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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 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.

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.

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-HT

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.

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.

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.

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.

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/6J 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.

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.

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.

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.

Purpose The present study assessed the influence of the GABA A receptor agonist muscimol and the GABA A receptor antagonist bicuculline on neostriatal dopamine D 2 receptor binding in relation to motor and exploratory behaviors in the rat. Methods D 2 receptor binding was measured in baseline and after challenge with either 1 mg/kg muscimol or 1 mg/kg bicuculline. In additional rats, D 2 receptor binding was measured after injection of saline. After treatment with muscimol, bicuculline and saline, motor and exploratory behaviors were assessed for 30 min in an open field prior to administration of [ 123 I]S-3-iodo- N -(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide ([ 123 I]IBZM). For baseline and challenges, striatal equilibrium ratios (V 3 ″) were computed as estimation of the binding potential. Results Muscimol but not bicuculline reduced D 2 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 D 2 receptor imaging studies. The results indicate direct GABAergic control over D 2 receptor binding in the neostriatum in relation to behavioral action, and, thus, complement earlier pharmacological studies.

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.

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.

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.

SummaryA 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.

The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc.

We here explore the utility of a paradigm that allows the simultaneous assessment of memory for object (what) and object location (where) and their comparative predominance. Two identical objects are presented during a familiarity trial; during the test trial one of these is displaced, and a new object is presented in a familiar location. When tested 5 or 80min later, rats explored both the novel and the displaced objects more than two familiar stationary objects, indicating intact memory for both, object and place. When tested 24h later rats explored the novel object more than the displaced familiar one, suggesting that forgetting differently influenced object and place memory, with memory for object being more robust than memory for place. Animals that received post-trial administration of the neurokinin-3 receptor agonist senktide and were tested 24h later, now explored the novel and displaced objects equally, suggesting that the treatment prevented the selective decay of memory for location. Next, animals received NMDA lesions in either the perirhinal cortex or the hippocampus, which are hypothesized to be preferentially involved in memory for objects and memory for place, respectively. When tested 5 or 80min later, the perirhinal cortex lesion group explored the displaced object more, indicating relatively deficient object memory, while the hippocampal lesion led to the opposite pattern, demonstrating comparatively deficient place memory. These results suggest different preferential engagement of the perirhinal cortex and hippocampus in their processing of memory for object and place. This preference test lends itself to application in the comparison of selective lesions of neural sites and projection systems as well as to the assessment of possible preferential action of pharmacological agents on neurochemical processes that subserve object vs place learning.

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.

Impairment of serotonin receptor and transporter function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ). We conducted a PubMed search, which provided a total of 136 in vivo studies with PET and SPECT, in which 5-HT synthesis, 5-HT transporter binding, 5-HT1 receptor binding or 5-HT2 receptor binding in patients with the primary diagnosis of acute AD, MDD, BD or SZ was compared to healthy individuals. A retrospective analysis revealed that AD, MDD, BD 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 receptor binding sites.

Animals treated with unilateral 6-hydroxydopamine (6-ODHA) injections, an animal model of Parkinson's disease, exhibit deficits in memory for temporal order, but show intact novel object recognition. Since senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in the aged rat and to alleviate scopolamine-induced impairment, the present study aimed to assess possible promnestic effects of senktide in the hemiparkinsonian rat model. Animals received unilateral 6-ODHA microinjections into the medial forebrain bundle. Two weeks later, they were randomly assigned to treatment with vehicle, 0.2, or 0.4 mg/kg senktide. Temporal order memory and place recognition tests were conducted, locomotor activity and turning behavior were assessed in the open field and anxiety-related behavior was measured in the light-dark box. Treatments were administered 30 min prior to behavioral testing with an interval of seven days between tests. The animals treated with 0.2 mg/kg senktide exhibited temporal order memory, unlike the vehicle-treated group. No significant treatment effects were found in the open field and light-dark box. Administration of 0.2 mg/kg senktide may influence the prefrontal cortex and hippocampus, leading to compensations for deficits in memory for temporal order.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ 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 Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.

Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in adult and aged rodents and to facilitate episodic-like memory (ELM) in mice when administrated before the learning trial. In the present study we assessed the effects of senktide on memory consolidation by administering it post-trial (after the learning trial) in adult rats. We applied an ELM test, based on the integrated memory for object, place and temporal order, which we developed (Kart-Teke, de Souza Silva, Huston, & Dere, 2006). This test involves two learning trials and one test trial. We examined intervals of 1h and 23 h between the learning and test trials (experiment 1) in untreated animals and found that they exhibited intact ELM after a delay of 1 h, but not 23 h. In another test for ELM performed 7 days later, vehicle or senktide (0.2 mg/kg, s.c.) was applied immediately after the second learning trial and the test was conducted 23 h later (experiment 2). Senktide treatment recovered components of ELM (memory for place and object) compared with vehicle-treated animals. After one more week, vehicle or senktide (0.2 mg/kg, s.c.) was applied post-trial and the test conducted 6h later (experiment 3). The senktide-treated group exhibited intact ELM, unlike the vehicle-treated group. Finally, animals received post-trial treatment with either vehicle or SR142801, a selective NK3-R antagonist (6 mg/kg, i.p.), 1 min before senktide injection (0.2 mg/kg, s.c.) in the ELM paradigm and were tested 6h later (experiment 4). The vehicle+senktide group showed intact ELM, while the SR142801+senktide group did not. The results indicate that senktide facilitated the consolidation or the expression of ELM and that the senktide effect was NK3-R dependent.

The present study assessed the influence of the GABADMuscimol but not bicuculline reduced DThe 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 D

Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.

The reuptake and release of dopamine (DA) can be estimated using in vivo imaging methods by assessing the competition between endogenous DA and an administered exogenous DA transporter (DAT) and D2 receptor (D2 R) radioligand, respectively. The aim of this study was to investigate the comparative roles of DA release vs DA reuptake in the rat striatum with small animal SPECT in relation to l-DOPA-induced behaviors. DAT and D2 R binding, together with behavioral measures, were obtained in 99 rats in response to treatment with either 5 or 10 mg/kg l-DOPA or vehicle. The behavioral parameters included the distance travelled, and durations and frequencies of ambulation, sitting, rearing, head-shoulder motility, and grooming. Data were subjected to a cluster analysis and to a multivariate principal component analysis. The highest DAT binding (i.e., the lowest DA reuptake) was associated with the highest, and the lowest DAT binding (i.e., the highest DA reuptake) was associated with the lowest motor/exploratory activity. The highest and the lowest D2 R binding (i.e., the lowest and the highest DA release, respectively) were merely associated with the second highest and second lowest levels of motor/exploratory activity. These findings indicate that changes in DA reuptake in response to fluctuating DA levels offer a better prediction of motor activity than the release of DA into the synaptic cleft. This dissociation, as reflected by in vivo DAT and D2 R binding data, may be accounted for by the regulatory sensitization meachnisms that occur at D2 R binding sites in response to altered levels of DA. Synapse 70:369-377, 2016. © 2016 Wiley Periodicals, Inc.

In the present study, we evaluated the contribution of the individual synaptic constituents of all assessed neurotransmitter systems by subjecting all available in vivo imaging studies on patients with unipolar major depressive disorder (MDD) and bipolar depression (BD) to a retrospective analysis. In acute MDD, findings revealed significant increases of prefrontal and frontal DA synthesis, decreases of thalamic and midbrain SERT, increases of insular SERT, decreases of midbrain 5-HT(1A) receptors and decreases of prefrontal, frontal, occipital and cingulate 5-HT(2A) receptors, whereas, in remission, decreases of striatal D₂ receptors, midbrain SERT, frontal, parietal, temporal, occipital and cingulate 5-HT(1A) receptors and parietal 5-HT(2A) receptors were observed. In BD, findings indicated a trend towards increased striatal D₂ receptors in depression and mania, decreased striatal DA synthesis in remission and decreased frontal D₁ receptors in all three conditions. Additionally, there is some evidence that ventrostriatal and hippocampal SERT may be decreased in depression, whereas in remission and mania elevations of thalamic and midbrain SERT, respectively, were observed. Moreover, in depression, limbic 5-HT(1A) receptors were elevated, whereas in mania a decrease of both cortical and limbic 5-HT(2A) receptor binding was observed. Furthermore, in depression, prefrontal, frontal, occipital and cingulate M2 receptor binding was found to be reduced. From this, a complex pattern of dysregulations within and between neurotransmitter systems may be derived, which is likely to be causally linked not only with the subtype and duration of disease but also with the predominance of individual symptoms and with the kind and duration of pharmacological treatment(s).

