Striatal Neuronal Activity and Responsiveness to Dopamine and Glutamate after Selective Blockade of D1 and D2 Dopamine Receptors in Freely Moving Rats

Abstract

Although striatal neurons receive continuous dopamine (DA) input, little information is available on the role of such input in regulating normal striatal functions. To clarify this issue, we assessed how systemic administration of selective D1 and D2 receptor blockers or their combination alters striatal neuronal processing in freely moving rats. Single-unit recording was combined with iontophoresis to monitor basal impulse activity of dorsal and ventral striatal neurons and their responses to glutamate (GLU), a major source of excitatory striatal drive, and DA. SCH-23390 (0.2 mg/kg), a D1 antagonist, strongly elevated basal activity and attenuated neuronal responses to DA compared with control conditions, but GLU-induced excitations were enhanced relative to control as indicated by a reduction in response threshold, an increase in response magnitude, and a more frequent appearance of apparent depolarization inactivation. In contrast, the D2 antagonist eticlopride (0.2 mg/kg) had a weak depressing effect on basal activity and was completely ineffective in blocking the neuronal response to DA. Although eticlopride reduced the magnitude of the GLU response, the response threshold was lower, and depolarization inactivation occurred more often relative to control. The combined administration of these drugs resembled the effects of SCH-23390, but whereas the change in basal activity and the GLU response was weaker, the DA blocking effect was stronger than SCH-23390 alone. Our data support evidence for DA as a modulator of striatal function and suggest that under behaviorally relevant conditions tonically released DA acts mainly via D1 receptors to provide a continuous inhibiting or restraining effect on both basal activity and responsiveness of striatal neurons to GLUmediated excitatory input.

Behavioral Electrophysiology of Psychostimulants

“…Thus, DA enhances the relative rather than absolute strength of the GLU signal. Further testing revealed that endogenous DA exerts this effect mainly via D1 receptors (Kiyatkin and Rebec, 1999b). In fact, with D1 receptor blockade, striatal neurons become hyper-responsive to GLU.…”

Striatal dopamine–NMDA receptor interactions in the modulation of glutamate release in the substantia nigra pars reticulata in vivo: opposite role for D1 and D2 receptors

“…It is noteworthy that, in the presence of raclopride, an increase in NMDA concentration up to 10 lM led to extinction of the NMDA effect. This may be related to a depolarization inactivation of projection neurons (Hu and White 1996), which is enhanced by D 2 receptor antagonism (Kiyatkin and Rebec 1999).…”

“…slices). Recently, studies employing DA receptor antagonists in vivo have shown that D 1 and D 2 receptors tonically modulate the excitability of striatal GABAergic neurons and their responsiveness to glutamate (GLU; Kiyatkin and Rebec 1999;West and Grace 2002). The capability of NMDA to release striatal GABA in vivo is also differentially modulated by DA receptor antagonists (Morari et al 1994).…”

Sensory effects of intravenous cocaine on dopamine and non-dopamine ventral tegmental area neurons

“…Both drugs were obtained from Sigma (St. Louis, MO), freshly dissolved, mixed, and injected subcutaneously. Neuronal data obtained between 20 min and 3 h following the injection of DA antagonists were accepted as occurring during full DA receptor blockade, as confirmed by the antagonism of striatal neuronal responses to iontophoretic DA (Kiyatkin and Rebec, 1999). DA blockade was maintained by additional injection of DA antagonists at half the dose, three hours after the initial administration.…”

“…Therefore, similar to our previous study, recordings were performed in animals administered with a mixture of D1-and D2-selective antagonists (SCH233900 and eticlopride), providing an effective blockade of DA transmission. DA receptor blockade greatly attenuates cocaine-induced motor activation, thus allowing artifact-free neuronal recording, but it keeps neuronal responses to sensory stimuli relatively intact (Kiyatkin and Rebec, 1999;Kiyatkin and Brown, 2007). The use of DA antagonists also excludes any possible contribution of DA mechanisms to the observed neuronal responses to sensory stimuli and cocaine.…”