5-HT1A and 5-HT2A receptor effects on recognition memory, motor/exploratory behaviors, emotionality and regional dopamine transporter binding in the rat.

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.

The 5-HT1A receptor agonist 8-OH-DPAT modulates motor/exploratory activity, recognition memory and dopamine transporter binding in the dorsal and ventral striatum.

In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.

Neuronal circuitry for recognition memory of object and place in rodent models.

Rats and mice are used for studying neuronal circuits underlying recognition memory due to their ability to spontaneously remember the occurrence of an object, its place and an association of the object and place in a particular environment. A joint employment of lesions, pharmacological interventions, optogenetics and chemogenetics is constantly expanding our knowledge of the neural basis for recognition memory of object, place, and their association. In this review, we summarize current studies on recognition memory in rodents with a focus on the novel object preference, novel location preference and object-in-place paradigms. The evidence suggests that the medial prefrontal cortex- and hippocampus-connected circuits contribute to recognition memory for object and place. Under certain conditions, the striatum, medial septum, amygdala, locus coeruleus and cerebellum are also involved. We propose that the neuronal circuitry for recognition memory of object and place is hierarchically connected and constructed by different cortical (perirhinal, entorhinal and retrosplenial cortices), thalamic (nucleus reuniens, mediodorsal and anterior thalamic nuclei) and primeval (hypothalamus and interpeduncular nucleus) modules interacting with the medial prefrontal cortex and hippocampus.

Boosted dopamine and blunted serotonin in Tourette syndrome - evidence from in vivo imaging studies.

The precise cortical and subcortical mechanisms of Tourette syndrome (TS) are still not fully understood. In the present retrospective analysis, adolescent and adult medication-naïve patients showed increased DA transporter (DAT) binding in nucleus caudate (CAUD), putamen (PUT) and/or whole neostriatum (NSTR). D2 receptor (R) binding and DA release were not different from controls throughout the nigrostriatal and mesolimbocortical system. When patients were medication-free (either medication-naïve or under withdrawal), DAT was still increased in PUT, but not different from controls in CAUD, NSTR and ventral striatum (VSTR). SERT was unaltered in midbrain/pons (MP), but decreased in PUT, thalamus (THAL) and hypothalamus. D2R was unaltered throughout the nigrostriatal and mesolimbocortical system, while DA release was not different from controls in PUT, CAUD and NSTR, but elevated in VSTR. 5-HT2AR binding was unaltered in neocortex and cingulate. In acutely medicated adults, DAT was unaltered in PUT, but still increased in CAUD, whereas DA release remained unaltered throughout the nigrostriatal and mesolimbocortical system. When part of the patients was acutely medicated, vesicular monoamine transporter (VMAT2), DAT, SERT and DA synthesis were not different from controls in striatal regions, whereas D2R was decreased in NSTR, THAL, frontal cortex and limbic regions. Conversely, 5-HT2AR binding was unaltered in striatal regions and THAL, but increased in neocortical and limbic areas. It may be hypothesized that both the DA surplus and the 5-HT shortage in key regions of the nigrostriatal and mesolimbic system are relevant for the bouts of motor activity and the deficiencies in inpulse control.

Disrupted-in-schizophrenia 1 Protein Misassembly Impairs Cognitive Flexibility and Social Behaviors in a Transgenic Rat Model.

Alterations in cognitive functions, social behaviors and stress reactions are commonly diagnosed in chronic mental illnesses (CMI). Animal models expressing mutant genes associated to CMI represent either rare mutations or those contributing only minimally to genetic risk. Non-genetic causes of CMI can be modeled by disturbing downstream signaling pathways, for example by inducing protein misassembly or aggregation. The Disrupted-in-Schizophrenia 1 (DISC1) gene was identified to be disrupted and thereby haploinsufficient in a large pedigree where it was associated with CMI. In a subset of CMI patients, the DISC1 protein misassembles to an insoluble protein. This has been modeled in a rat (tgDISC1 rat) where the full-length, non mutant human transgene was overexpressed and cognitive impairments were observed. Here, we investigated the scope of effects of DISC1 protein misassembly by investigating spatial memory, social behavior and stress resilience. In water maze tasks, the tgDISC1 rats showed intact spatial learning and memory, but were deficient in flexible adaptation to spatial reversal learning compared to littermate controls. They also displayed less social interaction. Additionally, there was a trend towards increased corticosterone levels after restraint stress in the tgDISC1 rats. Our findings suggest that DISC1 protein misassembly leads to disturbances of cognitive flexibility and social behaviors, and might also be involved in stress sensitization. Since the observed behavioral features resemble symptoms of CMI, the tgDISC1 rat may be a valuable model for the investigation of cognitive, social and - possibly - also stress-related symptoms of major mental illnesses.

