Pitx3-deficient aphakia mice display unique behavioral responses to psychostimulant and antipsychotic drugs

Abstract

The dorsal (A9) and ventral striatum (A10) of the midbrain mediate many of the effects of psychoactive drugs that alter emotion, cognition, and motor activity within the contexts of therapy or abuse. Although transgenic and knockout technologies have enabled development of genetic models to dissect contributions of specific dopamine (DA) receptor subtypes to psychoactive drug effects, few models exist that can distinguish contributions of A9 versus A10 circuits. Pitx3 is a transcription factor enriched in DA neurons. Aphakia (ak) mice deficient in Pitx3 show selective loss of nigrostriatal DA, while other DA pathways are relatively spared, and therefore could be a useful tool for investigating the role of this subclass of DA projections. We investigated the effects of stimulants amphetamine, apomorphine, and MK-801 and the antipsychotic drug haloperidol on behavior in ak mice. Whereas wild-type mice showed the characteristic locomotor hyperactivity in response to amphetamine (5 mg/kg) and apomorphine (4 mg/kg), these drugs caused a paradoxical suppression of locomotor hyperactivity in ak mice. MK-801 (0.2 mg/kg) induced hyperactivity was maintained in both wt and ak mice. Additionally, mutant but not wild-type mice were insensitive to the cataleptic effects of haloperidol (1 mg/kg). These studies indicate that the nigrostriatal DA circuit plays a critical role in maintaining normal responsiveness to psychotropic drugs that either stimulate or block DA neurotransmission. We propose that ak mice may represent a valuable genetic model not only to study Parkinson's disease, but also to dissect the pathophysiologic and pharmacotherapuetic mechanisms of other DA-mediated disorders such as attention-deficit hyperactivity disorder, drug abuse and schizophrenia.

Figure 1

Ak mice are hyperactive over a 90 min test session compared to wt mice after i.p. saline treatment in both groups. ***p<0.0001, Mann Whitney Test

Figure 2

Amphetamine paradoxically suppresses locomotor activity in ak mice (n=10–11) animals per group). Data is horizontal beam breaks by wt (2a-day,2b-night), or ak (2c-day,2d-night) mice treated with amphetamine (5mg/kg, black squares) or saline (open circle) over 90 min in the day or night. Each point represents mean breaks over a 10 min interval. Repeated measures ANOVA shows main effect of treatment on locomotor activity. p<0.001

Figure 3

Apomorphine paradoxically suppresses locomotor activity in ak mice. (n=10–11 per group). Data is horizontal beam breaks in wt (3a) or ak (3b) mice treated with apomorphine (4mg/kg, black squares) or saline (open circles) over 90 min. Each point represents mean breaks over a 10 min interval. Repeated measures ANOVA demonstrates main effect of treatment on locomotor activity. p<0.001

Figure 4

MK-801 induced hyperlocomotion is maintained in ak mice. Data is horizontal beam breaks in wt (4a,4b) and ak mice (4c,4d) after treatment with saline (open circles) or MK-801 (0.2 mg/kg, black squares) in the day or night over 90 min.

Figure 5

Haloperidol (1mg/kg) induced catalepsy is absent in ak mice. (n=6 per group) (5a) mean and SEM of latency (in seconds) to remove both forepaws from bar in wt (checkered bar) and ak (clear bar) mice during the day. (5b) percentage of wt or ak mice showing catelpsy defined as >10s on bar) after haloperidol treatment. ***p<0.01, students t-test. **p<0.01, Fisher’s exact test. The above effects were maintained when wt and ak mice were tested at night(5c).