TAAR1-dependent effects of apomorphine in mice

Abstract

G protein-coupled trace amine-associated receptor 1 (TAAR1) is expressed in several brain regions and modulates dopaminergic activity partially by affecting D2 dopamine receptor function. In vitro, the nonselective dopamine agonist apomorphine can activate mouse and rat TAAR1. The aim of the present study was to evaluate whether apomorphine activity at the rodent TAAR1 observed in in vitro studies contributes to its behavioral manifestation in mice. For this purpose, we compared the behavioral effects of a wide range of apomorphine doses in wild type (WT) and TAAR1 knockout (TAAR1-KO) mice. Apomorphine-induced locomotor responses (0.01-4.0 mg/kg) were tested in locomotor activity boxes, and stereotypic behavior at 5 mg/kg was tested by ethological methods. A gnawing test was used to analyze the effects of the highest dose of apomorphine (10 mg/kg). No statistically significant differences were observed between TAAR1-KO and WT mice following inhibitory pre-synaptic low doses of apomorphine. At higher doses (2.0-5.0 mg/kg), apomorphine-induced climbing behavior was significantly reduced in TAAR1 mutants relative to WT controls. Moreover, the lack of TAAR1 receptors decreased certain types of stereotypies (as reflected in by measures of the global stereotypy score, licking but not sniffing or gnawing) that were induced by high doses of apomorphine. These data indicate that apomorphine activity at TAAR1 contributes to some behavioral manifestations, particularly climbing, in rodents following high doses of this drug. The contribution of TAAR1 to apomorphine-induced climbing in rodents should be considered when apomorphine is used as a screening tool in the search for potential antipsychotics.

Trace Amines and Their Receptors

“…It should be stressed, however, that such effects often show pronounced species dependence, and this is perhaps most notable with the endogenous hallucinogen DMT and lysergic acid diethylamide, both of which show limited, if any, activity at the human isoform (Table 7). In addition to psychotropic agents, a variety of other synthetic compounds have been reported to exhibit agonistic activity at TAAR1, including apomorphine (Sukhanov et al, 2014), ractopamine (Liu et al, 2014), and the imidazoline ligands clonidine, guanabenz, and idazoxan (Hu et al, 2009) (Fig. 2; Table 7).…”

TAAR1 modulates cortical glutamate NMDA receptor function

“…Recently, TAAR1 functions have been extensively characterized, with particular attention paid to its role in the modulation of the midbrain dopamine system and its possible implications in psychiatric diseases (Borowsky et al, 2001;Bunzow et al, 2001;Lindemann and Hoener, 2005;Sotnikova et al, 2009;Leo et al, 2014;Sukhanov et al, 2014). TAAR1 knockout (TAAR1-KO) mice display a higher sensitivity to amphetamine and other psychostimulants (Wolinsky et al, 2007;Lindemann et al, 2008;Di Cara et al, 2011), and seem to have a supersensitive dopaminergic system (Wolinsky et al, 2007;Lindemann et al, 2008), making them an interesting model relevant for schizophrenia (Wolinsky et al, 2007).…”

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

“…apomorphine) have been used in animal models to induce hyperlocomotion (Medvedev et al, 2013;Sukhanov et al, 2014) and several stereotyped behaviors. The latter include climbing, which can also be induced by some N-methyl-D-aspartate receptor (NMDAR) antagonists, such as phencyclidine, dizocilpine (MK-801), and ketamine (Olszewski et al, 2004;Davis-MacNevin et al, 2013;Lai et al, 2014).…”