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PubMed2002

Functional aspects of dopamine metabolism in the putative prefrontal cortex analogue and striatum of pigeons (Columba livia).

Dopamine (DA) in mammalian associative structures, such as the prefrontal cortex (PFC), plays a prominent role in learning and memory processes, and its homeostasis differs from that of DA in the striatum, a sensorimotor region. The neostriatum caudolaterale (NCL) of birds resembles the mammalian PFC according to connectional, electrophysiological, and behavioral data. In the present study, DA regulation in the associative NCL and the striatal lobus parolfactorius (LPO) of pigeons was compared to uncover possible differences corresponding to those between mammalian PFC and striatum. Extracellular levels of DA and its metabolites (homovanillic acid [HVA], dihydroxyphenylacetic acid [DOPAC]) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis of urethane-anesthetized pigeons under basal conditions and after systemic administration of D-amphetamine. DA was reliably determined only in LPO dialysates, and DA metabolite levels were significantly higher in LPO than in NCL. The HVA/DOPAC ratio, indicating extracellular lifetime of DA, was more than twice as high in NCL than in LPO dialysates. After amphetamine, DA increased in LPO while still being undetectable in NCL, and DA metabolites decreased in both regions. 5-HIAA slightly decreased in NCL dialysates. Amphetamine effects were delayed in NCL compared with the striatum. In conclusion, effects of amphetamine on the pigeon's ascending monoamine systems resemble those found in mammals, suggesting similar regulatory properties. The neurochemical differences between NCL and LPO parallel those between associative regions, such as PFC and dorsal striatum in mammals. They may reflect weaker regulation of extracellular DA, favoring DAergic volume transmission, in associative than striatal forebrain regions.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

A pre- and postsynaptic modulatory action of 5-HT and the 5-HT2A, 2C receptor agonist DOB on NMDA-evoked responses in the rat medial prefrontal cortex.

Intracellular recordings were made from pyramidal neurons in layers V and VI of the rat medial prefrontal cortex in slice preparations to investigate the effect of the serotonin 5-HT2A,2C receptor agonist (-)-1-2,5-dimethoxy-4-bromophenol-2-aminopropane (DOB) and 5-hydroxytryptamine (5-HT) on N-methyl-D-aspartate (NMDA)-induced responses. Bath application of either DOB or 5-HT [in the presence of antagonists to 5-HT1A, 5-HT3 and gamma-aminobutytric acid (GABA) receptors] produced a concentration-dependent biphasic modulation of the NMDA responses. They facilitated and inhibited NMDA responses at low (</= 1 microM DOB and </= 50 microM 5-HT) and higher concentrations, respectively. Both the facilitating and inhibitory action were blocked by the highly selective 5-HT2A receptor antagonist R-(+)-alpha-(2, 3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidineme thanol (M100907) and the 5-HT2 receptor antagonist ketanserin, thus indicating that both facilitation and inhibition were mediated by the activation of the 5-HT2A receptor subtype. However, the facilitating, but not inhibitory, action of DOB showed a marked desensitization, suggesting that the facilitation and inhibition of NMDA responses resulted from activation of different 5-HT2A receptor subtypes and/or signal-transduction pathways. Indeed, the selective PKC inhibitor chelerythrine and the Ca2+/CaM-KII inhibitor KN-93 prevented the facilitating and inhibitory action of DOB, respectively. We have generated several lines of evidence to indicate the following scenario. Low concentrations of DOB, at presynaptic nerve terminals, markedly enhance NMDA-induced release of excitatory amino acids (EAAs), which then act upon both NMDA and non-NMDA receptors to elicit inward current. The massive inward current masks the postsynaptic inhibitory action of DOB. At higher concentrations, DOB inhibits the release of EAAs and discloses the postsynaptic inhibitory action.

Alkaloids↗

PubMed2006

Age, rapid-cycling, and pharmacotherapy effects on ventral prefrontal cortex in bipolar disorder: a cross-sectional study.