This review gives an overview of those in vivo imaging studies on synaptic neurotransmission, which so far have been performed on patients with movement disorders and/or dementia. Thereby, the focus is on disease-related deficiencies within the functional entity of the dopaminergic, serotonergic, cholinergic, glutamatergic, GABAergic or opioid synapse. In vivo investigations have yielded highly consistent results on the dysfunction of synaptic constituents in the majority of diseases covered by this overview. Findings show presynaptic dysfunctions in idiopathic as well as early-onset Parkinson's disease with decreases in striatal dopamine synthesis (57 out of a total of 59 reports on both types of Parkinson's disease), storage (nine out of nine reports), release (two out of three reports) and transporter binding (95 out of 95 reports). In contrast, the "Parkinson plus" syndromes multiple system atrophy and progressive supranuclear palsy are characterized by both pre- and postsynaptic deficiencies with reductions in striatal dopamine synthesis (11 out of a total of 11 reports on both types of "Parkinson plus" syndromes), storage (four of four reports), and transporter binding (27 out of 27 reports) as well as D1 (two out of two reports) and D2 receptor binding (34 out of 36 reports). This does not hold for the "Parkinson plus" syndromes dementia with Lewy bodies and corticobasal degeneration. For these diseases, for the time being, firm evidence of alterations in D1 and/or D2 receptor binding is lacking. In patients with Huntington's disease, mainly postsynaptic dysfunctions with reductions of striatal D1 (six out of six reports) and D2 receptor binding (15 out of 15 reports) were observed. Alzheimer's disease is characterized by both pre-and postsynaptic deficiencies of the cholinergic system with decreases of cortical acetylcholine storage (one out of two reports) and both musarinic (seven out of 10 reports) and nicotinic cholinergic receptor binding (three out of six reports). Moreover, reductions in cortical (one out of three reports) and limbic 5-HT1A (three out of three reports) and cortical (four out of four reports) and limbic 5-HT2A receptor binding (one out of two reports) were observed. Moreover, there is evidence for a cortical (four out of six reports) and cingulate (three out of three reports) increase of peripheral benzodiazepine receptor binding indicative of microglial activation. In the majority of investigations on patients with Alzheimer's disease, no alterations of presynaptic dopamine function were found, whereas all other forms of dementia including corticobasal degeneration, dementia with Lewy bodies, Parkinson's disease dementia and frontotemporal dementia were characterized by presynaptic dopaminergic deficiencies with reductions in striatal dopamine synthesis (10 out of a total of 10 reports on these types of dementia), storage (four out of four reports) and transporter binding (29 out of 29 reports). Taken together, in vivo imaging methods can be employed for the diagnosis of idiopathic and early-onset Parkinson's disease as well as "Parkinson plus" syndromes and Huntington's disease. Moreover, differentiation is feasible between, firstly, Parkinson's disease and the "Parkinson plus" syndromes multiple system atrophy and progressive supranuclear palsy, secondly, multiple system atrophy/progressive supranuclear palsy and the other "Parkinson plus" syndromes dementia with Lewy bodies and corticobasal degeneration, and, thirdly, Alzheimer's disease and other forms of dementia.

