Acute Cocaine Induces Fast Activation of D1 Receptor and Progressive Deactivation of D2 Receptor Striatal Neurons:In VivoOptical Microprobe [Ca²⁺]_iImaging

Abstract

Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine’s reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca2+]i) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R versus D2R expressing neurons in striatum. Acute cocaine (8 mg/kg ip) rapidly increased [Ca2+]i in D1R expressing neurons (10.6±3.2%) in striatum within 8.3±2.3min after cocaine administration after which the increases plateaued; these fast [Ca2+]i increases were blocked by pretreatment with a D1R antagonist (SCH 23390). In contrast cocaine induced progressive decreases in [Ca2+]i in D2R expressing neurons (10.4±5.8%) continuously throughout the 30min that followed cocaine administration; these slower [Ca2+]i decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R expressing neurons (direct-pathway) enhances cocaine reward whereas activation of D2R expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine’s rewarding effects entail both its fast stimulation of D1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer lasting deactivation of indirect-pathway neurons). We also provide direct in-vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration.

Predominant D1Receptors Involvement in the Over-expression of CART Peptides after Repeated Cocaine Administration

“…Moreover, the combined treatment of D1R and D2R antagonists produced less locomotor activity than D1R and D2R antagonists alone. In terms of mediation of reward induced by cocaine, the stimulation of D1R results in fast neuronal activation, and the stimulation of D2R results in progressive neuronal deactivation [7]. The weaker behavioral sensitization by cocaine was developed in the D1R-and D2R-KO mice compared to the WT mice, although repeated cocaine administration still induced behavioral sensitization in both D1R-and D2R-KO mice.…”

“…The striatonigral pathway (direct pathway) contains neurons with dynorphin, substance P, and dopaminergic D1 receptors (D1R), whereas striatopallidal pathway (indirect pathway) preferentially contains neurons with enkephalin and dopamine D2 receptors (D2R) [6]. D1R and D2R antagonists inhibited locomotor activity induced by psychostimulants [7,8]. However, the concomitant administration of D1R and D2R agonists enhances behavioral sensitization (BS) [9].…”

Chronic Cocaine Dampens Dopamine Signaling during Cocaine Intoxication and Unbalances D1over D2Receptor Signaling

“…This discrepancy is likely to reflect methodological differences; specifically, we measured the attenuation of D 1 R by cocaine (monitoring changes in intracellular Ca 2ϩ ) as opposed to electrophysiological responses of D 1 R-exressing neurons to high-frequency stimulation. Also, sensitization responses were measured several days after the last cocaine administration and are associated with changes in synaptic expression of AMPA receptors in MSNs (Boudreau et al, 2007;Kourrich et al, 2007), whereas our measurements were performed while mice were on cocaine and 24 h after the prior cocaine dose. On the other hand, our findings are consistent with those from a study that reported reduced membrane excitability of D 1 R-expressing MSNs in a brain slice preparation in the nucleus accumbens in mice previously exposed to repeated cocaine injections (5 days), though the membrane excitability of D 2 R-expressing MSNs was not affected (Kim et al, 2011) when compared with drug-naive mice.…”

“…Also, sensitization responses were measured several days after the last cocaine administration and are associated with changes in synaptic expression of AMPA receptors in MSNs (Boudreau et al, 2007;Kourrich et al, 2007), whereas our measurements were performed while mice were on cocaine and 24 h after the prior cocaine dose. On the other hand, our findings are consistent with those from a study that reported reduced membrane excitability of D 1 R-expressing MSNs in a brain slice preparation in the nucleus accumbens in mice previously exposed to repeated cocaine injections (5 days), though the membrane excitability of D 2 R-expressing MSNs was not affected (Kim et al, 2011) when compared with drug-naive mice. Also, in nonhuman primates repeated cocaine exposure was associated with reductions in D 1 R levels in striatum (Moore et al, 1998), though human studies failed to observe this (Martinez et al, 2009), and thus it is unclear whether chronic cocaine exposure reduces the levels of D 1 R in striatum.…”

“…The microprobe fluorescence imaging technique was applied to D 1 R-EGFP and D 2 R-EGFP transgenic mice (both control mice and chronic mice) to enable in vivo characterization of the dynamic [Ca 2ϩ ] i changes in striatal D 1 R and D 2 R neurons in response to an acute cocaine challenge. The principle of the endomicroscopic imaging technique has been outlined previously (Jung et al, 2004;Luo et al, 2011), and Figure 1 illustrates the system setup used in this study, in which modifications have been implemented to improve fluorescence coupling and image throughput. For instance, additional Piezoelectrically activated focusing mechanism is used to enable instantaneous fine focal tracking to maximize [Ca 2ϩ ] i -Rhod 2 fluorescence detection within the field of view (FOV).…”