BACKGROUND: Neuroimaging data suggest that deficits in ventral prefrontal cortex (VPFC) function in bipolar disorder (BD) progress during adolescence and young adulthood. However, the developmental trajectory of VPFC morphological abnormalities in BD is unknown. This study investigated potential age-dependent volume abnormalities in VPFC in BD. METHODS: Thirty-seven individuals diagnosed with BD I (14 adolescents, 10 young adults and 13 older adults) and 56 healthy comparison subjects (HC) participated in imaging. Gray and white matter volumes of VPFC were measured using high-resolution structural magnetic resonance imaging (MRI). We used a mixed model, repeated measures analysis to examine VPFC volumes across age groups while co-varying for total brain volume. Potential effects of illness features including rapid-cycling and medication were explored. RESULTS: VPFC volumes declined with age (p < .001). The diagnosis-by-age group interaction was significant (p = .01). Relative to HC subjects, VPFC gray and white matter volumes were significantly smaller in BD patients only in young adulthood (p = .04). In participants with BD, VPFC volumes were significantly smaller in participants with rapid-cycling than participants without rapid-cycling (p = .02). Conversely, current use of medication was associated with larger VPFC gray matter volumes (p = .005), independent of age. CONCLUSIONS: These preliminary findings suggest the presence of a more rapid initial decline in VPFC volumes with age in adolescents and young adults with BD than HC. These findings also suggest that the rapid-cycling subtype of BD is associated with larger VPFC volume deficits than the non-rapid-cycling subtype, and that pharmacotherapy may have trophic or protective effects on VPFC volumes in BD patients.

Adult↗

PubMed1996

Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization.

Interactions between serotonin (5-HT) and dopamine (DA) neuronal systems in the prefrontal cortex (PFC) may be important in the pathophysiology of cognitive disorders such as schizophrenia. We have examined the effect of 5-HT, applied locally through a microdialysis probe, on extracellular DA in the PFC, and compared the response to that observed in the striatum. 5-HT in concentrations of 1 to 10 microM increased extracellular DA dose-dependently to a greater extent in the PFC than in the striatum. The PFC response was pharmacologically characterized to determine the 5-HT receptor subtype mediating the increase in DA levels. The coperfusion of selective 5-HT2A and 5-HT3 antagonists MDL 100,907 ((R-(+)-(2,3-dimethoxyphenyl)-1-[2(4-flourophenylethyl)]-4- piperidine-methanol) and MDL 72222 (3-tropanyl-3,5-dichlorobenzoate), respectively, with 5-HT failed to significantly attenuate the 5-HT induced increase of extracellular DA. Furthermore, the local application of the 5-HT2A/2C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl aminopropane did not yield an increase in extracellular DA. On the other hand, coperfusion of the selective 5-HT1B/1D antagonist GR 127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide)) with 5-HT completely blocked the effect of 5-HT alone. Infusion of the selective 5-HT1B agonists CP 93,129 (3-(1,2,5,6-tetrahydro-4-pyridyl)pyrrolo[3,2-b]pyrid-5-one) and CP 94,253 (3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrolo[3,2-b]pyridine) resulted in a significant increase in extracellular DA and the effect of CP 93,129 was attenuated by coperfusion of GR 127935. The results obtained demonstrate a functional interaction between DA and 5-HT pathways in the PFC, with evidence of potential mediation by the 5-HT1B receptor subtype.

Animals↗

PubMed2005

Delta(9)-THC administered into the medial prefrontal cortex disrupts the spatial working memory.

RATIONALE: Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) disrupts working memory. The prefrontal cortex (PFC) is involved in the processing of working memory, and its medial portion (mPFC) is part of a brain reward circuit as constituted by the mesocorticolimbic dopaminergic system. OBJECTIVE: This study examined the involvement of the mPFC in the effects of Delta(9)-THC on spatial working memory. METHODS: Ten male Wistar rats well-trained in a radial arm maze and with bilateral cannula implanted in the mPFC received Delta(9)-THC intra-cortically (Delta(9)-THC IC) at doses of 0 (VEH), 32, 100 or 180 microg, 5 min before a 5-s or a 1-h delayed task in order to measure a short- or long-term spatial working memory, respectively. By contrast, 11 other animals received Delta(9)-THC intraperitoneally (Delta(9)-THC IP) at doses of 0 (VEH), 0.32, 1 or 1.8 mg/kg, 30 min before a 5-s or a 1-h delayed task. Additionally, after a 15-day washout, the effect of an IP or IC pre-exposure of Delta(9)-THC was examined by repeating both dose-effect curves in a crossover order for the routes of administration. RESULTS: Delta(9)-THC IP produced significantly larger number of errors at doses of 0.32 or 1 mg/kg as compared to VEH in the 1-h post-delay performance. Delta(9)-THC 100 microg IC also produced significantly larger number of errors as compared to VEH and also to the other doses (32 or 180 microg) IC in the 1-h post-delay performance. Previous exposure to Delta(9)-THC IP or IC did not significantly affect the disruptive effect of this cannabinoid. CONCLUSIONS: Delta(9)-THC administered directly in the mPFC impaired 1-h delayed task in the radial arm maze in a manner similar to that observed for its systemic administration, suggesting that the mPFC is involved in the disruptive effects of Delta(9)-THC on spatial working memory.

