Amphetamine-induced hypolocomotion in mice with more brain D2 dopamine receptors

The relationship between brain D2 dopamine receptors and locomotor response to amphetamine was investigated in eight strains of mice. The D2 receptor is defined as that dopaminergic site with high affinity (nanomolar) for neuroleptics and low affinity (micromolar) for agonists. D2 receptors were measured in the striatum and olfactory tubercle using [3H]spiperone and 10 microM sulpiride to define specific binding. Four inbred strains of mice (CBA/J; C57BL/6J; DBA/2J; SEC/1ReJ) had low receptor densities of about 380 and 160 fmoles/mg protein in the striatum and olfactory tubercle, respectively; all these mice were essentially nonresponsive (i.e., locomotion) to low doses of amphetamine (0.5 and 1.0 mg/kg i.p.) or showed hyperlocomotion to high doses (5 mg/kg). Three other mouse strains (BALB/cJ; A/J; C3H/HeJ) had higher densities of about 600 and 230 fmoles/mg protein in the striatum and olfactory tubercle, respectively, and these mice all responded with hypolocomotion to the low doses and hyperlocomotion to the high dose of amphetamine. The two genetically different populations, one of which responded to amphetamine with hypolocomotion while the other did not, are analogous to hyperactive children, only 70% of whom respond to amphetamine-like drugs. Thus, the mice with high receptor density may serve as a model for studying the hyperactivity syndrome which may be associated with dopaminergic dysfunction.