The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.     

Acute Effects of Typical and Atypical Antipsychotic Drugs on the Release of Dopamine from Prefrontal Cortex, Nucleus Accumbens, and Striatum of the Rat: An In Vivo Microdialysis Study

In vivo microdialysis has been used to study the acute effects of antipsychotic drugs on the extracellular level of dopamine from the nucleus accumbens, striatum, and prefrontal cortex of the rat. (-)-Sulpiride (20, 50, and 100 mg/kg i.v.) and haloperidol (0.1 and 0.5 mg/kg i.v.) enhanced the outflow of dopamine in the striatum and nucleus accumbens. In the medial prefrontal cortex, (-)-sulpiride at all doses tested did not significantly affect the extracellular level of dopamine. The effect of haloperidol was also attenuated in the medial prefrontal cortex; 0.1 mg/kg did not increase the outflow of dopamine and the effect of 0.5 mg/kg haloperidol was of shorter duration in the prefrontal cortex than that observed in striatum and nucleus accumbens. The atypical antipsychotic drug clozapine (5 and 10 mg/kg) increased the extracellular concentration of dopamine in all three regions. In contrast to the effects of sulpiride and haloperidol, that of clozapine in the medial prefrontal cortex was profound. These data suggest that different classes of antipsychotic drugs may have distinct effects on the release of dopamine from the nigrostriatal, mesolimbic, and mesocortical terminals.     

BIMG 80, a Novel Potential Antipsychotic Drug: Evidence for Multireceptor Actions and Preferential Release of Dopamine in Prefrontal Cortex

Abstract: In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT_1A, 5-HT_2A, 5-HT₆), dopamine (D₁, D_2L, D₄), and noradrenergic (α₁) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.     

3-Methoxytyramine Is the Major Metabolite of Released Dopamine in the Rat Frontal Cortex: Reassessment of the Effects of Antipsychotics on the Dynamics of Dopamine Release and Metabolism in the Frontal Cortex, Nucleus Accumbens, and Striatum by a Simple Two Pool Model

Abstract: 3-Methoxytyramine (3-MT) and 3,4-dihydroxyphenylacetic acid (DOPAC) rates of formation were used, respectively, to assess the dynamics of dopamine (DA) release and turnover in the rat frontal cortex, nucleus accumbens, and striatum. Assuming total (re)uptake and metabolism of released DA are relatively uniform among the three brain regions, a simplified two pool model was used to assess the metabolic fate of released DA. Under basal conditions, 3-MT formation was found to comprise >60% of total DA turnover (sum of 3-MT plus DOPAC rates of formation) in the frontal cortex, and not more than 15% in the nucleus accumbens and striatum. Haloperidol increased the 3-MT rate of formation to a greater extent in the frontal cortex than in the two other regions. Clozapine increased the 3-MT rate of formation in the frontal cortex and decreased it in the striatum. Both drugs increased DOPAC rate of formation in the frontal cortex and nucleus accumbens. It was elevated by haloperidol but not clozapine in the striatum. It is concluded that (1) O -methylation is a prominent step in the catabolism of DA in the frontal cortex under both physiological conditions and after acute treatment with antipsychotics, (2) 3-MT is the major metabolite of released DA in the frontal cortex and possibly also in the nucleus accumbens and striatum, (3) in contrast to the frontal cortex, most of the DOPAC in the nucleus accumbens and striatum appear to originate from intraneuronal deamination of DA that has not been released, (4) because presynaptic uptake and metabolism of DA give rise to DOPAC, whereas postsynaptic uptake and metabolism produced both DOPAC and 3-MT, the ratio of 3-MT to DOPAC rates of formation can be a useful index of reuptake inhibition.     

Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits

Postmortem studies in schizophrenic patients revealed alterations in NMDA receptor binding and gene expression of specific subunits. Because most of the patients had been treated with antipsychotics over long periods, medication effects might have influenced those findings. We treated animals with haloperidol and clozapine in clinical doses to investigate the effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Rats were treated with either haloperidol (1,5 mg/kg/day) or clozapine (45 mg/kg/day) given in drinking water over a period of 6 months. Quantitative receptor autoradiography with [³H]-MK-801 was used to examine NMDA receptor binding. In situ hybridization was performed for additional gene expression studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [³H]-MK-801 binding was found to be increased after haloperidol treatment in the striatum and nucleus accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the nucleus accumbens. There were no alterations in gene expression of NMDA subunits in any of the three regions. However, the NR2A subunit was down-regulated in the hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D subunits did not differ between treatment groups and controls. Both altered NMDA receptor binding and subunit expression strengthen a hyperglutamatergic function after haloperidol treatment and may contribute to some of our postmortem findings in antipsychotically treated schizophrenic patients. Because the effects seen in different brain areas clearly vary between haloperidol and clozapine, they may also be responsible for some of the differences in efficacy and side effects.     