Animals↗

PubMed2006

Individual differences in ethanol self-administration following withdrawal are associated with asymmetric changes in dopamine and serotonin in the medial prefrontal cortex and amygdala.

BACKGROUND: Ethanol withdrawal alters brain neurochemistry, causes asymmetric activation of neurons in the medial prefrontal cortex (mPFC) and amygdala (AMY), and increases ethanol craving and drinking. Rats with intrinsic rightward-turning preferences drink more ethanol than those with left or no preferences; they also exhibit an ethanol-induced neurochemical activation that favors the right side of the mPFC. Our experiments used rats with different turning preferences to assess differences in withdrawal effects on mPFC and AMY neurochemistry as well as ethanol self-administration. METHODS AND RESULTS: Rats with left-turning, right-turning, and nonturning preferences were fed a 6% ethanol-containing liquid diet (WD) or a pair-fed control diet for 14 days. Differences in dopamine (DA), serotonin (5HT), norepinephrine (NE), and metabolite [3,4-dihydroxphenylacetic acid, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid) concentrations were assessed in each side of the mPFC and AMY during acute withdrawal. Similar groups were fed the same diets and tested for consumption of 10% ethanol versus water and 1% sucrose versus water. WD increased HVA/DA in the mPFC and caused depletions of DA and 5HT in the mPFC and 5HT in the AMY. These effects were greater in the right than in the left side of these structures in rats with right-turning preferences. WD reduced ethanol drinking but right turners drank significantly more than left turners on day 2 of testing and drank more on days 2 and 3 than on day 1. No effects were observed on sucrose drinking. Similar groups were also trained to self-administer ethanol using a sucrose-fade sipper tube procedure that separated measures of ethanol seeking (bar pressing) and consumption. Following 14 days of vapor chamber exposure to ethanol, rats of all turning preferences had a lower rate of bar pressing on the first postwithdrawal day and shorter latencies to begin bar pressing on the third withdrawal day versus prewithdrawal baseline. Only right-turning-preference rats consumed more ethanol following withdrawal. CONCLUSIONS: These studies show that individual rats differ in postwithdrawal brain neurochemistry and ethanol consumption and that these differences are associated with differences in functional brain asymmetry.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Environmental enrichment reduces the function of D1 dopamine receptors in the prefrontal cortex of the rat.

Environmental enrichment produces changes in spontaneous and psychostimulant-induced motor activity. Dopamine in the prefrontal cortex (PFC), through the activation of D1 receptors, has been suggested to play a role in modulating motor activity. The present study investigated the effects of environmental enrichment on spontaneous motor activity, prefrontal acetylcholine release following local D1 receptor stimulation and D1 receptor expression in the PFC. Male wistar rats (3 months of age) were housed in enriched or isolated conditions during 90 days. Animals were then implanted with guide cannulae to perform microdialysis experiments in the PFC. Spontaneous motor activity and acetylcholine extracellular concentrations were monitored simultaneously. Also spontaneous motor activity was measured in an open field. On completion of the experiments, the density of D1 receptors in the PFC was studied by immunocytochemistry. Rats housed in an enriched environment showed significantly lower spontaneous motor activity in the open field compared to isolated animals. Perfusion of the D1 agonist SKF38393 (50 microM; 40 min) in the PFC produced long lasting increases of spontaneous motor activity and of local dialysate concentrations of acetylcholine in both groups of rats. However, increases of both motor activity and acetylcholine concentrations were significantly lower in enriched compared to isolated animals. Moreover, the density of D1 receptors in the PFC was significantly reduced in animals housed in an enriched environment. These results are the first evidence suggesting that environmental enrichment during adult life changes the function of D1 dopamine receptors in the PFC.