This review gives an overview of those in vivo imaging studies on synaptic neurotransmission, which so far have been performed on patients with mental and affective disorders. Thereby, the focus is on disease-related deficiencies within the functional entities of the dopaminergic, serotonergic, cholinergic, histaminergic, glutamatergic, or GABAergic synapse. So far, in vivo investigations have yielded rather inconsistent results on the dysfunctions of specific synaptic constituents in the pathophysiology of the diseases covered by this overview. Among the more congruent results are the findings of increased synthesis (8 out of a total of 12 reports) and release of dopamine (4 out of 4 reports) in the striatum of schizophrenic patients, which supports the dopamine hypothesis of schizophrenia. Results on both dopaminergic and serotonergic neurotransmission are inconsistent in both major depressive disorder and bipolar illness, and fail to clearly agree with the dopamine and/or serotonin hypothesis of depression. The majority of in vivo findings suggest no alterations (25 out of a total of 50 reports on serotonin synthesis, transporter as well as receptor binding) rather than a deficiency (merely 13 out of these 50 reports) of cortical serotonergic neurotransmission in major depression, whereas a decrease of cortical serotonergic neurotransmission (3 out of a total on 5 reports) can be assumed in bipolar illness. In borderline personality disorder, an increased binding of serotonin transporter binding was observed (merely 1 report). Due to the limited evidence, this result only with due caution may be interpreted as an indication for increased availability of serotonin in the synaptic cleft. Patients with Tourette syndrome exhibited increases of DAT binding in the neostriatum (5 out of 10 reports) increases of dopamine storage and dopamine release in the ventral striatum (1 report, each). Moreover, striatal D2 receptor binding was found to be decreased in advanced stages of the disease. Results, tentatively, may be interpreted in terms of an increased dopaminergic neurotransmission in the mesolimbic system. There is limited evidence of decreased dopamine synthesis in both children and adults with attention-deficit/hyperactivity disorder (4 out of a total of 10 reports). These findings as well as the reduction of striatal dopamine release observed in adults (merely 1 report) are in line with the notion of mesocortical dopaminergic hypofunction in attention-deficit/hyperactivity disorder. Thereby, however, in children, results on dopamine synthesis indicate a deficiency in the ventral tegmentum rather than in the prefrontal cortex, whereas, with increasing age, the prefrontal cortex rather than the sites of origin of DAergic innervation become predominantly affected (merely 1 report, each). In anxiety disorders, varying results have been obtained for both pre- and/or postsynaptic dopaminergic, serotonergic and GABAergic binding sites. Thereby, results on posttraumatic stress disorder are homogenous reporting a decrease of GABA A receptor binding in all investigated brain regions including striatum, thalamus, neocortex and limbic system (2 out of 2 reports, each). Moreover, patients with obsessive-compulsive disorder displayed increases of dopamine transporter binding (2 out of 4 reports) and decreases of both D1 (merely 1 report) and D2 receptor binding (4 out of 5 reports), respectively. These findings, tentatively, may be interpreted in terms of an increased availability of synaptic dopamine in the neostriatum, which is compensated for both pre- and postsynaptically by increasing dopamine reuptake into the presynaptic terminal, and decreasing (inhibitory) signal transduction of efferent fibers. The observed reduction of GABA A receptor binding in frontocortical neurons (in 11 out of a total of 21 reports on anxiety disorders) is in line with this assumption. The inconsistency (and, partially, also incompleteness) of in vivo findings on mental and affective disorders constitutes a major result of this overview. Discrepancies indicate that the regulation state of synaptic constituents may not only vary between the subtypes of disorders but also between subject cohorts and, even, individual patients depending on variables such as the predominance of symptoms, medication status or onset and duration of disease. This, for the time being, limits the application of in vivo imaging methods for differential diagnosis of mental and affective disorders. In vivo imaging results on anxiety disorders, however, are of possible interest with regard to psychoanalysis, as they offer a neurochemical correlate for Freud's theories on the pathogenesis of anxiety- and compulsion-related disorders.

In the present study, the binding potential (BP) of the D2 receptor radioligand ( 18 F)N-methyl-benperidol (( 18 F)FMB) was determined with in vivo saturation binding analysis using either cerebellum or parietal cortex as reference region. For the purpose of validation, BP additionally was determined in the same set of animals by computing the equilibrium ratios of the distribution volumes (V3''). With in vivo saturation binding analysis, the striatal BP as obtained with a cortical estimate for the free and non-specifically bound radioligand fell short of the BP as obtained with a cerebellar estimate by 70%. Similarly, with the equilibrium distribution volume method, the employment of a cortical REF led to a striatal V3'', which was 30% lower than the V3'' obtained with a cerebellar REF. The BP determined with in vivo saturation binding analysis and a cerebellar REF provided a closer approximation to the BP previously obtained with in vitro autoradiography relative to the BP determined with in vivo saturation binding analysis and a cortical REF. Findings show that in vivo saturation binding analysis is a feasible approach to obtain receptor binding parameters if scanner characteristics or other technical limitations preclude the kinetic modelling of binding data. However, caution should be exerted in choosing the reference tissue with regard to the intended investigation.

Synaptic dopamine is mainly regulated by presynaptic dopamine transporter (DAT) activity. We hypothesized that variations in synaptic dopamine are reflected by variations of DAT radioligand binding. The effect of haloperidol, which increases synaptic dopamine concentrations, was therefore assessed in the rat striatum using (123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)-nortropane ((123)I-FP-CIT) as a DAT radioligand.Striatal (123)I-FP-CIT binding was measured in 24 rats under baseline conditions (no pretreatment) and at 1 h after injection of haloperidol or a vehicle (1 mg/kg) using a small-animal SPECT camera.Baseline equilibrium ratios (V(3)'') were 1.32 +/- 0.24 (mean +/- SD). After the haloperidol injection, V(3)'' decreased to 0.99 +/- 0.38 (P(2-tailed)0.0001), corresponding to a mean reduction of DAT binding by 25%.Our results are indicative of competition between the DAT ligand (123)I-FP-CIT and synaptic dopamine elevated by haloperidol, suggesting that the assessment of (123)I-FP-CIT binding may be suitable to study variations in synaptic dopamine in vivo.

