PubMed · 13820111
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E ELST. 1959. [Amphetamine psychoses].. https://pubmed.ncbi.nlm.nih.gov/13820111/
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The performance of small animal PET for neuroreceptor studies in a psychopharmacological challenge paradigm is not yet well-described. Therefore, we used microPET and [(11)C]raclopride to map the availability of dopamine D(2/3) receptors in brain of anesthetized rats, first in a baseline condition, and again after challenge with saline or d-amphetamine. Parametric maps of the specific binding (binding potential, pB) were calculated using a reference tissue input from cerebellum, and spatially normalized to a digitized stereotaxic coordinate system for rat brain. In volumes of interest (VOIs), the mean baseline pB (n=6) was 2.05 in dorsal striatum (caudate-putamen), and 1.34 in ventral striatum (nucleus accumbens), and did not significantly differ upon retest 2 h later. The availability of [(11)C]raclopride binding sites at baseline was 8% higher in the right striatum. Challenge with amphetamine sulfate (1 mg/kg, i.v., n=4) decreased pB by 19% in both ventral and dorsal striatum. We have earlier predicted that blockade of monoamine oxidase (MAO) should potentiate the amphetamine-evoked dopamine release, thus enhancing the displacement of [(11)C]raclopride binding in vivo. However, pretreatment of rats with pargyline hydrochloride (4 mg/kg, n=4; 20 mg/kg, n=4) 1 day prior to PET did not potentiate the amphetamine-evoked reduction in dopamine receptor availability within the extended striatum. We conclude that small animal PET can be used to investigate stimulant-induced dopamine release, but that the spatial resolution is insufficient to detect differences between relative changes in dorsal vs. ventral divisions of the rat striatum. Furthermore, the present results do not reveal potentiation of the amphetamine-evoked release of dopamine in rats with MAO inhibition.
The synthetic amines methamphetamine (METH), amphetamine (AMPH), and their metabolite para-hydroxyamphetamine (POHA) are chemically and structurally related to the catecholamine neurotransmitters and a small group of endogenous biogenic amines collectively referred to as the trace amines (TAs). Recently, it was reported that METH, AMPH, POHA, and the TAs para-tyramine (TYR) and beta-phenylethylamine (PEA) stimulate cAMP production in human embryonic kidney (HEK)-293 cells expressing rat trace amine-associated receptor 1 (rTAAR1). The discovery that METH and AMPH activate the rTAAR1 motivated us to study the effect of these drugs on the mouse TAAR1 (mTAAR1) and a human-rat chimera (hrChTAAR1). Furthermore, because S-(+)-isomers of METH and AMPH are reported to be more potent and efficacious in vivo than R-(-), we determined the enantiomeric selectivity of all three species of TAAR1. In response to METH, AMPH, or POHA exposure, the accumulation of cAMP by HEK-293 cells stably expressing different species of TAAR1 was concentration- and isomer-dependent. EC50 values for S-(+)-METH were 0.89, 0.92, and 4.44 microM for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1, whereas TYR was a full agonist for the rodent TAAR1s but was a partial agonist at h-rChTAAR1. Interestingly, both isomers of METH were full agonists at mTAAR1 and h-rChTAAR1, whereas both were partial agonists at rTAAR1. Taken together, these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs.
Dopamine (DA) D2 receptors regulate DA transporter (DAT) activity, and mediate some behavioral effects of amphetamine. DA clearance and amphetamine-stimulated locomotion are reduced in hypoinsulinemic [streptozotocin (STZ)-treated] rats, and these deficits are normalized by repeated treatment with amphetamine. Here, a role for D2 receptors in mediating amphetamine-induced normalization of these parameters was investigated. One week after a saline or STZ injection (50 mg/kg), rats were treated with amphetamine (1.78 mg/kg), raclopride (0.056 mg/kg), saline, or combinations thereof, every-other-day for 8 days with locomotor activity measured following each treatment. Conditioned place preference (CPP) for amphetamine and in vivo chronoamperometry to measure DA clearance were carried out on days 17 and 18, respectively, after STZ or saline. Baseline locomotion and DA clearance were significantly reduced in STZ-treated rats compared with control rats. In STZ-treated rats, amphetamine treatment normalized DA clearance, and restored the locomotor-stimulating effects of amphetamine. Raclopride prevented normalization of these parameters. Amphetamine produced CPP in both STZ-treated and control rats; raclopride significantly attenuated amphetamine-induced CPP in control and not in STZ-treated rats. These results support a role for D2 receptors in regulating DA transporter activity, and further demonstrate that D2 receptors contribute to changes in sensitivity to amphetamine in hypoinsulinemic rats.