Involvement of Dopamine D1 and D2 Receptors in the Regulation of Proenkephalin mRNA Abundance in the Striatum and Accumbens of the Rat Brain

The effects of short-term treatment (6 h) with selective D1 or D2 agonists and antagonists on the mRNA for proenkephalin in the medial and anterior aspects of the caudate-putamen and the nucleus accumbens were assessed by in situ hybridization histochemistry. Proenkephalin mRNA abundance was significantly changed in the striatum and accumbens in response to D2 receptor manipulation. D2 blockade with haloperidol or raclopride increased, whereas D2 stimulation with LY-171555 (D2 agonist) decreased, striatal and accumbens proenkephalin mRNA abundance. Antagonism of D1 receptor activity with SCH-23390 significantly decreased proenkephalin mRNA abundance in all brain regions. Concurrent administration of the D1 agonist SKF-38393 prevented the SCH-23390 effect in all brain areas. The data demonstrate that acute treatment with dopaminergic D2 agonists and antagonists affects proenkephalin mRNA abundance in the striatum and accumbens via a D2 receptor mechanism, consistent with the concept that D2 receptor function inhibits the synthesis of the mRNA encoding the enkephalin peptides. Moreover, D1 receptor activity, directly or indirectly, exerts modulatory effects on proenkephalin mRNA abundance in the striatum and nucleus accumbens.     

Differential Effect of Stress on In Vivo Dopamine Release in Striatum, Nucleus Accumbens, and Medial Frontal Cortex

Microdialysis was used to assess extracellular dopamine in striatum, nucleus accumbens, and medial frontal cortex of unanesthetized rats both under resting conditions and in response to intermittent tail-shock stress. The dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid also were measured. The resting extracellular concentration of dopamine was estimated to be approximately 10 nM in striatum, 11 nM in nucleus accumbens, and 3 nM in medial frontal cortex. In contrast, the resting extracellular levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were in the low micromolar range. Intermittent tail-shock stress increased extracellular dopamine relative to baseline by 25% in striatum, 39% in nucleus accumbens, and 95% in medial frontal cortex. 3,4-Dihydroxyphenylacetic acid and homovanillic acid also were generally increased by stress, although there was a great deal of variability in these responses. These data provide direct in vivo evidence for the global activation of dopaminergic systems by stress and support the concept that there exist regional variations in the regulation of dopamine release.     

Effects of acute and long-term treatment with neuroleptics on regional telencephalic neurotensin levels in the male rat

By means of radioimmunoassay measurements of regional neurotensin (NT) levels in the forebrain of the male rat it was shown that selective D2 DA receptor antagonists, such as haloperidol and sulpiride, and unselective D1 and D2 antagonists such as thioridazine, flupenthixol clozapine and fluperlapine, can acutely increase NT levels in the striatum and the nucleus accumbens without affecting NT levels in the amygdaloid or anteromedial frontal cortex. Conversely, acute treatment with the D1 DA receptor antagonist Schering 23390 (SCH 23390) produced a selective reduction of striatal NT levels. After long-term treatment clozapine, fluperlapine or SCH 23390, tolerance developed with regard to their ability to modulate striatal and accumbens levels. No tolerance occurred after chronic haloperidol, chlorpromazine and sulpiride. The results indicate that the acute administration of D1 and D2 DA receptor antagonists differentially modifies NT levels in the striatum and nuc. accumbens, and that antipsychotic drugs showing a relative lack of extrapyramidal side effects may be characterised by a failure to maintain increased NT levels in the basal ganglia upon long-term treatment.     