Acetylcholine↗

PubMedDate not supplied

An integrative theory of the phasic and tonic modes of dopamine modulation in the prefrontal cortex.

This paper presents a model of both tonic and phasic dopamine (DA) effects on maintenance of working memory representations in the prefrontal cortex (PFC). The central hypothesis is that DA modulates the efficacy of inputs to prefrontal pyramidal neurons to prevent interferences for active maintenance. Phasic DA release, due to DA neurons discharges, acts at a short time-scale (a few seconds), while the tonic mode of DA release, independent of DA neurons firing, acts at a long time-scale (a few minutes). The overall effect of DA modulation is modeled as a threshold restricting incoming inputs arriving on PFC neurons. Phasic DA release temporary increases this threshold while tonic DA release progressively increases the basal level of this threshold. Thus, unlike the previous gating theory of phasic DA release, proposing that it facilitates incoming inputs at the time of their arrival, the effect of phasic DA release is supposed to restrict incoming inputs during a period of time after DA neuron discharges. The model links the cellular and behavioral levels during performance of a working memory task. It allows us to understand why a critical range of DA D1 receptors stimulation is required for optimal working memory performance and how D1 receptor agonists (respectively antagonists) increase perseverations (respectively distractability). Finally, the model leads to several testable predictions, including that the PFC regulates DA neurons firing rate to adapt to the delay of the task and that increase in tonic DA release may either improve or decrease performance, depending on the level of DA receptors stimulation at the beginning of the task.

Animals↗

PubMed1996

Positron emission tomographic imaging of serotonin activation effects on prefrontal cortex in healthy volunteers.

Serotonergic system abnormalities have been implicated in major depression, suicide, violence, alcoholism, and other psychopathologies. The prolactin response to fenfluramine has been widely used as a neuroendocrine probe to study brain serotonin responsivity. We have extended this methodology by using the positron emission tomography (PET) 18F-fluorodeoxyglucose (18FDG) method to examine the fenfluramine-induced changes in regional cerebral glucose metabolism (rCMRglu), an indicator of changes in regional neuronal activity. We report results on 16 healthy controls, each of whom underwent two PET studies. One group of six subjects had a placebo on day 1 and a single 60 mg oral dose of fenfluramine on day 2. The second group, of 10 subjects, was tested on two consecutive occasions without drug or placebo. Data were analyzed for significant rCMRglu changes on day 2 vs day 1 using the statistical parametric mapping method (p < 0.01). Subjects who did not receive drugs showed no statistically significant areas of rCMRglu increase or decrease on day 2 versus day 1. In contrast, the group that received fenfluramine showed significant fenfluramine-induced responses. Areas of rCMRglu increases involved mainly the left prefrontal and left temperoparietal cortex. Within the prefrontal cortex, two major areas of rCMRglu increase included, first, an area centered on the anterior cingulate and, second, an area in the lateral prefrontal cortex involving principally the inferior, middle, and superior frontal gyri. Some decreases in rCMRglu were observed, principally in the right hemisphere. This PET-fenfluramine paradigm is a potentially useful method for studying abnormalities of serotonin function in the prefrontal cortex.

Adult↗

PubMed1978

The prefrontal cortex of the cat: anatomical subdivisions based on retrograde labeling of cells in the mediodorsal thalamic nucleus.

Different areas of the frontal cortex of the cat were injected with small amounts of horseradish peroxidase. The region of labeled cells in the mediodorsal nucleus of the thalamus (MD) were related to the injected areas. Distinct relations between subdivisions of MD and of the prefrontal cortex were established: a rather large central sector of MD projects to the gyrus proreus and the anterior parts of the gyri sigmoideus, rectus, and frontalis. A narrow lateral band of anterior MD neurons projects predominantly to an area on both sides of the sulcus praesylvius, whereas a postero-lateral band sends fibers to a region on the ventral anterior sylvian gyrus. The area between the presylvian sulcus and the sylvian gyrus is apparently free of MD afferents, but not of other thalamic afferents. A fourth sector of MD, situated dorsomedially, projects to the middle parts of the gyri rectus and frontalis. And a fifth sector, located ventrally to the dorsomedial MD sector, projects to the ventral part of the gyrus rectus. The established subfields of MD and of the prefrontal cortex are discussed with respect to previous anatomical research in the cat.

