Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

Abstract

Positron emission tomography (PET), in combination with 11 C-raclopride, was used to examine the effects of phencyclidine (PCP) on dopamine (DA) in the primate striatum. In addition, we explored the hypotheses that GABAergic pathways as well as molecular targets beyond the N-methyl-D-aspartate (NMDA) receptor complex (ie dopamine transporter proteins, DAT) contribute to PCP's effects. In the first series of experiments, 11 C-raclopride was administered at baseline and 30 min following intravenous PCP administration. In the second series of studies, g-vinyl GABA (GVG) was used to assess whether enhanced GABAergic tone altered NMDA antagonistinduced changes in DA. Animals received an initial PET scan followed by pretreatment with GVG (300 mg/kg), then PCP 30 min prior to a second scan. Finally, we explored the possible contributions of DAT blockade to PCP-induced increases in DA. By examining 11 Ccocaine binding a paradigm in which PCP was coadministered with the radiotracer, we assessed the direct competition between these two compounds for the DAT. At 0.1, 0.5, and 1.0 mg/kg, PCP decreased 11 C-raclopride binding by 2.1, 14.9 7 2.2 and 8.18 7 1.1%, respectively. These effects were completely attenuated by GVG (3.38 7 3.1% decrease in 11 C-raclopride binding). Finally, PCP (0.5 mg/ kg) decreased 11 C-cocaine binding by 25.5 7 4.3%, while at 1.0 mg/kg this decrease was 13.5%, consistent with a competitive interaction at the DAT. These results suggest that PCP may be exerting some direct effects through the DAT and that GABA partially modulates NMDA-antagonist-induced increases in striatal DA.

Imaging of striatal dopamine release elicited with NMDA antagonists: is there anything there to be seen?

“…Only three imaging studies reported separate estimations of dorsal and ventral striatal binding. Among the positive studies, neither Vollenweider, nor Schiffer found greater effects on ventral striatal as opposed to the dorsal striatal binding (Vollenweider et al, 2000;Schiffer et al, 2003), while the negative study by Kegeles reports a similar lack of regional effects (Kegeles et al, 2002). Third, recent reports indicate that neither ketamine nor PCP is selective for the NMDA site.…”

“…Notwithstanding this, there is no obvious relationship between the dose of ketamine and a significant change in imaging parameters. In a single study using phencyclidine (PCP), a significant change in 11 C-raclopride BP was seen, however it was not dose dependent, being present at 0.5 mg/kg Ϫ1 , but not at 0.1 mg/kg Ϫ1 or 1 mg/kg Ϫ1 (Schiffer et al, 2003).…”

Modulation of Striatal Dopamine Release by Glycine Transport Inhibitors

“…Infusion of NMDA into striatum in intact animals increases both DA and GABA release (Hernandez et al, 2003), consistent with this model. Further, GABAergic inhibitory mechanisms in striatum have been demonstrated in both rodent (Hanania and Johnson, 1999;Hernandez et al, 2003) and primate (Schiffer et al, 2003) striatum, demonstrating in vivo relevance of this pathway to intrinsic DA regulation.…”

N-Methyl-d-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

“…Their actions are variably attenuated by antipsychotics such as haloperidol and clozapine (Malhotra et al 1997;Lahti et al 2001;Oranje et al 2002, Van Berckel 2003. Neuronal mechanisms underlying the effects of OCBs are many, of which the following should be briefly evoked: 1) Sensitisation of subcortical and cortical dopaminergic pathways (Kegeles et al 2000(Kegeles et al , 2002Balla et al 2003;Laruelle et al 2003) 2) Activation of mesolimbic serotonergic pathways and consequent recruitment of corticolimbic populations of 5-HT 2A receptors, effected independents of NMDA receptors One common mechanism underlying these changes may be interruption of a NMDA receptor-mediated, tonic excitation of GABAergic interneurones inhibitory to projection neurones (Carlsson et al 2001;Farber 2003;Schiffer et al 2003;Shi and Zhang 2003;de Lima et al 2004). Underpinning a role of NMDA receptors in the psychotomimetic effects of PCP and ketamine in man and rodents, they are at least partially mimicked by antagonists at the NMDA recognition site (Lowe et al 1994;Muir and Lees 1995;Bakshi et al 1999;Dyker et al 1999).…”