Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression.

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling. In a previous study, we identified single-nucleotide polymorphisms (SNPs) and a frequent haplotype associated with cognitive and imaging phenotypes that have been linked with schizophrenia, as well as with expression of prefrontal cortical DARPP-32 messenger RNA (mRNA) in a relatively small sample of postmortem brains. In this study, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex (DLPFC), hippocampus and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder, and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders.

Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain.

Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility.

RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder.

RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.

8.6Mb interstitial deletion of chromosome 4q13.3q21.23 in a boy with cognitive impairment, short stature, hearing loss, skeletal abnormalities and facial dysmorphism.

We describe a 16-year-old boy with an 8.6Mb interstitial deletion of chromosome 4q 13.3q21.23 identified by oligo array-CGH. The patient presents psychomotor developmental delay, absent speech, marked progressive growth restriction, hearing loss, skeletal defects and minor facial anomalies. The patient required surgical treatment for cleft lip and palate, bilateral cryptorchidism and a neurofibroma. The analysis of the presented patient against previously published cases allowed us to expand further on the phenotype and to reevaluate previously proposed critical overlapping region at 4q21. As an addition to PRKG2 and RASGEFIB genes, we propose to include BMP3 gene as the principal determinant of the observed common phenotype. BMP3 haploinsufficiency appears to be causative of hearing loss and peculiar skeletal abnormalities including hemivertebrae and brachydactyly.

Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: A human post-mortem study.

There is growing interest in oxytocin as a putative treatment for various psychiatric disorders including major depressive disorder, bipolar disorder and schizophrenia/schizoaffective disorder. However, potential alterations in the endogenous brain oxytocin system in these disorders are poorly characterized. Brain expression of oxytocin and its receptor genes in patients with these psychiatric disorders has not been well studied outside the hypothalamus. We measured expression of mRNA for oxytocin and its receptor in the dorsolateral prefrontal cortex of postmortem brains using quantitative polymerase chain reaction in a total of 581 individuals. These individuals either were diagnosed with major depressive disorder (n = 135), bipolar disorder (n = 57), schizophrenia/schizoaffective disorder (n = 169), or were control subjects, defined as individuals with no lifetime history of any of these disorders (n = 220). Diagnoses of major depressive disorder and bipolar disorder were associated with significantly increased oxytocin receptor mRNA levels in the dorsolateral prefrontal cortex. This finding is discussed in light of the extant literature on the dysregulation of oxytocin signaling in individuals with major psychiatric disorders.

Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus.

BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.

Prefrontal cortical and hippocampal modulation of haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors in the rat.

Effects of prefrontal cortical or hippocampal excitotoxic lesions on behavioral parameters related to dopaminergic transmission in the basal ganglia were investigated in the rat. We examined haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviors after ibotenic acid lesions of the medial prefrontal cortex (MPFC), dorsal (DH), or ventral hippocampus (VH) in adult rats. Haloperidol-induced (1 mg/kg) catalepsy was decreased in rats with either MPFC or VH but not DH lesions. While both DH and VH lesioned animals demonstrated a reduction in apomorphine-induced (0.75 mg/kg) stereotypic behaviors, the VH lesioned animals also showed an enhancement of locomotor activity. MPFC lesioned rats tended towards potentiation of stereotypic behaviors and reduced locomotion after apomorphine administration. These data indicate that loss of prefrontal cortical or hippocampal modulation leads to an enhancement of DA transmission within the basal ganglia, though the pattern of augmentation depends on the area lesioned.

Prefrontal neurons and the genetics of schizophrenia.

This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness.

Subchronic treatment with haloperidol and clozapine in rats with neonatal excitotoxic hippocampal damage.