The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration.

OBJECTIVE This study investigated dopamine transporter blockade in the rat striatum after treatment with various doses of methylphenidate using a high-resolution small animal SPECT ('TierSPECT') and I-FP-CIT. METHODS I-FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (3 mg.kg, 10 mg.kg) or vehicle. Rats underwent scanning 2 h after radioligand application. From the spatial resolution of the imaging system and the size of the rat striatum followed that 'true' radioactivity concentrations were underestimated by approximately 50%. From cerebellar and partial volume corrected striatal radioactivity concentrations, striatal equilibrium ratios (V3'') were computed as estimations of the binding potential. RESULTS Vehicle-treated animals yielded striatal V3'' values of 3.5+/-0.9 (mean+/-SD). After pre-treatment with 3 mg.kg and 10 mg.kg methylphenidate, striatal V3'' values were reduced to 2.4+/-0.8 (independent t-test, two-tailed, P=0.026) and 1.7+/-0.6 (P

SummaryNumerous neurologic and psychiatric conditions are treated with pharmacological compounds, which lead to an increase of synaptic dopamine (DA) levels. One example is the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted to DA in the presynaptic terminal. If the increase of DA concentrations in the synaptic cleft leads to competition with exogenous radioligands for presynaptic binding sites, this may have implications for DA transporter (DAT) imaging studies in patients under DAergic medication.This paper gives an overview on those findings, which, so far, have been obtained on DAT binding in human Parkinson’s disease after treatment with L-DOPA. Findings, moreover, are related to results obtained on rats, mice or non-human primates. Results indicate that DAT imaging may be reduced in the striata of healthy animals, in the unlesioned striata of animal models of unilateral Parkinson’s disease and in less severly impaired striata of Parkinsonian patients, if animal or human subjects are under acute or subchronic treatment with L-DOPA. If also striatal DAT binding is susceptible to alterations of synaptic DA levels, this may allow to quantify DA reuptake in analogy to DA release by assessing the competition between endogenous DA and the administered exogenous DAT radioligand.

This study assessed [123I]iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT.Subsequent to baseline quantifications of D2 receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D2 receptors and dopamine transporters, respectively.Striatal baseline equilibrium ratios (V3'') of [123I]iodobenzamide binding were 1.42+/-0.31 (mean+/-SD). After pre-treatment with haloperidol and methylphenidate, V3'' values decreased to 0.54+/-0.46 (p0.0001) and 0.98+/-0.48 (p=0.009), respectively.The decrease in [123I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D2 receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [123I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [123I]iodobenzamide binding to D2 receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine.

SummaryDuring the recent years, in vivo imaging of small animals using SPECT has become of growing relevance. Along with the development of dedicated high-resolution small animal SPECT cameras, an increasing number of conventional clinical scanners has been equipped with single or multipinhole collimators. This paper reviews the small animal tomographs, which are operating at present and compares their performance characteristics. Furthermore, we describe the in vivo imaging studies, which have been performed so far with the individual scanners and survey current approaches to optimize molecular imaging with small animal SPECT.

