2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Muscle-Rigidity

Adenosine A2A receptor agonists produce a hypokinetic state (catalepsy) that is believed to reflect antagonistic interaction of A2A and dopamine D2 receptors in the basal ganglia. In addition to catalepsy, pharmacological blockade of D2 receptors produces rigidity. However there are conflicting data about the effect of A2A agonists on muscle tone, with some reports indicating an increase, while other data suggest that A2A catalepsy is dominated by muscle hypotonia. We investigated the effect on resistance to imposed movements of systemic cataleptic doses of the selective A2A agonist CGS21680 (5 mg/kg), and compared it with the effect of the D2 antagonist raclopride (5 mg/kg), in rats. Total resistance is made up of elastic and viscous components. The elastic component is velocity independent, and is referred to as "stiffness," whereas viscosity, which dampens responses to imposed movements, is velocity dependent. Using a method for quantifying total joint resistance that enabled separate identification of stiffness and viscosity, we found that during catalepsy evoked by either drug there was a clear increase in joint rigidity. Both CGS21680 and raclopride significantly increased joint stiffness, the velocity independent component of rigidity that is most affected in Parkinsonism. In contrast, the effect of CGS21680 on the velocity-dependent viscosity component was less robust than for raclopride, and did not reach significance, possibly reflecting an interaction with sedative effects via extrastriatal receptors. The effect of CGS21680 and raclopride on joint stiffness is thus consistent with previous findings suggesting functional antagonism of A2A and D2 receptors in the basal ganglia.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Biomechanical Phenomena; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Hindlimb; Joints; Male; Muscle Rigidity; Muscle Tonus; Phenethylamines; Raclopride; Rats; Rats, Wistar; Receptors, Adenosine A2

Recently it has been suggested that adenosine A(2A) receptor agonists may be potential antipsychotic drugs. It is, however, not clear whether these compounds may exert their antipsychotic effect without producing extrapyramidal side-effects (e.g. catalepsy, muscle rigidity, ataxia). It is known that such side-effects may be due to overactivation of the GABAergic strio-pallidal pathway, which may be estimated as an increased expression of proenkephalin (PENK) mRNA in the striatum.. The aim of this study was to determine whether CGS 21680, a selective adenosine A(2A) receptor agonist, can reverse the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by the non-competitive antagonist of NMDA receptors phencyclidine (PCP) without producing motor side-effects in rats.. Systemic administration of PCP (5 mg/kg) produced profound reduction of the PPI, which was reversed by CGS 21680 (1 mg/kg). CGS 21680 (0.1 and 1 mg/kg) was without effect on catalepsy, muscle rigidity and rotarod performance in rats as well as on the PENK mRNA expression in the striatum estimated by in situ hybridization. Only after the highest dose used (5 mg/kg) were signs of catalepsy (measured using a 9-cm cork test), disturbed balance and a loss of hind limb control (measured in the rotarod test) seen. Moreover, increased muscle resistance during passive extension measured mechanomyographically after this dose of CGS 21680 was observed.. The present results support the hypothesis that adenosine A(2A) receptor agonists may be potentially useful antipsychotic agents with the low incidence of extrapyramidal side-effects.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Catalepsy; Corpus Striatum; Dopamine Agonists; Enkephalins; Hallucinogens; In Situ Hybridization; Lameness, Animal; Male; Motor Activity; Muscle Rigidity; Nucleus Accumbens; Phencyclidine; Phenethylamines; Protein Precursors; Rats; Rats, Wistar; Reflex, Startle; RNA, Messenger; Rotarod Performance Test

The aim of the present study was to assess contribution of striatal adenosine A2A receptors to regulation of the muscle tone in rats. The muscle tone was examined by a combined mechano- and electromyographic method, which measured simultaneously muscle resistance (MMG) of a rats hind foot to passive extension and flexion in the ankle joint and the electromyographic activity (EMG) of the antagonistic muscles: gastrocnemius and tibialis anterior. CGS 21680 (1 and 2 microg/0.5 microl), injected bilaterally into the rostral part of the striatum, dose-dependently increased both MMG and the EMG. The present results show that stimulation of striatal adenosine A2A receptors by CGS 21680 evokes parkinsonian-like muscle rigidity which may be due to activation of the GABAergic strio-pallidal pathway.

Topics: Adenosine; Animals; Ankle Joint; Corpus Striatum; Electromyography; Male; Muscle Rigidity; Muscle Tonus; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Wistar; Receptor, Adenosine A2A; Receptors, Purinergic P1