine turnover in the rat.

Catecholamine turnover in brain areas innervated by dopaminergic neurons was examined 2, 6, and 12 days after bilateral, N-methyl-D-aspartate lesions confined to the rat medial prefrontal cortex. The lesion produced a significant regional increase in the concentration of 3,4-dihydroxyphenylethylamine (DA, dopamine) in both the medial prefrontal cortex and the ventral tegmental area. DA concentrations were increased in the nucleus accumbens on day 6 (128% of control), in the ventral tegmental area on day 2 (130% of control), and in the medial prefrontal cortex on days 2 (145% of control) and 6 (127% of control). The only significant changes in the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) (197% of control), and in the ratio DOPAC/DA (163% of control) were found in the medial prefrontal cortex on day 6 post-lesion. All parameters had returned to control levels by day 12. DA depletion after the administration of alpha-methyl-p-tyrosine (AMPT) was not significantly different between excitotoxin-lesioned and sham animals on day 6 in all brain regions. Noradrenaline (NA) and 3,4-dihydroxyphenylethyleneglycol concentrations and their ratios, and the depletion of noradrenaline after AMPT were also determined, and the lesion resulted in a significant regional increase in NA in both the nucleus accumbens and the ventral tegmental area. An elevation of NA (147% of control) in the nucleus accumbens was found on day 12. Since the excitotoxin lesion destroys corticofugal efferents from medial prefrontal cortex to the nucleus accumbens, the anterior corpus striatum and the ventral tegmental area, our results provide no evidence for a role of these cortical projections in the regulation of subcortical DA metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of unilateral microinjections of sulpiride into the medial prefrontal cortex on circling behavior of rats

1. Bilateral 6-OHDA lesions of rats' medial prefrontal cortex increased locomotor activity after 7–10 days suggesting that cortical DA may normally inhibit motor behaviour. However, hyperactivity may have resulted from enhanced subcortical DA function. 2. Acute manipulation of frontal cortical DA neurotransmission in the present experiment avoided lesion-induced subcortical changes. 3. Sulpiride (0, 6, 12, 24 ug in 1 ul) was Injected unilaterallv into the medial prefrontal cortex of rats pretreated with (+)-amphetamine (1.5 mg/kg i.p.). 4. Circling behavior was scored during four 5-min intervals of a 60-min test session which began with injections and placement in a flat, circular arena. 5. SUL resulted in ipslversive circling whereas its vehicle did not. These results were consistent with those seen with other DA drugs and suggest an excitatory influence of frontal cortical DA on locomotor activity.