The 5-HT1A receptor antagonist WAY-100635 decreases motor/exploratory behaviors and nigrostriatal and mesolimbocortical dopamine D2/3 receptor binding in adult rats.

Serotonin(5-HT)ergic projections run from the raphe nuclei to dopamin(DA)ergic cells in substantia nigra/ventral tegmental area (SN/VTA) and to the terminal fields of DA neurons in nucleus accumbens, caudateputamen and neocortex. In the present studies, we assessed the effect of the 5-HT1A receptor (R) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarbox-amide maleate (WAY-100635) on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. D2/3R binding was determined in the same animals after systemic application of WAY-100635 (0.4 mg/kg) and 0.9% saline (SAL), respectively, with [123I]IBZM as SPECT ligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after treatment with WAY-100635 or SAL, motor/exploratory behaviors were assessed for 30 min in two different batches of animals in an open field. WAY-100635 reduced D2/3R binding in caudateputamen, thalamus, frontal cortex, parietal cortex and ventral hippocampus relative to SAL. Network analysis of regional binding data after WAY-100635 yielded positive connections between (1) caudateputamen and substantia nigra/ventral tegmental area, (2) caudateputamen and ventral hippocampus, (3) substantia nigra/ventral tegmental area and parietal cortex, (4) thalamus and dorsal hippocampus and (5) frontal cortex and parietal cortex, which were not present after SAL. Moreover, WAY-100635 decreased parameters of motor activity (overall activity, ambulation duration and frequency) but increased the duration of grooming behavior relative to SAL. The effect on exploration was time-dependent with an early increase and a subsequent decrease of behavioral parameters (rearing duration and frequency, frequency of head-shoulder motility). For WAY-100635, findings imply a region-specificity as well as a time-dependency of DAergic action.

Monoaminergic hypo- or hyperfunction in adolescent and adult attention-deficit hyperactivity disorder?

Disturbances of dopamine (DA), serotonin (5-HT) and/or norepinephrine (NE) functions are implied in attention-deficit hyperactivity disorder (ADHD). However, the precise cortical and subcortical mechanisms are still not fully understood. In the present survey, we conducted a PUBMED search, which provided 37 in vivo investigations with PET and SPECT on 419 ADHD patients and 490 controls. The retrospective analysis revealed increased striatal DA transporter (DAT) in adolescent as well as adult medication-naïve and not acutely medicated patients. In acutely medicated adults, DAT was not different from controls. Midbrain DAT was normal in adults, but decreased in adolescents. Striatal D2 receptor (R) binding was normal in both adolescents (not acutely medicated) and adults (acutely medicated and not acutely medicated). In medication-naïve adults, DA synthesis was decreased in putamen and amygdala, but normal in the whole striatum and midbrain. In not acutely medicated adults, DA synthesis was reduced in putamen, whole striatum, prefrontal cortex, frontal cortex, amygdala and midbrain, whereas, in adolescents, no regional differences were observed. In adult (not acutely medicated) subjects, cingulate D1R was reduced. 5-HT transporter (SERT) binding was decreased in striatum and thalamus, but normal in midbrain, neocortex and limbic regions, whereas, in medication-naïve adults, SERT was diminished in striatum and midbrain, but normal in thalamus and neocortex. The findings suggest transient stages of synaptic DA shortage as well as DA surplus in individual brain regions, which elicit presynaptic as well as postsynaptic compensatory mechanisms, striving to attain functional homeostasis. Thereby, it remains a matter of debate, whether ADHD may be characterized by a general hypo- or hyperactivity of DA and/or 5-HT function.

Serotonergic Modulation of Nigrostriatal and Mesolimbic Dopamine and Motor/Exploratory Behaviors in the Rat.