Afferent Pathways↗

PubMed1984

Cortical cholinergic projections from the basal forebrain of the rat, with special reference to the prefrontal cortex innervation.

The topographic organization of cells containing choline-acetyltransferase (CAT) and located within the magnocellular nuclei of the basal forebrain was studied by correlating maximum CAT decrease in one or another cortical region with a given localization of the cell lesions. Lesions were made by using ibotenic acid. Lesions affecting the ventral pallidum decreased CAT activity in the antero-medial prefrontal cortex and lesions of the internal and ventral borders of the pallidum decreased CAT activity in sensori-motor and parieto-temporal cortices. None of these lesions produced a decrease of CAT activity in the hippocampus. These results suggest that it is possible to show the presence of a specific cholinergic projection from the basal forebrain to the medial-associative prefrontal cortex of the rat.

Animals↗

PubMed2002

Sensitization of glutamate release and N-methyl-D-aspartate receptor response by transient dopamine pretreatment in prefrontal cortex of rats.

We studied biochemically the effect of transient dopamine pretreatment on the regulation of glutamate transmission in medial prefrontal cortex of rats in vivo and in vitro. Aversive stimuli transiently increased the glutamate concentration and its repetition reduced the response in the medial prefrontal microdialysate of freely moving rats. The rate of habituation obeyed linear regression. The medial prefrontal intracellular calcium response to repetitive N-methyl-D-aspartate perfusion showed linearly regressive desensitization in fluorescence videomicroscopy of the fura-2 stained slice in vitro. Transient dopamine treatment 10-20 min prior to repetition restored both decreased responses in a linearly regressive manner, also indicating that their decrease was not due to fatigue. These findings suggest that the effect of transient dopamine pretreatment continues redundantly to sensitize/resensitize subsequent pre- and postsynaptic prefrontal glutamate transmission in an orderly manner.

Animals↗

PubMed1998

The functional roles of prefrontal cortex in episodic memory. I. Encoding.

Functional neuroimaging studies of episodic memory consistently report an association between memory encoding operations and left prefrontal cortex (PFC) activation. Encoding-related activation has been described in dorsolateral, ventrolateral and anterior prefrontal regions. We tested the hypothesis that a specific component of this left PFC activation reflects organizational processes necessary for optimal memory encoding. Subjects underwent PET scans while learning auditorily presented word lists under dual task conditions. The degree to which they were required to organize word lists semantically was systematically varied across three experimental conditions. A task in which words were already organized produced the least degree of left PFC activity whereas a task requiring subjects to generate an organizational structure was associated with maximal activity in this region. This activation was localized to a region just above the inferior frontal sulcus. The functional specificity of this increased activity for organizational processes was tested using a concurrent distracting task known to disrupt these processes. Distraction resulted in a significant attenuation of this activation during the task emphasizing organizational processes but not other encoding tasks. In contrast, the distraction task resulted in reduced activity in a more ventral/anterior PFC region expressed equally for all memory tasks. The findings indicate that a key function of left dorsolateral PFC at encoding relates specifically to the use of executive processes necessary for the creation of an organizational structure. Activity in more ventral and anterior left PFC regions would appear to reflect a less specific component of episodic memory encoding.

Adult↗

PubMed1999

The left dorsolateral prefrontal cortex and random generation of responses: studies with transcranial magnetic stimulation.