A neurotoxic dose of methamphetamine induces gene expression of Homer 1a, but not Homer 1b or 1c, in the striatum and nucleus accumbens

Homer proteins, which regulate the signaling pathway of metabotropic glutamate receptors, may contribute to the glutamatergic modulation of dopamine neurons in the basal ganglia. This study examined whether the induction of Homer 1 genes is or not associated with the methamphetamine-induced dopaminergic neurotoxicity in the discrete brain regions of rats. Basal levels of Homer 1a and 1c mRNAs in the forebrain regions were higher than those in the substantia nigra, whereas Homer 1b mRNA levels were higher in the substantia nigra than those in the forebrain regions examined. A neurotoxic dose (40 mg/kg, i.p.) of methamphetamine increased the mRNA and protein levels of Homer 1a in the striatum and nucleus accumbens, but not in the medial prefrontal cortex or the substantia nigra. Both Homer 1b and 1c mRNAs were not affected in any brain regions examined. These results suggest that the induction of Homer 1a gene may be involved at least in part in the methamphetamine-induced dopaminergic neurotoxicity, possibly through the glutamate-dopaminergic interaction.     

Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics

Usage of 'typical' but not 'atypical' antipsychotic drugs is associated with severe side effects involving extrapyramidal tract (EPT). Single dose of haloperidol caused selective inhibition of complex I in frontal cortex, striatum and midbrain (41 and 26%, respectively) which was abolished by pretreatment of mice with thiol antioxidants, alpha-lipoic acid and glutathione isopropyl ester, and reversed, in vitro, by disulfide reductant, dithiothreitol. Prolonged administration of haloperidol to mice resulted in complex I loss in frontal cortex, hippocampus, striatum and midbrain, while chronic dosing with clozapine affected only hippocampus and frontal cortex. Risperidone caused complex I loss in frontal cortex, hippocampus and striatum but not in midbrain from which extrapyramidal tract emanates. Inhibition of the electron transport chain component, complex I by haloperidol is mediated through oxidation of essential thiol groups to disulfides, in vivo. Further, loss of complex I in extrapyramidal brain regions by anti-psychotics correlated with their known propensity to generate side-effects involving extra-pyramidal tract.     

Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum

Preclinical and clinical studies suggest that cannabidiol (CBD), a major component of Cannabis sativa, could produce antipsychotic effects without causing extra-pyramidal side-effects. In the present paper we employed the detection of Fos protein to investigate neuronal activation in the dorsal striatum and nucleus accumbens of male Wistar rats after systemic administration of CBD (120 mg/kg), haloperidol (1 mg/kg) or clozapine (20 mg/kg). Only haloperidol was able to increase the number of Fos immunoreactive neurons (FIr) in the dorsal striatum (vehicle: 0.07 +/- 0.07/0.1 mm(2), haloperidol: 28.3 +/- 8.9/0.1 mm(2), p < 0.01). In contrast, both haloperidol and CBD significantly increased FIr in the nucleus accumbens (Vehicle: 0 +/- 0/0.1 mm(2), haloperidol: 7.2 +/- 2.7/0.1 mm(2), CBD: 4.0 +/- 1.9/0.1 mm(2), p < 0.05). Clozapine also produced a barely significant increase in FIr (3.0 +/- 1.7/0.1 mm(2), p = 0.062). These results show that CBD is able to induce FIr in a limbic- but not in a motor-related area.     

Effect of DN-1417, a thyrotropin releasing hormone analog, on dopaminergic neurons in rat brain

Acute and chronic effects of γ-butyrolactone-γ-carbonyl-histidyl-prolinamide (DN-1417) were investigated on motor activity, dopamine (DA) metabolites and DA receptors in various brain regions of rats. The motor activity, as measured with Automex recorder, was enhanced after a single injection with DN-1417 (20 mg/kg, IP), and the motor stimulating action persisted during 21 daily injections. Acute DN-1417 elevated both homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in 7 brain regions, prefrontal cortex polar, medial and lateral fields, nucleus accumbens, olfactory tubercles, amygdala and striatum. After chronic treatment for 7 days, the acute effect of DN-1417 on DA metabolites disappeared in all regions except for the striatum in which DN-1417 still increased HVA and DOPAC. The response of striatal DA metabolites was also observed after chronic treatment for 21 days. Chronic DN-1417 produced no significant change in ³H-spiperone binding in the prefrontal cortex, nucleus accumbens, olfactory tubercles and striatum, while striatal ³H-DA binding displaced by 30 nM spiperone was enhanced after chronic treatment. These results indicate that DN-1417 interacts with mesocortical, mesolimbic and nigrostriatal DA systems in the different modes of action. The lack of tolerance to motor hyperactivity, however, raises the question as to whether DN-1417-induced hyperactivity may be mediated by the activation of mesolimbic DA neurons. The involvement of nigrostriatal neurons in DN-1417-induced motor hyperactivity is suggested.     