Purpose: The 5-HT2A receptor (R) is known to modulate dopamine (DA) release in the mammalian brain. Altanserin (ALT) and 2,5-dimethoxy-4-iodoamphetamine (DOI) act as 5-HT2AR antagonist and agonist, respectively. In the present study, we assessed the effects of ALT and DOI on motor and exploratory behaviors and on D2/3R binding in the rat brain with in vivo imaging methods. Methods: D2/3R binding was determined after systemic application of ALT (10 mg/kg) or DOI (0.5 mg/kg) and the respective vehicles [dimethyl sulfoxide (DMSO) and 0.9% saline (SAL)] with [123I]IBZM as a single-photon emission computed tomography (SPECT) radioligand. Anatomical information for the delineation of the target regions was obtained with dedicated small animal MRI. Immediately after 5-HT2AR antagonistic or agonistic treatment, motor/exploratory behaviors were assessed for 45 (ALT) or 30 min (DOI) in an open field. Additional rats underwent behavioral measurements after injection of DMSO or SAL. Results: ALT increased D2/3R binding in the ventral hippocampus relative to vehicle, while DOI augmented D2/3R binding in caudate putamen, frontal cortex, motor cortex, and ventral hippocampus. The 5-HT2AR agonist as well as antagonist decreased parameters of motor activity and active exploration. However, ALT, in contrast to DOI, decreased explorative head-shoulder motility and increased sitting. Conclusions: The regional increases of D2/3R binding after ALT and DOI (90 and 75 min post-challenge) may be conceived to reflect decreases of synaptic DA. The reductions of motor/exploratory activities (min 1-45 and min 1-30 after challenge with ALT and DOI, respectively) contrast the regional reductions of D2/3R binding, as they indicate elevated DA levels at the time of behavioral measurements. It may be concluded that ALT and DOI modulate DA in the individual regions of the nigrostriatal and mesolimbocortical pathways differentially and in a time-dependent fashion.

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism.

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher "complexity" and lower "texture". Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat.

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.

Intranasal pregnenolone increases acetylcholine in frontal cortex, hippocampus, and amygdala-Preferentially in the hemisphere ipsilateral to the injected nostril.

This study determined the effects of intranasal pregnenolone (IN-PREG) on acetylcholine (ACh) levels in selected areas of the rat brain, using in vivo microdialysis. Previous studies showed that PREG rapidly reaches the rodent brain after intranasal administration and that direct infusion of PREG and PREG-S into the basal forebrain modulates ACh release in frontal cortex, amygdala, and hippocampus. In the present study, we investigated the effects of IN-PREG on the cholinergic system in the rat brain. In the first experiment, IN-PREG (5.6 and 11.2 mg/ml) or vehicle was applied bilaterally, and we hypothesized that IN-PREG would increase ACh levels in amygdala, hippocampus, and frontal cortex, relative to baseline and vehicle. Dialysate was collected for 100 min, based on pilot data of duration of effect. Bilateral IN-PREG (5.6 and 11.2 mg/ml) increased frontal cortex and hippocampal ACh relative to both baseline and vehicle. Moreover, 11.2 mg/ml PREG increased ACh in the amygdala relative to baseline, the lower dose, and vehicle. Therefore, in the second experiment, IN-PREG (11.2 mg/ml) was applied only into one nostril, with vehicle applied into the other nostril, in order to determine whether ACh is predominantly increased in the ipsilateral relative to the contralateral amygdala. Unilateral application of IN-PREG increased ACh in the ipsilateral amygdala, whereas no effect was observed on the contralateral side, suggesting that PREG was transported from the nostrils to the brain via the olfactory epithelial pathway, but not by circulation. The present data provide additional information on IN-PREG action in the cholinergic system of frontal cortex, amygdala, and hippocampus. This may be relevant for therapeutic IN application of PREG in neurogenerative and neuropsychiatric disorders.

Differential effects of D-cycloserine and amantadine on motor behavior and D2/3 receptor binding in the nigrostriatal and mesolimbic system of the adult rat.

D-cycloserine (DCS) and amantadine (AMA) act as partial NMDA receptor (R) agonist and antagonist, respectively. In the present study, we compared the effects of DCS and AMA on dopamine D2/3R binding in the brain of adult rats in relation to motor behavior. D2/3R binding was determined with small animal SPECT in baseline and after challenge with DCS (20 mg/kg) or AMA (40 mg/kg) with [123I]IBZM as radioligand. Immediately post-challenge, motor/exploratory behavior was assessed for 30 min in an open field. The regional binding potentials (ratios of the specifically bound compartments to the cerebellar reference region) were computed in baseline and post-challenge. DCS increased D2/3R binding in nucleus accumbens, substantia nigra/ventral tegmental area, thalamus, frontal, motor and parietal cortex as well as anterodorsal and posterior hippocampus, whereas AMA decreased D2/3R binding in nucleus accumbens, caudateputamen and thalamus. After DCS, ambulation and head-shoulder motility were decreased, while sitting was increased compared to vehicle and AMA. Moreover, DCS increased rearing relative to AMA. The regional elevations of D2/3R binding after DCS reflect a reduction of available dopamine throughout the mesolimbocortical system. In contrast, the reductions of D2/3R binding after AMA indicate increased dopamine in nucleus accumbens, caudateputamen and thalamus. Findings imply that, after DCS, nigrostriatal and mesolimbic dopamine levels are directly related to motor/exploratory activity, whereas an inverse relationship may be inferred for AMA.

