Opposite effect of simple tetrahydroisoquinolines on amphetamine- and morphine-stimulated locomotor activity in mice

Abstract

Endogenous tetrahydroisoquinolines, such as 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), were tested for their interaction with motor effects of amphetamine and morphine in C57BL/6 mice. TIQ binding to cortical adrenergic alpha1, alpha2 and beta receptors, striatal dopamine D1 and D2 receptors and cortical L-type calcium channels in the Wistar rat was also studied. Both compounds in high doses reduced the mouse locomotor activity, and in doses not affecting activity inhibited the motor stimulation induced by amphetamine, 2 or 3 mg/kg i.p., but facilitated the hyperactivity induced by 10 mg/kg of morphine. TIQ did not displace ligands that are antagonists for several receptor sites (including D1 and D2 receptors), but displaced an agonist of alpha2-adrenoceptor, clonidine. It is proposed that TIQ and salsolinol specifically antagonize the agonistic conformation of dopamine receptor and that endogenous 1,2,3,4-tetrahydroisoquinolines may play a role of natural feedback regulators of the activity of dopaminergic system.

Further validation of LABORAS™ using various dopaminergic manipulations in mice including MPTP-induced nigro-striatal degeneration

“…The increased LMA, detected by LABORAS TM on administration of amphetamine 5 mg/kg, is comparable with published data in which doses of amphetamine at 2 mg/kg or above were required to induce a significant potentiation of LMA duration above vehicle controls, in standard LMA boxes (O'Neill and Shaw, 1999;Starr and Starr, 1986;Vetulani et al, 2001). In addition, the high dose inhibition (amphetamine, 5 mg/kg) of groom activity is also comparable with a previous investigation, in which doses of amphetamine at 2 mg/kg or above were observed to significantly decrease groom duration in mice (Starr and Starr, 1986).…”

“…Indeed, the algorithms used by LABORAS TM to detect behaviours in mice are unique and distinct from those used to detect comparable behaviours in rats. An initial pharmacological validation of the LABORAS TM system was therefore carried out using a variety of tool compounds to include: (1) the indirectly acting dopamine (DA) agonist, amphetamine (O'Neill and Shaw, 1999;Starr and Starr, 1986;Vetulani et al, 2001);…”

A possible physiological role for cerebral tetrahydroisoquinolines

“…The present paper reviews some our earlier (Antldewicz-Michaluk et al, 2000a;Vetulani et al, 2001) and some unpublished results suggesting indeed a physiological role for cerebral neurodegenerative neurotoxins. The present paper reviews some our earlier (Antldewicz-Michaluk et al, 2000a;Vetulani et al, 2001) and some unpublished results suggesting indeed a physiological role for cerebral neurodegenerative neurotoxins.…”

1-Methyl-1,2,3,4-Tetrahydroisoquinoline, an Endogenous Amine with Unexpected Mechanism of Action: New Vistas of Therapeutic Application

“…Early studies on tetrahydroisoquinolines revealed their neuroleptic-like properties (Ginos and Doroski 1979) and our more recent results suggest that TIQ and its derivatives are antagonists of agonistic conformation of the dopamine D 2 receptor (Antkiewicz-Michaluk et al 2007; Vetulani et al 2001, 2003a). This explains why TIQ and its congeners effectively block dopaminergic stimulation without affecting much the basal locomotor activity.…”