Stress-Induced Sensitization of Dopamine and Norepinephrine Efflux in Medial Prefrontal Cortex of the Rat

Abstract: We examined whether prior exposure to chronic cold (17–28 days, 5°C) alters basal or stress-evoked (30-min tail shock) catecholamine release in medial prefrontal cortex, nucleus accumbens, and striatum, using in vivo microdialysis. Basal norepinephrine (NE) concentrations in medial prefrontal cortex did not differ between chronically cold-exposed rats and naive control rats (2.7 ± 0.3 vs. 2.5 ± 0.2 pg/20 µl, respectively). Basal dopamine (DA) efflux in any of the brain regions was not significantly different between chronically cold-exposed rats and naive rats. However, a trend for lower basal DA efflux in the cold-exposed relative to naive rats was observed in medial prefrontal cortex (1.5 ± 0.2 vs. 2.2 ± 0.3 pg/20 µl, respectively), nucleus accumbens (3.7 ± 0.8 vs. 5.4 ± 0.9 pg/20 µl, respectively), and striatum (4.4 ± 0.5 vs. 7.2 ± 1.5 pg/20 µl, respectively). In medial prefrontal cortex of rats previously exposed to cold, tail shock elicited a greater increase from baseline in both DA and NE efflux relative to that measured in naive rats (DA, 2.3 ± 0.3 vs. 1.2 ± 0.1 pg, respectively; NE, 3.8 ± 0.4 vs. 1.4 ± 0.2 pg, respectively). However, in nucleus accumbens or striatum of rats previously exposed to cold, the stress-induced increase in DA efflux was not significantly different from that of naive rats (nucleus accumbens, 1.8 ± 0.7 vs. 1.5 ± 0.3 pg, respectively; striatum, 1.9 ± 0.4 vs. 2.6 ± 0.7 pg, respectively). Thus, both cortical NE projections and cortically projecting DA neurons sensitize after chronic exposure to cold. In contrast, subcortical DA projections do not sensitize under these conditions.     

In Vivo Assessment of Dopamine Uptake in Rat Medial Prefrontal Cortex: Comparison with Dorsal Striatum and Nucleus Accumbens

Abstract: In vivo electrochemistry was used to characterize dopamine clearance in the medial prefrontal cortex and to compare it with clearance in the dorsal striatum and nucleus accumbens. When calibrated amounts of dopamine were pressure-ejected into the cortex from micropipettes adjacent to the recording electrodes, transient and reproducible dopamine signals were detected. The local application of the selective uptake inhibitors GBR-12909, desipramine, and fluoxetine before the application of dopamine indicated that at the lower recording depths examined (2.5–5.0 mm below the brain surface), locally applied dopamine was cleared from the extracellular space primarily by the dopamine transporter. The norepinephrine transporter played a greater role at the more superficial recording sites (0.5–2.25 mm below the brain surface). To compare clearance of dopamine in the medial prefrontal cortex (deeper sites only), striatum, and nucleus accumbens, varying amounts of dopamine were locally applied in all three regions of individual animals. The signals recorded from the cortex were of greater amplitude and longer time course than those recorded from the striatum or accumbens (per picomole of dopamine applied), indicating less efficient dopamine uptake in the medial prefrontal cortex. The fewer number of transporters in the medial prefrontal cortex may be responsible, in part, for this difference, although other factors may also be involved. These results are consistent with the hypothesis that regulation of dopaminergic function is unique in the medial prefrontal cortex.     

