Sex differences in dopaminergic and cholinergic activity and function in the nigro-striatal system of the rat

Possible sex differences in the balance between dopaminergic and cholinergic activity in the rat striatum were investigated. Female rat show a greater vulnerability to neuroleptic-induced catalepsy compared to male rats. This vulnerability to neuroleptics has a human counterpart in that women show an increased frequency of neuroleptic-induced extrapyramidal syndrome (EPS) compared to men. In humans, EPS can be alleviated by increasing dopaminergic activity or by decreasing cholinergic activity. Conversely, EPS can be precipitated by decreasing dopaminergic activity with neuroleptics, and pre-existing EPS can be made worse with cholinergic agonists. Thus, the presence of EPS in humans or catalepsy in animals, as a result of neuroleptic agents, appears to be related to low dopaminergic and/or high cholinergic activity. In the present studies of sex differences it was found that: (1) cycling female rats had fewer striatal dopamine receptors than did male rats. Estradiol treatment significantly reduced the number in males and also reduced the number, although not significantly in ovariectomized (OVX) rats; (2) cycling female rats had lower apomorphine-induced stereotypy during phases with high estrogen levels as compared to phases with low estrogen levels. Estrogen treatment of male or OVX rats resulted in attenuation of induced stereotypy compared to untreated male or OVX rats; (3) female rats had a significantly higher affinity of striatal cholinergic receptors of 3H-QNB than did males and also had higher choline acetyltransfease activity than male rats. The data from these experiments provide the first direct evidence that estrogen plays a role in shifting the balance toward cholinergic predominance in the striatum, a state that favors the development of cataleposy in female rats and EPS in women.