Reversal of Dopamine D₂Receptor Responses by an Anandamide Transport Inhibitor

Abstract

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D(2) family receptors. Rat brain slices accumulated [(3)H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D(2) family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines.

The endogenous cannabinoid system and the treatment of marijuana dependence

“…Importantly, cocaine elicits a similar response (Centonze et al, 2004), suggesting a role for anandamide in the actions of these psychostimulant drugs. The ability of the anandamide transport inhibitor AM404 to reduce D 2 agonistinduced hyperactivity, discussed below, further supports this possibility (Beltramo et al, 2000).…”

“…3), has provided important information on the properties of anandamide transport, not only aiding the in vitro characterization of this process, but also helping to reveal its possible functions in animals. Importantly, the partial cannabimetic profile exhibited by this agent in vivo suggests that anandamide transport might provide a useful target in disease conditions in which the endocannabinoid system is hypofunctional (Beltramo et al, 2000). Evidence indicates that one such condition could be opiate withdrawal, which is markedly reduced in rodents by administering AM404 (Del Arco et al, 2002).…”

“…This effect is accompanied by a series of behavioral responses that, though blocked by the CB 1 antagonist rimonabant (SR141716A), are clearly distinguishable from those of direct cannabinoid agonists. For example, administration of AM404 into the cerebral ventricles of rats decreases exploratory activity without producing catalepsy (rigid immobility) and analgesia, two hallmarks of direct CB 1 receptor activation (Beltramo et al, 2000). In addition, AM404 reduces two characteristic effects caused by activation of D 2 family receptors: the yawning response elicited in mice by low doses of the D 1 /D 2 -receptor agonist apomorphine; and the stimulation of locomotor activity evoked in rats by the D 2 -receptor agonist quinpirole (Beltramo et al, 2000).…”

“…For example, administration of AM404 into the cerebral ventricles of rats decreases exploratory activity without producing catalepsy (rigid immobility) and analgesia, two hallmarks of direct CB 1 receptor activation (Beltramo et al, 2000). In addition, AM404 reduces two characteristic effects caused by activation of D 2 family receptors: the yawning response elicited in mice by low doses of the D 1 /D 2 -receptor agonist apomorphine; and the stimulation of locomotor activity evoked in rats by the D 2 -receptor agonist quinpirole (Beltramo et al, 2000). These effects are observed at doses of AM404 that selectively target anandamide transport and produce only mild hypokinesia when the drug is administered alone (Beltramo et al, 2000).…”

“…In addition, AM404 reduces two characteristic effects caused by activation of D 2 family receptors: the yawning response elicited in mice by low doses of the D 1 /D 2 -receptor agonist apomorphine; and the stimulation of locomotor activity evoked in rats by the D 2 -receptor agonist quinpirole (Beltramo et al, 2000). These effects are observed at doses of AM404 that selectively target anandamide transport and produce only mild hypokinesia when the drug is administered alone (Beltramo et al, 2000). The results of this study, which have been confirmed in several subsequent reports (for review, see Piomelli, 2003), demarcate the pharmacological profile of AM404 from those of direct-acting cannabinoid drugs.…”