We have previously demonstrated that rats with neonatal excitotoxic hippocampal damage manifest abnormal dopamine (DA)-related behaviors after puberty, a phenomenon that has implications for an animal model of schizophrenia. In this study we investigated the effects of subchronic treatment with haloperidol and clozapine in these animals. The ventral hippocampus (VH) of rat pups was lesioned with ibotenic acid on postnatal day 7 (PD7). Starting at PD56, rats were treated for 21 days with either vehicle (VEH), haloperidol (HAL) (0.1 mg/kg, IP), or clozapine (CLOZ) (4 mg/kg, IP). Spontaneous locomotor activity was measured 0.5 hour after the last injection. Apomorphine (APO)-induced stereotypy and locomotion were evaluated five days later. The VH lesioned rats treated with VEH expressed enhanced novelty- and apomorphine-induced hyperlocomotion, as well as potentiated apomorphine-induced stereotypic behaviors as compared to sham-lesioned counterparts. Spontaneous locomotor activity was suppressed by haloperidol but not by clozapine in the sham-operated group, whereas both drugs were effective in suppressing hyperlocomotion in the VH lesioned rats. Withdrawal supersensitivity to apomorphine was seen in the haloperidol but not in the clozapine-treated lesioned rats, and none of the drugs produced significant supersensitivity in the sham-operated animals. These results indicate that the two neuroleptics exerted differential behavioral effects in neurologically intact and hippocampally lesioned animals, and that these effects were also drug-specific.

To model a psychiatric disorder in animals: schizophrenia as a reality test.

Animal modeling has been instrumental in dissecting pathophysiological mechanisms and designing more effective therapies in many areas of medicine but not so in psychiatry. The critical obstacle in modeling psychiatric disorders has been limited information about their origin and underlying neural mechanisms. Recently, with rapidly growing knowledge about the neurobiology and genetics of psychiatric disorders, animal models of these diseases are gaining popularity in psychiatric research. New models of schizophrenia mimic biological phenomena associated with the clinical condition, particularly developmental changes in the cortex, abnormalities of glutamate neurotransmission, and genetic characteristics of selected behavioral traits. The biological fidelity of some aspects of these new models suggests that they will be useful in the development of new therapies, in identifying candidate genes, and in providing new insights about pathophysiology and etiology.

Excitotoxic lesions of the rat medial prefrontal cortex. Effects on abnormal behaviors associated with neonatal hippocampal damage.

Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.

Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia.

The constellation of major phenomena associated with schizophrenia (e.g., postpubertal onset, congenital hippocampal area damage, cortical functional deficits, limbic dopamine (DA) dysregulation, and vulnerability to stress) have been difficult to explain with a unitary animal model. Although it has been shown that rats develop increased mesolimbic DA transmission and reduced cortical DA turnover following adult excitotoxic lesions of the ventral hippocampus (VH), the implications of early developmental VH lesions are not known. To determine the developmental sequelae of such changes, we produced ibotenic acid lesions of the ventral hippocampal formation in rats on the 7th day after birth (PD7). Motor activity in a novel environment, after saline injection and after d-amphetamine administration were similar in control and lesioned rats at PD35. However, in early adulthood, at PD56, animals with the hippocampal lesion were hyperactive in each of these conditions. The emergence of the hyperactivity at PD56 could be prevented by pretreatment with haloperidol. Moreover, rats lesioned as neonates, in contrast to a similar lesion induced in adult animals, were also hyperresponsive to stress evaluated with a swim test. This latter effect is analogous to that seen after adult lesions of the medial prefrontal cortex, rather than after adult lesions of VH, suggesting that the neonatal VH lesion may affect functional development of the medial prefrontal cortex. These results demonstrate that in rats with neonatally induced excitotoxic VH lesions, behavioral indices consistent with increased mesolimbic DA responsivity to stressful and to pharmacologic stimuli emerge only in early adulthood. Homologous mechanisms may underlie certain aspects of the pathophysiology of schizophrenia.

Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on In vivo 1H-MRS signals.

The rat medial prefrontal cortex (mPFC) regulates subcortical dopamine transmission via projections to the striatum and ventral tegmental area. We used in vivo proton magnetic resonance spectroscopy (1H-MRS) at 4.7 T to determine whether excitotoxic lesions of the mPFC result in alterations of N-acetylaspartate (NAA), a marker of neuronal integrity, both locally and downstream in the striatum. Lesioned rats exhibited persistent reductions of NAA and other metabolites within the prefrontal cortex; selective reductions of NAA were seen in the striatum, but not in the parietal cortex. Consistent with earlier reports, lesioned rats exhibited a transient enhancement in amphetamine-induced hyperlocomotion. Prefrontal NAA losses correlated with lesion extent. In the striatum, while there was no change in tissue volume, expression of striatal glutamic acid decarboxylase-67 mRNA was significantly reduced. In vivo NAA levels thus appear sensitive to both local and downstream alterations in neuronal integrity, and may signal meaningful effects at cellular and behavioral levels.

Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function.

