Upregulation Of Dopamine D2 Receptors Research Articles

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.

Lesioning of locus coeruleus projections by DSP-4 neurotoxin treatment: effect on amphetamine-induced hyperlocomotion and dopamine D2 receptor binding in rats.

DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP-4 treatment on amphetamine-induced hyperlocomotion are contradictory. In this study, DSP-4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D2 receptors in the striatum as evidenced by [3H]-raclopride binding. In an open field test, DSP-4 reduced locomotor activity. D-Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP-4-pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP-4-pretreated animals. These data suggest that supersensitivity of D2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP-4-treated rats is masked by neophobia.

Lesioning of Locus coeruleus Projections by DSP‐4 Neurotoxin Treatment: Effect on Amphetamine‐Induced Hyperlocomotion and Dopamine D2 Receptor Binding in Rats

Abstract:DSP‐4 is a neurotoxin highly selective for the noradrenergic nerve terminals of the locus coeruleus projections. Data on the effect of DSP‐4 treatment on amphetamine‐induced hyperlocomotion are contradictory. In this study, DSP‐4 (50 mg/kg) caused reduction of noradrenaline levels by 70% in the cerebral cortex and by 79% in the cerebellum. This treatment resulted in upregulation of dopamine D2 receptors in the striatum as evidenced by [3H]‐raclopride binding. In an open field test, DSP‐4 reduced locomotor activity. D‐Amphetamine (1.5 mg/kg) caused a similar increase in locomotor activity in control and DSP‐4‐pretreated animals not familiar to the apparatus. However, when the rats were habituated to the test apparatus, the effect of amphetamine on horizontal activity was significantly larger in the DSP‐4‐pretreated animals. These data suggest that supersensitivity of D2 receptors develops after locus coeruleus denervation, but that the enhanced efficacy of amphetamine in DSP‐4‐treated rats is masked by neophobia.

Effect of antipsychotics on regional cerebral blood flow measured with positron emission tomography

Positron Emission Tomography (PET) imaging of regional cerebral blood flow (rCBF) provides an in vivo method for studying brain function. We used [15O]H20 PET to assess the effect of antipsychotic medications on rCBF in 17 subjects with schizophrenia. Each subject was scanned while receiving antipsychotic medication, and after having been withdrawn from antipsychotic medication for a 3-week period. The two scans were subtracted from one another, using a within subjects design, and the areas of difference were identified using the Montreal method. Subjects treated with antipsychotic medication had significantly higher rCBF in the left basal ganglia and left fusiform gyrus compared with the "off-medication" condition. Significantly higher relative rCBF in the anterior cingulate, left dorsolateral and inferior frontal cortex, and left and right cerebellum was observed when off antipsychotic medication. Upregulation of dopamine D2 receptors may lead to a regional increase of blood flow and metabolism in the basal ganglia, which may explain recently reported anatomical enlargement in these regions.

Dopamine D2 receptor upregulation in rat neostriatum following in vivo infusion of forskolin.

Intracerebroventricular (i.c.v.) forskolin infusion for 5 days resulted in a concentration-dependent increase in rat striatal dopamine (DA) D2 receptors measured with [3H]raclopride. In animals given 50 nmol/h forskolin, the highest concentration used, raclopride-mediated suppression of spontaneous locomotor activity was attenuated, and (+/-)-7-hydroxy-dipropyl-aminotetralin HBr (7-OH-DPAT)-mediated inhibition of striatal DA synthesis, as estimated by the accumulation of DOPA following inhibition of cerebral decarboxylase, was enhanced. These data suggest that the DA D2 receptor increase comprises receptors localized both post- and presynaptically. The density of striatal DA D1 receptors was also changed with the forskolin treatment, in a concentration-dependent fashion, but in the opposite direction to DA D2 receptors. These findings suggest that striatal DA receptor sensitivity can be changed by manipulation at the second messenger level (e.g. independent of direct neurotransmitter-receptor interactions) in vivo.

Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine.

Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters 6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling. 6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens, olfactory tubercle and ventral tegmental area. In the substantia nigra pars compacta and the ventral tegmental area, the number of Nissl-stained neurons decreases in parallel with the reduction in [3H]mazindol binding. The reduction in [3H]mazindol binding in the striatum and the nucleus accumbens, and the reduction in [3H]mazindol binding and in the number of Nissl-stained neurons in the substantia nigra pars compacta and the ventral tegmental area is stable for up to 12 weeks after the lesion. Macroscopically, forebrain coronal sections showed normal morphology, except for rats receiving 5.0 micrograms/microliters 6-hydroxydopamine in which striatal cross-sectional area was reduced, suggesting that this high dose non-specifically damages intrinsic striatal neurons. Nissl-stained sections revealed an area of neuronal loss and intense gliosis centered around the needle track, which increased in size with the dose of neurotoxin. Striatal [3H]sulpiride binding was increased by 2.5 micrograms/microliters and 5.0 micrograms/microliters 6-hydroxydopamine, suggesting up-regulation of dopamine D2 receptors. Striatal binding of [3H]CGS 21680-labeled adenosine A2a receptors, but not of [3H]SCH 23390-labeled dopamine D1 receptors, was reduced at the highest dose, suggesting preservation of the striatal intrinsic neurons with the lower doses. This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3.5 microliters of 2.5 micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induces a lesion characterized by robust drug-induced rotation, changes in binding consistent with approximately 70% dopamine denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic striatal damage and stability for at least 12 weeks. This study outlines a technique for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Morphometric study of synaptic patterns in the rat caudate nucleus and hippocampus under haloperidol treatment

A morphometric study of the synapses on dendritic shafts and spines was performed in the rat caudate nucleus and the CAI area of the hippocampus under chronic haloperidol treatment. In the nucleus caudatus, the synaptic density on dendritic shafts increased by 83% and those on spines by 53%. Most of the parameters measured in axospinous synapses were significantly increased: the area of presynaptic axon terminals (20%), the number of mitochondria per axon terminal (51%), the length of active zone (11%), the area of postsynaptic density (23%), and the perimeter of postsynaptic density (12.5%). The area of postsynaptic spines showed no changes. In the synapses on dendritic shafts, the area of presynaptic terminals decreased (31%), the area of mitochondria per terminal decreased (40%), the length of active zone increased (14%), and other parameters were unchanged. There were no significant differences in the same parameters measured in the hippocampus. The data are discussed as morphological correlates of behavioral supersensitivity and dopamine D2 receptor up-regulation.

Differences in the time course of haloperidol-induced up-regulation of rat striatal and mesolimbic dopamine receptors

Regional differences in the onset and persistence of increased dopamine D2 receptor density in rat brain were studied following daily injections of haloperidol for 3, 7, 14, or 28 days. Striatal [ 3H] - spiroperidol Bmax values were significantly increased following 3 – 28 days of haloperidol treatment, as compared to saline controls. Olfactory tubercle Bmax values were significantly increased only after 14 or 28 days of haloperidol treatment. Nucleus accumbens Bmax values were significantly increased only in the 14-day drug treatment group, suggesting that dopamine D2 receptor up-regulation in nucleus accumbens may reverse during ongoing neuroleptic treatment. These findings suggest that important differences in adaptive responses to chronic dopamine blockade may exist between dopaminergic synapses located in various rat brain regions.

Tardive dyskinesia: review and update.

Tardive dyskinesia is an extrapyramidal syndrome associated with the chronic administration of major neuroleptic agents. The pathogenesis of the disorder appears to relate to chronic striatal dopaminergic receptor site blockade; the pathophysiology of tardive dyskinesia appears to relate to the resultant denervation hypersensitivity. Agents that deplete the brain of dopamine are the mainstay of therapy for tardive dyskinesia. Cholinergic agents that potentially modulate the balance between dopamine and acetycholine in the striatum offer possible additional therapeutic options. Clearly, resumption of neuroleptic therapy is treatment with the presumed pathogenic agent and is to be avoided whenever possible.