Pubertal changes in gonadal hormones do not underlie adolescent dopamine receptor overproduction

Abstract

Males, but not females, overproduce dopamine receptors in the striatum of rats across the periadolescent period followed by their elimination during young adulthood. In order to investigate the role that gonadal hormones play in this pubertal process, rats were castrated or ovariectomized at postnatal day (P) 28 when estrogen and testosterone levels are beginning to surge. Dopamine D1 and D2 striatal receptor density was then determined with autoradiography at P40 (adolescence) and P80 (young adulthood) to determine if either testosterone stimulates the overproduction of receptors in males or if estrogen inhibits this process in females. Neither castration nor ovariectomy altered dopamine receptor density, although enhanced testosterone levels increased D1 receptor binding 4.2% and 19.5% in males and females, respectively. The results of this study suggest that the endogenous rise in gonadal steroid hormones during puberty is not responsible for the overproduction of receptors in males or the lack of overproduction in females.

Introduction

One of the most puzzling aspects of psychiatric illnesses is the occurrence of dramatic sex differences in prevalence rates and course without equally dramatic anatomical differences between males and females. Early childhood disorders, like Attention Deficit Hyperactivity Disorder (ADHD) and Tourettes syndrome (TS), preferentially effect males over females (ADHD: 2–9-fold more prevalent in males; Anderson et al., 1995, Bird et al., 1988; TS: 3–4-fold more prevalent in males than females; Leckman et al., 1995). Differences in the onset of psychotic symptoms in schizophrenia are also subject to gender differences, but in this case, it is the age of onset that is delayed by an average of 4–5 years in females, rather than gender differences in prevalence rate (Hafner et al., 1991, Lewine, 1988). However a second peak of onset of schizophrenia is observed between 45–49 years of age that coincides with menopause (Hafner et al., 1991).

Maturational changes that occur during the periadolescent period have been hypothesized to play a role in the emergence and course of these disorders. The rise and fall of dopamine receptors in the brain during adolescence parallels the waxing and waning of symptoms in ADHD and TS (Andersen et al., 1997, Andersen and Teicher, 2000), while the fall of dopamine receptors/synapses may serve as a permissive factor for the emergence of schizophrenia (Andersen et al., 2000, Feinberg, 1982, Keshaven et al., 1994). Lifespan changes in symptoms and their severity coincide with hormonal changes. ADHD and TS get significantly worse during puberty, but then symptoms wane (Leckman et al., 1995). Schizophrenia typically appears post-pubertally, and neuroleptics are effective in lower doses in females than in males, at least until postpartum and during menopause when symptoms get worse (reviewed by Seeman and Lang, 1990). Furthermore, treatment response with dopamine antagonists (used for both TS and schizophrenia) also differs with age, where children are at greater risk for motor dystonias than adults (Baldessarini et al., 1993). At least in terms of dopamine-related disorders, being female offers some advantage or protection over males for risk or severity of these illnesses.

We have previously demonstrated that dopamine D1 and D2 receptor density in rat striatum and prefrontal cortex peaked at approximately 40 postnatal days of age (P40), and declined by 58–75% by adulthood (Andersen et al., 2000, Teicher et al., 1995). The overproduction of synapses and receptors occurs in humans (Huttenlocher, 1979, Seeman et al., 1987) and primates (Lidow et al., 1991, Rakic et al., 1986, Rosenberg and Lewis, 1995) as well. Between 7 and 15 years of age in humans, synaptic density in the frontal cortex decreases by approximately 40% (Huttenlocher, 1979, Rakic, 1991). Important gender differences exist in this process: males, but not females, overexpress D1 and D2 receptors in striatum during adolescence (Andersen et al., 1997) in a regionally-specific manner. In both sexes, accumbens dopamine receptors are not overproduced to the same dramatic extent as striatum, however, D1 receptor density remains higher in males than females by adulthood. Because these changes occur during the periadolescent period, we hypothesized that pre-pubertal gonadal hormone surges that occur at P28 (Compechot et al., 1981) may stimulate the increase in dopamine receptor development. The purpose of this study was to examine the effects of gonadectomy at P28 on dopamine D1 and D2 receptor density in the striatum and accumbens in male and female rats. The effects of enhanced testosterone on dopamine receptors were also investigated during puberty and adulthood.