Amantadine enhances nigrostriatal and mesolimbic dopamine function in the rat brain in relation to motor and exploratory activity.

PURPOSE: The present study assessed the influence of the NMDA receptor (R) antagonist amantadine (AMA) on cerebral dopamine D2/3R binding in relation to motor and exploratory activity in the rat. METHODS: D2/3R binding was determined in anaesthetized animals with small animal SPECT in baseline and after challenge with AMA (10 or 40 mg/kg) using [123I]IBZM as radioligand. Immediately post-challenge and prior to radioligand administration, motor/exploratory behaviors were assessed for 30 min in an open field. Each rat underwent measurements with a dedicated small animal MRI in order to gain anatomical information. Regions of interest were defined on SPECT-MRI overlays. The regional binding potentials in baseline and post-challenge were estimated by computing ratios of the specifically bound compartments to the cerebellar reference region. RESULTS: 40 mg/kg AMA reduced D2/3R binding in nucleus accumbens, caudateputamen and thalamus, while 10 mg/kg decreased D2/3R binding in the anterodorsal hippocampus. The higher dose decreased ambulatory activity, rearing and grooming, but elevated sitting and head-shoulder motility relative to both vehicle and the lower dose in the first 15 min post-challenge. CONCLUSIONS: Results showed reductions of D2/3R binding in regions of the nigrostriatal and mesolimbic system after challenge with AMA, which reflect an increased availability of dopamine. Thereby, an inverse relationship between nigrostriatal and mesolimbic dopamine and motor/exploratory activity can be inferred. Findings may be relevant for the treatment of neurological and psychiatric conditions such as Parkinson's disease, Huntington's disease or schizophrenia, which are characterized by both dopaminergic and glutamatergic dysfunction.

Acute anxiety disorder, major depressive disorder, bipolar disorder and schizophrenia are related to different patterns of nigrostriatal and mesolimbic dopamine dysfunction.

Dopamine (DA) receptor and transporter dysfunctions play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) in the manic (BDman) or depressive (BDdep) state and schizophrenia (SZ). We performed a PUBMED search, which provided a total of 239 in vivo imaging studies with either positron emission tomography (PET) or single-proton emission computed tomography (SPECT). In these studies, DA transporter binding, D1 receptor (R) binding, D2R binding, DA synthesis and/or DA release in patients with the primary diagnosis of acute AD (n=310), MDD (n=754), BDman (n=15), BDdep (n=49) or SZ (n=1532) were compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BDman, BDdep and SZ differed as to affected brain region(s), affected synaptic constituent(s) and extent as well as direction of dysfunction in terms of either sensitization or desensitization of transporter and/or receptor binding sites. In contrast to AD and SZ, in MDD, BDman and BDdep, neostriatal DA function was normal, whereas MDD, BDman, and BDdep were characterized by the increased availability of prefrontal and frontal DA. In contrast to AD, MDD, BDman and BDdep, DA function in SZ was impaired throughout the nigrostriatal and mesolimbocortical system with an increased availability of DA in the striatothalamocortical and a decreased availability in the mesolimbocortical pathway.

Aß dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aß) dimers and is devoid of Aß plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aß plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aß dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.

GABAergic Control of Nigrostriatal and Mesolimbic Dopamine in the Rat Brain.

Purpose: The present study assessed the effects of the GABAA receptor (R) agonist muscimol (MUS), and the GABAAR antagonist bicuculline (BIC) on neocortical and subcortical radioligand binding to dopamine D2/3Rs in relation to motor and exploratory behaviors in the rat. Methods: D2/3R binding was measured with small animal SPECT in baseline and after challenge with either 1 mg/kg MUS or 1 mg/kg BIC, using [123I]IBZM as radioligand. Motor/exploratory behaviors were assessed for 30 min in an open field prior to radioligand administration. Anatomical information was gained with a dedicated small animal MRI tomograph. Based on the Paxinos rat brain atlas, regions of interest were defined on SPECT-MRI overlays. Estimations of the binding potentials in baseline and after challenges were obtained by computing ratios of the specifically bound compartments to the cerebellar reference region. Results: After MUS, D2/3R binding was significantly reduced in caudateputamen, nucleus accumbens, thalamus, substania nigra/ventral tegmental area, and posterior hippocampus relative to baseline (0.005 ≤ p ≤ 0.012). In all these areas, except for the thalamus, D2/3R binding was negatively correlated with grooming in the first half and positively correlated with various motor/exploratory behaviors in the second half of the testing session. After BIC, D2/3R binding was significantly elevated in caudateputamen (p = 0.022) and thalamus (p = 0.047) relative to baseline. D2/3R binding in caudateputamen and thalamus was correlated negatively with sitting duration and sitting frequency and positively with motor/exploratory behaviors in the first half of the testing time. Conclusions: Findings indicate direct GABAergic control over nigrostriatal and mesolimbic dopamine levels in relation to behavioral action. This may be of relevance for neuropsychiatric conditions such as anxiety disorder and schizophrenia, which are characterized by both dopaminergic and GABAergic dysfunction.