Effect of Excitotoxin Lesions in the Medial 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)     

Effect of TRH analog (DN-1417) on tyrosine hydroxylase activity in mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of rat brain

Tyrosine hydroxylase (TH) was assayed in eight regions of rat brain following repeated treatment with a TRH analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide). Repeated DN-1417 treatment (20 mg/kg/day, IP) for 7 days increased TH activity in the ventral tegmental area and decreased in the prefrontal cortex polar, medial and lateral fields and olfactory tubercles. No significant change in TH activity was found in the nucleus accumbens, striatum and substantia nigra. Kinetic analysis showed that the increased TH activity in the ventral tegmental area was due to an increase in Vmax, but not a change in the apparent Km of TH for a cofactor, 6-methyl-tetrahydropteridine. When TH was assayed at a suboptimal pH and in the presence of a subsaturating cofactor, the striatal TH was activated significantly after DN-1417. In the prefrontal cortex medial field, nucleus accumbens and olfactory tubercles, TH activity assayed under the suboptimal condition was not modified by DN-1417 treatment. These results suggest an intimate involvement of central dopaminergic systems in the actions of DN-1417.     

Alterations in NMDA receptor subunit levels in the brain regions of rats chronically administered typical or atypical antipsychotic drugs

It has been hypothesized that glutamatergic neurotransmission is related to the therapeutic effect of antipsychotic drugs. To test this hypothesis, we measured by use of the Western blot technique the polypeptide levels of NMDA receptor subunits, that is, NMDAR1, 2A, 2B, and 2C, in several regions of the rat brain after chronic treatment with haloperidol (HPD) or clozapine (CLZ). Each rat was intraperitoneally injected with HPD or CLZ at 10:00 h daily for 14 days. The brain regions examined were frontal cortex, striatum, nucleus accumbens, hippocampus, and cerebellum. Decreases in the polypeptide level of NMDAR2B were seen in hippocampus (but not in other brain regions) following the treatment with HPD or CLZ. Altered levels in NMDAR1-, 2A-, and 2C were not detected in any brain regions examined. We infer that an alteration in NMDAR2B in hippocampus is related to therapeutic effects of antipsychotic drugs.     

Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system

The mesocorticolimbic dopamine system is essential for cognitive and emotive brain functions and is thus an important target in major brain diseases like schizophrenia, drug addiction, and attention deficit hyperactivity disorder. However, the cellular basis for the diversity in behavioral functions and associated dopamine-release pattern within the mesocorticolimbic system has remained unclear. Here, we report the identification of a type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and small DAT/TH mRNA expression ratios that selectively projects to prefrontal cortex and nucleus accumbens core and medial shell as well as to basolateral amygdala. In contrast, well-described conventional slow-firing dopamine midbrain neurons only project to the lateral shell of the nucleus accumbens and the dorsolateral striatum. Among this dual dopamine midbrain system defined in this study by converging anatomical, electrophysiological, and molecular properties, mesoprefrontal dopaminergic neurons are unique, as only they do not possess functional somatodendritic Girk2-coupled dopamine D2 autoreceptors.     

Effect of Chronic Typical and Atypical Neuroleptic Treatment on Proenkephalin mRNA Levels in the Striatum and Nucleus Accumbens of the Rat

We measured proenkephalin (PEK) mRNA levels in the anterior and medial aspects of the caudate-putamen (CPU) and in the nucleus accumbens (NAc) of the rat by in situ hybridization histochemistry after chronic treatment for 21 days with typical (haloperidol and prolixin) and atypical (molindone, thioridazine, and clozapine) neuroleptics. Chronic administration with these drugs resulted in PEK mRNA levels that were 60-80% higher than controls in the anterior and medial aspects of the CPU but only 25-30% over controls in the NAc. All three atypical neuroleptics studied increased PEK mRNA in the following order: anterior-CPU, thioridazine greater than clozapine and molindone; medial-CPU, thioridazine and molindone greater than clozapine; and NAc, thioridazine much greater than molindone and clozapine. Chronic treatment with the specific dopamine D2 antagonist sulpiride also caused elevation in PEK mRNA levels in all three brain regions studied whereas the specific serotonin S2 receptor blocker, cinanserin, had no significant effects on PEK mRNA levels. These results are consistent with the hypothesis that elevated levels of the enkephalins in the mesolimbic system may be necessary for antipsychotic activity. They also support the idea that the undesirable motoric signs and symptoms observed after chronic treatment with typical neuroleptics may not be the result of increased levels of enkephalins in the basal ganglia because atypical neuroleptics which are almost totally devoid of these side effects caused similar increases in PEK mRNA in the CPU.