Evidence from PET studies suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in generation of random responses. We used TMS to examine the specific role of this area in random generation of responses, a task which requires holding information 'on line', suppression of habitual or stereotyped response patterns, intrinsic response generation, monitoring of responses and modification of production strategies. From the results of a previous study of the effects of TMS on random number generation, we proposed a network modulation model, whereby suppression of habitual responses is considered a key process of random response generation and is achieved through the modulatory influence of the left DLPFC over an associative network distributed in the superior temporal cortex. The aim of the present study was to further investigate the generality of this model by examining the effects of short trains of TMS over the left or right DLPFC or medial frontal cortex on random letter generation in healthy participants. TMS over the left DLPFC significantly increased non-randomness relative to control no stimulation trials, which was not obtained with TMS over the right DLPFC or medial frontal cortex. The results suggest the generality of network modulation model of random response generation.

Adult↗

PubMed1999

Comparison of dopamine and noradrenaline release in mouse prefrontal cortex, striatum and hippocampus using microdialysis.

In vivo release of dopamine (DA) and noradrenaline (NA) in mouse medial prefrontal cortex, medial striatum and hippocampus was characterized using in vivo microdialysis. Basal release of NA was similar in these areas, but DA in striatum was 13-30 times higher than in other areas. Unconditioned stimuli (handling, novelty) induced strong increases, except for striatal DA. Striatal NA was more sensitive to handling than NA in other areas.

Animals↗

PubMed2001

Haloperidol and clozapine increase neural activity in the rat prefrontal cortex.

Haloperidol and clozapine have been widely used to alleviate schizophrenic symptoms, but their physiological effects in the prefrontal cortex (PFC) are not known. Effects of haloperidol and clozapine on single unit activity were investigated in the medial PFC of anesthetized rats. Injection (intraperitoneal) of haloperidol (1 mg/kg) or clozapine (20 mg/kg) significantly elevated discharge rates of PFC neurons. Considering that hypofrontality is one characteristic of schizophrenic symptoms, these results raise the possibility that enhancement of PFC neural activity contributes to therapeutic effects of haloperidol and clozapine.

Action Potentials↗

PubMed1998

Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease.

BACKGROUND: The cortex of patients with schizophrenia exhibits a deficit in neuropil, but the nature and extent of cellular abnormalities remain unclear. To gain further insight into this abnormality, neuronal and glial somal size were analyzed in postmortem brains from 9 patients with schizophrenia, 10 normal (control) patients, and 7 patients with Huntington disease, the latter representing a known neurodegenerative disorder. METHODS: A 3-dimensional image analyzer was used to measure the perimeters of 10722 neuronal and 19913 glial profiles in Brodmann areas 9 and 17. Neurons and glia were classified by size and layer to assess specific vulnerabilities with respect to cortical architecture and circuitry. RESULTS: The schizophrenic prefrontal cortex was characterized by a downward shift in neuronal sizes accompanied by 70% to 140% per layer increases in the density of small neurons. In layer III only, a significant reduction in mean neuronal size was associated with a significant decrease in the density of very large neurons in sublayer Illc. Neither neuronal size in occipital area 17 nor glial size in prefrontal or occipital cortexes were reduced. In cortex with Huntington disease, neuronal degeneration was evidenced by concurrence of reduced neuronal size, decreased density of large neurons, and dramatic elevation in density of large glia. CONCLUSIONS: Distinct cytometric abnormalities support the hypothesis that neuronal degeneration in the prefrontal cortex is not a prominent feature of the neuropathological changes in schizophrenia, although an ongoing process in Huntington disease. Rather, schizophrenia appears to involve more subtle abnormalities, with the largest corticocortical projection neurons of layer IIIc expressing the greatest somal reduction.

Adult↗

PubMed1999

Dopamine D1 and D2 receptor agents and their interaction influence the synaptic density of the rat prefrontal cortex.

Recent findings indicate that some monoamines contribute to synaptic maintenance. We examined the synaptic density of the prefrontal cortex of rats with the single or combined administration of D1 and D2 antagonists and agonists. When each agent was administered individually, we observed a significant difference in synaptic density. This indicates that dopamine regulates synaptic maintenance. With the combined administration of antagonists or agonists at high dosages, a synergistic effect was observed. With the combined administration of a D1 antagonist and D2 agonist or a D1 agonist and D2 antagonist, a low dose of the D2 receptor drug enhanced the effect of the D1 receptor drug. The D1 receptor drug offset the effect of the high dose of D2 receptor drug, suggesting the possibility that the D1 receptor family is essential for synaptic maintenance.

Animals↗