Zusammenfassung Die vorliegende Arbeit stellt die Leistungsparameter einer neuen Kleintierkamera (TierSPECT) vor, konstruiert zur In-vivo-Messung von Labortieren mit radioaktiv markierten Substanzen. Die Kamera besitzt im Streumedium eine tomographische Ortsauflosung von 2,7 mm und eine Sensitivitat von 22 cps/MBq in einem nutzbaren Messfeld von 82 mm im Durchmesser. Die planare Homogenitat betragt 3,3%, die tomographische abstandsabhangig zwischen 3,2% und 3,5%. Die Abweichungen zwischen eingefullter und gemessener Aktivitatskonzentration in einem zylindrischen 4-Kammer-Phantom waren geringer als 2,6%. Mittels eines neuartigen Rattenkopfphantoms mit Kammervolumina in der Grosenordnung der Ortsauflosung (zwischen 0,065 ml und 0,19 ml) konnte demonstriert werden, dass mit dem TierSPECT unter Beachtung physiologischer Randbedingungen Studien am neostriatalen dopaminergen System der Ratte moglich sind. In-vivo-Studien mit [ 99m Tc]diphosphonato-1,2-propandicarbonsaure ( 99m Tc-DPD) und [ 123 I]N-ω-fluorpropyl-2β-carbomethoxy-3β-(4-iodphenyl)-nortropan ( 123 I-FP-CIT) zeigten, dass Knochenstoffwechsel und Dopamintransporterbindung mit dem TierSPECT visualisiert werden konnen. Dabei ermoglichte die Fusion von 99m Tc-DPD- und 123 I-FP-CIT-Bildern die eindeutige Differenzierung zwischen intra- und extrazerebralen Strukturen. Nach Gabe von Methylphenidat war eine deutliche Blockade des Dopamintransporters feststellbar.

Summary Aim: The study presented here firstly compars the distribution of the binding potential of the serotonin-5HT2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. Methods: Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT2A ligand 18F-altanserin. The binding potential was quantified in 12 regions using Logan’s graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. Results: The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p

Animals treated with unilateral 6-hydroxydopamine (6-ODHA) injections, an animal model of Parkinson's disease, exhibit deficits in memory for temporal order, but show intact novel object recognition. Since senktide, a potent neurokinin-3 receptor (NK3-R) agonist, has been shown to have promnestic effects in the aged rat and to alleviate scopolamine-induced impairment, the present study aimed to assess possible promnestic effects of senktide in the hemiparkinsonian rat model. Animals received unilateral 6-ODHA microinjections into the medial forebrain bundle. Two weeks later, they were randomly assigned to treatment with vehicle, 0.2, or 0.4 mg/kg senktide. Temporal order memory and place recognition tests were conducted, locomotor activity and turning behavior were assessed in the open field and anxiety-related behavior was measured in the light-dark box. Treatments were administered 30 min prior to behavioral testing with an interval of seven days between tests. The animals treated with 0.2 mg/kg senktide exhibited temporal order memory, unlike the vehicle-treated group. No significant treatment effects were found in the open field and light-dark box. Administration of 0.2 mg/kg senktide may influence the prefrontal cortex and hippocampus, leading to compensations for deficits in memory for temporal order.

SummaryImpairment of GABAA receptor function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD) and schizophrenia (SZ). Patients, method: We conducted a PUBMED search, which provided a total of 23 in vivo investigations with PET and SPECT, in which GABAA receptor binding in patients with the primary diagnosis of AD (n = 14, 160 patients, 172 controls), MDD (n = 2, 24 patients, 28 controls) or SZ (n = 6, 77 patients, 90 controls) was compared to healthy individuals. Results: A retrospective analysis revealed that AD, MDD and SZ differed as to both site(s) and extent(s) of GABAergic impairment. Additionally, it may be stated that, while the decline of GABAA receptor binding AD involved the whole mesolimbocortical system, in SZ it was confined to the frontal and temporal cortex. Conclusion: As GABA is known to inhibit dopamine and serotonin, GABAergic dysfunction may be associated with the disturbances of dopaminergic and serotonergic neurotransmission in neuropsychiatric disorders.

Prior studies have shown that the neurokinin substance P (SP) has anxiolytic-like effects when administered into the nucleus basalis (NB) area of the rat ventral pallidum. The present work was performed to examine whether the anxiolytic effects of SP in the nucleus basalis can be assigned its amino (N)- or carboxy (C)-terminal moiety. Using the elevated plus-maze model of anxiety in combination with unilateral injection of N-terminal SP 1-7 or C-terminal SP 7-11 into the NB region, we found that the treatment with either SP-fragment increased the number of entries into and time spent on the open arms as well as excursions into the end of the open arms, indicative of an anxiolytic-like profile. Furthermore, the effective doses of SP 1-7 (0.67 ng) and SP 7-11 (0.45 ng) were equimolar to the dosage of the whole SP molecule (1 ng), which was effective to reduce anxiety. Thus, the results support earlier findings that ventral pallidal injection of SP has anxiolytic-like effects and provide new evidence that fragments of SP, representing the N- and C-terminal domain of the peptide can reduce fear-parameters at a concentration similar to that of the parent peptide.

Intranasal application of dopamine (IN-DA) has been shown to increase motor activity and to release DA in the ventral (VS) and dorsal striatum (DS) of rats. The aim of the present study was to assess the effects of IN-DA treatment on parameters of DA and excitatory amino acid (EEA) function in prepuberal rats of the Naples High Excitability line (NHE), an animal model for attention-deficit hyperactivity disorder and normal random-bred (NRB) controls. Methods: NHE and NRB rats were daily administered INDA (0.075, 0.15, 0.30 mg/kg) or vehicle for 15 days from postnatal day 28 to 42 and subsequently tested in the Làt maze and in the eight arm radial Olton maze. Soluble Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation and membrane-trapped L-Glutamate (L-Glu) and L-Aspartate (L-Asp) levels as well as NMDAR1 subunit protein levels were determined post mortem in IN-DA- and vehicletreated NHE and NRB rats in prefrontal cortex (PFc), DS and VS. Moreover DA transporter (DAT) protein and tyrosine hydroxylase (TH) levels were assessed in PFc, DS, VS and mesencephalon (MES) and in ventral tegmental area and substantia nigra, respectively. Results: In NHE rats, IN-DA (0.30mg/kg) decreased horizontal activity and increased non-selective attention relative to vehicle, whereas the lower dose (0.13 mg/kg) increased selective spatial attention. In NHE rats, basal levels of soluble EEAs were reduced in PFc and DS relative to NRB controls, while membrane-bound EEAs were elevated. Moreover, basal NMDAR1 subunit protein levels were increased in PFc, DS and VS relative to NRB controls. Also DAT protein levels were elevated in PFc, VS and MES relative to NRB controls. IN-DA led to a number of changes of EAA, NMDRR1 subunit protein, TH and DAT protein levels in PFc, DS, VS, MES and VTA, in both NHE and NRB rats with significant differences between strains. Conclusions: Our findings indicate that the NHE rat model of ADHD may be characterized by (1) prefrontal and striatal DAT hyperfunction, indicative of DA hyperactivty, and (2) prefrontal and striatal NMDA receptor hyperfunction indicative of net EAA hyperactivty. IN-DA had ameliorative effects on activity level, attention, and working memory, which are likely to be associated with DA action at inhibitory D2 autoreceptors, leading to a reduction of striatal DA hyperactivity and, possibly, DA action striatal EAA levels, leading to a reduction of striatal EAA hyperfunction (with persistence of prefrontal EAA hyperfunction). Previous studies on IN-DA treatment in rodents have indicated antidepressant, anxiolytic and anti-parkinsonian effects in relation to enhanced central dopaminergic activity. Our present results strengthen the prospects of potential therapeutic applications of intranasal application of dopamine by indicating also an enhancement of selective attention and working memory in a deficit model.

In the last two decades, functional imaging methods such as positron (PET) and single photon emission computed tomography (SPECT) have emerged as valuable tools to study the dopaminergic synapse in vivo. Investigations of dopamine transporter (DAT) and dopamine D2 receptor (D2R) binding have yielded evidence that various neurological and psychiatric conditions such as Parkinson's disease,1, 2, 3 schizophrenia,4 depression,5, 6 attention-deficit/hyperactivity disorder,7 and drug abuse8 are related to dysfunctions of the dopaminergic system.

To evaluate the contribution of individual synaptic constituents, all available in vivo imaging studies on schizophrenic patients were subjected to a retrospective analysis. For the pool of drug-naive, drug-free, and acutely medicated patients, major findings were increases in neostriatal dopamine (DA) synthesis and release and decreases in neostriatal DA transporters and D1 receptors, neostriatal, thalamic, frontal, and parietal D2 receptors, mesencephalic/pontine and temporal 5-HT1A receptors, frontal and temporal HT2A and μ-amino butyric acid (GABA)A receptors. Based on the findings on drug-naive and drug-free patients, it may be hypothesized that schizophrenia initially is characterized by an impaired mechanism of D2 autoreceptor and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA. Neuroleptic medication blocks neostriatal D2 autoreceptor and heteroreceptors, reducing neostriatal DA and disinhibiting DA action mediated by D2 heteroreceptor binding sites. Ultimately, this may result in a restitution of GABA function, leading to a recovery of inhibitory input to the target regions of the descending corticothalamostriatal efferents. Furthermore, a blockade of inhibitory and excitatory neocortical 5-HT function may be inferred, which is likely to reduce (excitatory) DAergic input to the mesolimbic target regions of corticothalamostriatal projections.