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene.

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14-15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. RESULTS: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. CONCLUSIONS: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.

Interaction between the medial prefrontal cortex and hippocampal CA1 area is essential for episodic-like memory in rats.

The interplay between medial prefrontal cortex (mPFC) and hippocampus, particularly the hippocampal CA3 area, is critical for episodic memory. To what extent the mPFC also interacts with the hippocampus CA1 subregion still requires elucidation. To investigate this issue, male rats received unilateral N-methyl-D-aspartate lesions of the mPFC together with unilateral lesions of the hippocampal CA1 area, either in the same (control) or in the opposite hemispheres (disconnection). They underwent an episodic-like memory test, combining what-where-when information, and separate tests for novel object preference (what), object place preference (where) and temporal order memory (when). Compared to controls, the disconnected mPFC-CA1 rats exhibited disrupted episodic-like memory with an impaired integration of the what-where-when elements. Both groups showed intact memories for what and when, while only the control group showed intact memory for where. These findings suggest that the functional interaction of the mPFC-CA1 circuit is crucial for the processing of episodic memory and, in particular, for the integration of the spatial memory component.

Different patterns of dopaminergic and serotonergic dysfunction in manic, depressive and euthymic phases of bipolar disorder.

A variety of alterations in brain neurotransmitter systems has been proposed as the cause of bipolar disorder (BD). We conducted a PUBMED search, which provided a total of 45 in vivo investigations with PET and SPECT, in which binding to serotonin transporter (SERT), 5-HT1A receptor (R), 5-HT2AR, dopamine transporter (DAT), vesicular monoamine transporter (VMAT2), D1R, D2R, muscarinic M2R and nicotinic ß2-nAChR as well as dopamine synthesis and/or dopamine release were assessed in BD patients in the manic (6 studies, 39 patients, 77 controls), depressive (15 studies, 248 patients, 488 controls) or eu- thymic condition (18 studies, 265 patients, 293 controls) and in mixed collectives of BD patients (6 studies, 55 patients, 80 controls). The retrospective analysis revealed a complex pattern of dysregulations within and between neurotransmitter systems, which is causally linked to the acute and euthymic states of BD. While increased mesencephalic, limbic and parietotemporoccipital serotonin and increased frontal dopamine underlie mania, the depressive state is characterized by decreased frontal and limbic serotonin, increased frontal and limbic acetylcholine and increased frontal dopamine. Also in euthymia, no normalization of receptor and transporter densities was observed. Alterations of regulation states of bindings sites, however, act together to achieve a normalization of mesencephalic, limbic and cortical serotonin.

GABAergic control of neostriatal dopamine D2 receptor binding and behaviors in the rat.

PURPOSE: The present study assessed the influence of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline on neostriatal dopamine D2 receptor binding in relation to motor and exploratory behaviors in the rat. METHODS: D2 receptor binding was measured in baseline and after challenge with either 1mg/kg muscimol or 1mg/kg bicuculline. In additional rats, D2 receptor binding was measured after injection of saline. After treatment with muscimol, bicuculline and saline, motor and exploratory behaviors were assessed for 30min in an open field prior to administration of [123I]S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([123I]IBZM). For baseline and challenges, striatal equilibrium ratios (V3″) were computed as estimation of the binding potential. RESULTS: Muscimol but not bicuculline reduced D2 receptor binding relative to baseline and to saline. Travelled distance, duration of rearing and frequency of rearing and of head-shoulder motility were lower after muscimol compared to saline. In contrast, duration of rearing and grooming and frequency of rearing, head-shoulder motility and grooming were elevated after bicuculline relative to saline. Moreover, bicuculline decreased duration of sitting and head-shoulder motility. CONCLUSIONS: The muscimol-induced decrease of motor/exploratory behaviors can be related to an elevation of striatal dopamine levels. In contrast, bicuculline is likely to elicit a decline of synaptic dopamine, which, however, is compensated by the time of D2 receptor imaging studies. The results indicate direct GABAergic control over D2 receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies.