D-Amphetamine Stimulates D₂Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

Abstract

In rat brain, dopaminergic D 2 -like but not D 1 -like receptors can be coupled to phospholipase A 2 (PLA 2 ) activation, to release the second messenger, arachidonic acid (AA, 20:4n-6), from membrane phospholipids. In this study, we hypothesized that D-amphetamine, a dopamine-releasing agent, could initiate such AA signaling. The incorporation coefficient, k* (brain radioactivity/integrated plasma radioactivity) for AA, a marker of the signal, was determined in 62 brain regions of unanesthetized rats that were administered i.p. saline, D-amphetamine (2.5 or 0.5 mg/kg i.p.), or the D 2 -like receptor antagonist raclopride (6 mg/kg, i.v.) before saline or 2.5 mg/kg D-amphetamine. After injecting [1-14 C]AA intravenously, k* was measured by quantitative autoradiography. Compared to saline-treated controls, D-amphetamine 2.5 mg/kg i.p. increased k* significantly in 27 brain areas rich in D 2 -like receptors. Significant increases were evident in neocortical, extrapyramidal, and limbic regions. Pretreatment with raclopride blocked the increments, but raclopride alone did not alter baseline values of k*. In independent experiments, D-amphetamine 0.5 mg/kg i.p. increased k* significantly in only seven regions, including the nucleus accumbens and layer IV neocortical regions. These results indicate that D-amphetamine can indirectly activate brain PLA 2 in the unanesthetized rat, and that activation is initiated entirely at D 2 -like receptors. D-Amphetamine's lowdose effects are consistent with other evidence that the nucleus accumbens, considered a reward center, is particularly sensitive to the drug.

Baclofen, raclopride, and naltrexone differentially reduce solid fat emulsion intake under limited access conditions

“…The fact that effects were only seen at the highest fat concentration in the intermittent groups suggests that both the manner and amount of fat consumed may influence actions within regions of the brain relevant to reward. For instance, fat intake, either total amount over time or large bolus amounts, may alter D2 actions via changes in arachidonic acid-dependent signal transduction and/or the formation of lipid rafts (Bhattacharjee, et al, 2005(Bhattacharjee, et al, , 2006Jacobowitz and Kallarakal, 2004).…”

Chronic Carbamazepine Administration Attenuates Dopamine D2-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

“…In control animals fed a LiCl-free diet, quinpirole-induced increases in k* are robust and widespread in brain regions within dopaminergic circuits, and can be blocked by pre-treatment with the D 2 -like receptor antagonists, butaclamol or raclopride [16,29]. In addition to LiCl, chronic CBZ has been reported to attenuate dopamine function in rats, suggesting that normalization of a dysfunctional dopamine neurotransmission may underlie CBZ effects in bipolar disorder [2,4,35,38].…”

In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease

“…With it, we showed in unlesioned unanesthetized rats that acute administration of quinpirole, a D 2 -receptor agonist, increased k* for AA in brain regions with high densities of D 2 -receptors, and that the increases could be blocked by the preferential D 2 -receptor antagonist, butaclamol (Bhattacharjee et al, 2005;Bristow et al, 1998;Hayakawa et al, 2001). We also reported that D-amphetamine, which increases synaptic DA by increasing presynaptic DA release and reducing DA reuptake by the DAT, increased k* for AA in a dosedependent manner in brain areas rich in D 2 -receptors (Bhattacharjee et al, 2006). Damphetamine's effects could be prevented entirely by pre-administration of raclopride, a selective D 2 -receptor antagonist (Bhattacharjee et al, 2006;Kohler et al, 1985), indicating that they were mediated specifically by D 2 -receptors.…”

“…We also reported that D-amphetamine, which increases synaptic DA by increasing presynaptic DA release and reducing DA reuptake by the DAT, increased k* for AA in a dosedependent manner in brain areas rich in D 2 -receptors (Bhattacharjee et al, 2006). Damphetamine's effects could be prevented entirely by pre-administration of raclopride, a selective D 2 -receptor antagonist (Bhattacharjee et al, 2006;Kohler et al, 1985), indicating that they were mediated specifically by D 2 -receptors.…”

“…We therefore quantified k* for AA on the intact and lesioned sides of chronically left-sided 6-OHDA lesioned rats acutely administered saline 1 ml/kg i.p., quinpirole 1.0 mg/kg i.v., or D-amphetamine 5.0 mg/kg i.p. These doses were chosen on the basis of our prior studies in which drug-induced changes in k* were measured following injection of [1-14 C]AA (Basselin et al, 2005;Bhattacharjee et al, 2005;Bhattacharjee et al, 2006;Hayakawa et al, 2001). …”