Genetic variations in midbrain dopamine cell number: Parallel with differences in responses to dopaminergic agonists and in naturalistic behaviors mediated by central dopaminergic systems

Abstract

Mice of the inbred strain BALB/cJ have more midbrain dopaminergic cell bodies and greater activity of the catecholamine-synthesizing enzyme, tyrosine hydroxylase (TH), in the nigrostriatal and mesolimbic dopaminergic systems than mice of the CBA/J strain. This difference in cell number and TH activity in the midbrain dopaminergic systems are paralleled by differences in drug responses and behaviors which are dependent on the release of dopamine in midbrain dopaminergic systems. BALB/cJ mice showed greater locomotion and stereotypy than CBA/J mice after d-amphetamine (2–20 mg/kg, i.p.). There was no difference in the amount of amphetamine accumulated in brain at the peak of drug response or in the duration of drug effect, suggesting that the differences in behavioral effect were not due to strain differences in pharmacokinetic distribution of the drug. In contrast to the greater stereotypy to d-amphetamine, BALB/cJ mice showed less stereotypy after apomorphine (2–10 mg/kg, i.p.) than CBA/J mice. BALB/cJ mice also showed more exploration than CBA/J mice, measured as locomotion and rearing in a novel open field and investigation of a novel object. Genetically determined differences in the number of midbrain dopaminergic cell bodies and in the relative density of innervation of DA terminals in target fields and in TH activity in the nigrostriatal and mesolimbic dopaminergic systems are paralleled by differences in behavioral responses mediated by release of dopamine. The number of cells of a particular neurochemical class may dictate the magnitude of behaviors, drug-induced or spontaneous, mediated by those neurons.