Catechol O-methyltransferase (COMT) is involved in the inactivation of catecholamines, including the neurotransmitter dopamine. A Val(108/158) Met functional polymorphism of the COMT gene has been shown to affect working memory-associated frontal lobe function in humans. In the present study, in situ hybridization histochemistry was employed to determine the mRNA expression profile of COMT in the human prefrontal cortex, striatum and midbrain and in the rat forebrain. In both species, COMT mRNA signals were observed in large pyramidal and smaller neurons in all cortical layers of the prefrontal cortex as well as in medium and large neurons in the striatum. Levels of COMT mRNA were obviously higher in neurons than in glia. The striatum, which receives a dense dopaminergic input, expressed lower levels of COMT mRNA as compared with the prefrontal cortex. Consistent with previous protein expression data, COMT mRNA was abundant in ependymal cells lining the cerebral ventricles. In the midbrain, COMT mRNA was detected in dopaminergic neurons in both species, albeit at low levels. In the rat forebrain, dense labeling was also detected in choroid plexus and hippocampal dentate gyrus and Ammon's horn neurons. Contrary to expectations that COMT would be expressed predominantly in non-neuronal cells, the present study shows that neurons are the main cell populations expressing COMT mRNA in the prefrontal cortex and striatum. Combined with previous data about protein localization, the present results suggest that the membrane-bound isoform of COMT having a high affinity for dopamine is expressed at neuronal dendritic processes in human cortex, consistent with functional evidence that it plays an important role in dopaminergic neurotransmission.

Serum levels and clinical response in long-term pharmacotherapy with zuclopenthixol decanoate.

Twenty-six patients diagnosed as chronic schizophrenics were given injections of zuclopenthixol decanoate (cis(Z)-clopenthixol decanoate) 200 mg every 3 weeks for at least 6 months. Before treatment and on each day of injection the patients' mental state was assessed by Brief Psychiatric Rating Scale (BPRS), 18 items. A registration of side effects and basal laboratory data was also performed. Blood samples were drawn on each day of injection before injection and 3-7 days after injection (time of maximum concentration). Neuroleptic activity, which was considered equivalent to the concentration of zuclopenthixol, was determined in serum by radio-receptor assay (RRA). Based on amelioration scores greater than or equal to 50% on the BPRS, 15 patients were characterized as responders and 11 as non-responders. The responder group showed a statistically significant reduction in BPRS score, whereas this was not the case for the non-responders. Apart from a few patients, the serum concentrations showed a low intra-individual variation, but a relatively high inter-individual variation. The responder group had a significantly higher mean pre-injection concentration than the non-responder group, whereas no significant difference was found in day 3-7 concentrations. The fluctuation of the serum concentration expressed as the ratio between maximum (days 3-7) and minimum (pre-inj.) was found to be significantly lower for responders than for non-responders. Thus although the present study did not demonstrate a clear relationship between serum level and clinical effect, it indicates that the best antipsychotic effect is obtained with a serum concentration which fluctuates only slightly (the ratio max/min concentration not exceeding 2.1).

Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood.

The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 micromol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.

Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in adult rats.

Sensorimotor gating of the startle reflex is impaired in humans with schizophrenia and in rats after mesolimbic D2 dopamine receptor activation. The loss of startle gating after D2 activation in rats has been used as an animal model of impaired sensorimotor gating in schizophrenia, because the ability of antipsychotics to restore startle gating in D2-activated rats correlates significantly with antipsychotic clinical potency. Substantial evidence indicates that the pathophysiology of schizophrenia includes structural and functional deficits in prefrontal and temporal regions, particularly the dorsolateral prefrontal cortex and the hippocampus and parahippocampal gyrus. The present study assessed startle gating in adult rats after ibotenic acid lesions of the medial prefrontal cortex or ventral hippocampus. Medial prefrontal cortex lesioned rats exhibited normal startle amplitude and normal sensorimotor gating, as reflected by prepulse inhibition (PPI) of the startle reflex. Hippocampus lesioned rats exhibited elevated startle amplitude, and similar to rats with medial prefrontal cortex lesions, did not show significant changes in basal PPI. Low doses of the mixed dopamine agonist apomorphine did not significantly reduce PPI in sham lesioned rats, but significantly disrupted PPI in both medial prefrontal cortex- and ventral hippo-campus lesioned rats. These data are consistent with the hypothesis that cell damage in frontal and temporal cortex increases the sensitivity to the sensorimotor gating-disruptive effects of dopamine receptor activation.

Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine.

Neonatal excitotoxic hippocampal damage in the rat results in postpubertal onset of a variety of abnormal behaviors related to excessive dopaminergic transmission in the mesolimbic/nigrostriatal system, and thus may be considered an animal model of some aspects of schizophrenia. Because sensorimotor gating is impaired in adult patients with schizophrenia and in rats with experimentally induced mesolimbic dopamine hyperactivity, the present experiments investigated the effects of neonatal (postnatal day 7, PD7) ibotenic acid (3 micrograms) lesions of the ventral hippocampus (VH) on the amplitude and prepulse inhibition (PPI) of acoustic startle in prepubertal (PD35) and postpubertal (PD56) rats. Startle was elicited using 105 and 118-dB pulses alone or preceded by 4, 8, or 16 dB above-background prepulses in rats treated with vehicle or apomorphine (APO; 0.025 or 0.1 mg/kg SC). At PD35, PPI in VH-lesioned rats did not differ significantly from these measures in sham operated rats. Apomorphine significantly increased startle amplitude and reduced PPI in both sham operated and VH-lesioned rats at PD35. At PD56, startle amplitude in VH-lesioned rats was not significantly different from controls, but PPI was reduced significantly compared to controls. Ventral hippocampus lesioned rats also exhibited an exaggerated reduction in PPI after treatment with APO. These findings provide further evidence of postpubertal impairments that may be related to increased mesolimbic dopamine transmission and receptor sensitivity in rats with neonatal hippocampal damage, and provide further support for the fidelity of this animal model of schizophrenia.

Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground.

Two of the favorite hypotheses of schizophrenia research-maldevelopment of cerebral cortex and malfunction of brain dopamine systems-have often seemed difficult to reconcile. This article reviews recent research that suggests a heuristically useful reconciliation centered on the functional neuroanatomical concept of prefrontal-temporolimbic cortical connectivity. Anatomical findings from postmortem studies and neuropsychological and neuroimaging studies of brain function in patients with schizophrenia have implicated a developmental 'dysconnection' of temporolimbic-prefrontal cortices. The possibility that such dysconnection can account for the principal phenomenology of the illness, including its delayed onset and its treatment, is suggested by neurologic disease analogies such as metachromatic leukodystrophy and by recent studies in animals with developmental cortical lesions. Studies mapping neuronal gene expression indicate that all antipsychotic drugs modulate DNA transcription in a region of the nucleus accumbens that receives converging inputs from prefrontal and temporolimbic cortices, suggesting that indirect compensation for dysfunctional communication between prefrontal and temporolimbic cortices is a therapeutic mechanism of these drugs. Treatments aimed at direct cortical compensation may be more effective.

Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus.

There is experimental evidence from radioligand binding experiments for the existence of strong antagonistic interactions between different subtypes of adenosine and dopamine receptors in the striatum, mainly between adenosine A1 and dopamine D1 and between adenosine A2A and dopamine D2 receptors. These interactions seem to be more powerful in the ventral compared to the dorsal striatum, which might have some implications for the treatment of schizophrenia. The binding characteristics of different dopamine and adenosine receptor subtypes were analysed in the different striatal compartments (dorsolateral striatum and shell and core of the nucleus accumbens), by performing saturation experiments with the dopamine D1 receptor antagonist [125I]SCH-23982, the dopamine D2-3 receptor antagonist [3H]raclopride, the adenosine A1 receptor antagonist [3H]DPCPX and the adenosine A2A receptor antagonist [3H]SCH 58261. The experiments were also performed in rats with a neonatal bilateral lesion of the ventral hippocampus (VH), a possible animal model of schizophrenia. Both dopamine D2-3 and adenosine A2A receptors follow a similar pattern, with a lower density of receptors (40%) in the shell of the nucleus accumbens compared with the dorsolateral caudate-putamen. A lower density of adenosine A1 receptors (20%) was also found in the shell of the nucleus accumbens compared with the caudate-putamen. On the other hand, dopamine D1 receptors showed a similar density in the different striatal compartments. Therefore, differences in receptor densities cannot explain the stronger interactions between adenosine and dopamine receptors found in the ventral, compared to the dorsal striatum. No statistical differences in the binding characteristics of any of the different adenosine and dopamine receptor antagonists used were found between sham-operated and VH-lesioned rats.