Adenosinergic modulation of 3α-hydroxy-5α-pregnan-20-one induced catalepsy in mice

Abstract

  Rationale: Neurosteroid 3α, 5α THP, a positive allosteric modulator of the GABA_A receptor Cl^– ionophore complex, induces catalepsy-like dopamine antagonists, adenosine agonists or GABA agonists. Adenosine and dopamine receptors are co-localized on GABAergic neurons in the striatum and regulate GABA-mediated neurotransmission. Moreover, the antagonistic interactions between specific subtypes of adenosine and dopamine receptors are involved in motor depressant or motor stimulant effects of adenosine receptor agonists or antagonists, respectively. Such interaction may modulate neurosteroid-induced catalepsy. Objective: This study examined the modulation of 3α, 5α THP-induced catalepsy by adenosinergic agents. Methods: Catalepsy induced by 3α, 5α THP (2–8 µg, ICV) was assessed by bar test periodically up to 3 h in mice. Adenosine A₁, A_2A or A₃ receptor agonists or antagonists were given IP or ICV prior to 3α, 5α THP. Some animals received IP dopamine D₂ receptor agonist or antagonist 30 min prior to above combination treatment. Results: Adenosine A₁, A_2A, and A₃ receptor agonists potentiated, whereas adenosine A_2A receptor antagonists, but not A₁ antagonists, reversed 3α, 5α THP-induced catalepsy. These effects of adenosine agonists and antagonists were abolished by prior administration of bromocriptine, the dopamine D₂ receptor agonist and spiperone, the dopamine D₂ receptor antagonist, respectively. Conclusions: These findings suggest specific adenosine-dopamine receptor interaction in the striatum to modulate 3α, 5α THP-induced catalepsy.