Increased baseline occupancy of D ₂ receptors by dopamine in schizophrenia

Abstract

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D2 receptor. We measured in vivo occupancy of striatal D 2 receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D2 receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D 2 receptor availability in patients with schizophrenia (19% ؎ 11%) compared with control subjects (9% ؎ 7%, P ‫؍‬ 0.003). The increased occupancy of D2 receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D2 receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.

Nicotine-Induced Dopamine Release in Primates Measured with [11C]Raclopride PET

“…For example, D 2 blockers are effective treatment for psychosis, and patients with schizophrenia are much more likely to smoke tobacco and to be heavier smokers than the general population or other psychiatric patients de Leon et al, 1995;Diwan et al, 1998;Olincy et al, 1997). Patients with schizophrenia have excessive DA release in the striatum after challenge with amphetamine Laruelle et al, 1996Laruelle et al, , 1999 and after relative DA depletion (Abi-Dargham et al, 2000).…”

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

“…Schizophrenia has for decades been associated with dopaminergic (DA) hyperactivity (Abi-Dargham et al, 2000;see Carlsson et al, 2001). The beneficial effects of classic antipsychotic drugs (eg haloperidol), especially with regard to ameliorating the positive symptoms of schizophrenia, are thought to be related to a reduced DA neurotransmission within the limbic region of the brain (see Carlsson et al, 2001), in particular, to antagonism of DA-D 2 receptors.…”

A Simple Method to Measure Baseline Occupancy of Neostriatal Dopamine D2 Receptors by Dopamine In Vivo in Healthy Subjects

“…DA levels during stimulant-induced release have been estimated by comparing radiotracer binding at baseline and after amphetamine or methylphenidate challenges using PET and the DA D 2 receptor (D 2 R) radiotracer [ 11 C]raclopride (Volkow et al 1994;Breier et al 1997) as well as SPECT and (Booij et al 1997;Abi-Dargham et al 1998). DA levels during baseline release have been estimated by comparing radiotracer binding at baseline and after a rapid DA depletion induced by the competitive and reversible tyrosine hydroxylase inhibitor ␣ -methyl-para-tyrosine (AMPT) (Engelman et al 1968) using SPECT and [ 123 I]IBZM (Laruelle et al 1997;Abi-Dargham et al 2000) or [ 123 I]epidepride (Fujita et al 2000).…”

“…The good response of [ 11 C]raclopride to changes in extracellular DA makes this tracer, so far, a good candidate for the PET measurement of changes in synaptic DA levels (Moresco et al 1999;Laruelle 2000). This PET study design required more work before injection of the tracer and more effort analyzing the results after the data were acquired, but was very patient friendly, in contrast to the previously applied bolus infusion technique that required less work before and after imaging data acquisition, but that was not so patient friendly (Laruelle et al 1997;Abi-Dargham et al 2000).…”

“…In the two previous DA depletion imaging studies in healthy subjects, 8 g AMPT was administered over two days (Laruelle et al 1997;Abi-Dargham et al 2000), and 5.5 g/70 kg body weight of AMPT were given over 37 hours in a third study (Fujita et al 2000). In the 67 healthy subjects who participated in these three studies, the following adverse effects were attributed to AMPT: eight developed acute dystonias, six had akathisia of sufficient severity to warrant psychotropic medication, four developed crystalluria, two showed significant increases in dysphoric mood states (anxiety and tension), and one diarrhoea.…”