Individual differences in psychostimulant responses of female rats are associated with ovarian hormones and dopamine neuroanatomy - PubMed (original) (raw)

Comparative Study

Individual differences in psychostimulant responses of female rats are associated with ovarian hormones and dopamine neuroanatomy

Q David Walker et al. Neuropharmacology. 2012 Jun.

Abstract

Ovarian hormones modulate the pharmacological effects of psychostimulants and may enhance vulnerability to drug addiction. Female rats have more midbrain dopamine neurons than males and greater dopamine uptake and release rates. Cocaine stimulates motor behavior and dopamine efflux more in female than male rats, but the mediating mechanisms are unknown. This study investigated individual differences in anatomic, neurochemical, and behavioral measures in female rats to understand how ovarian hormones affect the relatedness of these endpoints. Ovarian hormone effects were assessed by comparing individual responses in ovariectomized (OVX) and sham adult female rats. Locomotion was determined before and following 10mg/kg cocaine. Electrically-stimulated dopamine efflux was assessed using fast cyclic voltammetry in vivo. Dopamine neuron number and density in substantia nigra (SN) and ventral tegmental area (VTA) were determined in the same animals using tyrosine-hydroxylase immunohistochemistry and unbiased stereology. Locomotor behavior and dopamine efflux did not differ at baseline but were greater in sham than OVX following cocaine. Cocaine increased dopamine release rates in both groups but uptake inhibition (K(m)) was greater in sham than OVX. Dopamine neuron number and density in SN and VTA were greater in shams. Sham females with the largest uterine weights exhibited the highest density of dopamine neurons in the SN, and the most cocaine-stimulated behavior and dopamine efflux. Ovariectomy eliminated these relationships. We postulate that SN density could link ovarian hormones and high-psychostimulant responses in females. Similar mechanisms may be involved in individual differences in the addiction vulnerability of women.

Copyright © 2012. Published by Elsevier Ltd.

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Figures

Fig. 1

Fig. 1

Motor activity during habituation to a novel open-field device and following 10 mg/kg cocaine injection i.p. The habituation data from all sham (N = 16) and OVX (N = 13) rats for each of the three behavioral topographies horizontal ambulations (A), fine movements (B) and rearing (C) showed no main effect of ovariectomy or an interaction with time. Ambulations (D, significant main effects of surgery and time and interaction with time) and fine movements (E, significant effect of time and interaction of surgery and time) were lower in the OVX rats following cocaine administration, especially at the earliest time points. Ovariectomy did not significantly affect rearing behavior. *significantly different than sham group at same time point. Group means ± standard errors are shown in this and all figures.

Fig. 2

Fig. 2

Fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used to assess electrically-stimulated dopamine efflux in dorsal striatum of anesthetized sham and OVX female rats, in vivo. Representative recordings at 100 ms intervals in sham and ovariectomized female rats are shown before (open circles) and after 10 mg/kg cocaine (filled circles). Sixty pulse electrical stimulations (300 µA) of the medial forebrain bundle evoked extracellular dopamine in each rat at the frequencies indicated. The identical scale bars for each rat apply to all frequencies. The lines under the recordings indicate the duration of the electrical stimulation injection.

Fig. 3

Fig. 3

The maximal concentration of stimulated dopamine efflux was determined from overflow curves like those shown in Fig. 2. Group averages of those maximal concentrations are shown across the range of stimulation frequencies at baseline (A) and following 10 mg/kg cocaine i.p. (B). The time course of cocaine-induced dopamine efflux following 20 Hz stimulations (C) showing peak or maximal extracellular dopamine concentrations (DAmax). In vivo dopamine release and uptake kinetics at baseline and following 10 mg/kg cocaine i.p. in dorsal striatum were determined from overflow curves following 10–60 Hz stimulations that were analyzed simultaneously to resolve release (D) and uptake parameters, _V_max (E) and _K_m (F) (see Methods). * indicates sham and ovex are significantly different, # indicates significantly different from baseline.

Fig. 4

Fig. 4

Ovariectomy altered dopamine anatomy in the midbrain but not in the forebrain. OVX rats had fewer TH-IR neurons in both the SN and VTA (A, D) but maintained the volume of both midbrain regions (B, E). As a result the OVX rats had a lower density of DA neurons in the SN and VTA (C, F). The number of non-TH-IR, cresyl violet stained cells was not affected by ovariectomy (data not shown). Likewise, the number of TH-IR terminals and their density in dorsal striatum was not affected by ovariectomy (data not shown).

Fig. 5

Fig. 5

Correlations between anatomic and functional endpoints. Linear regression analysis reported R2 and p values for sham and OVX rats, which are presented on all panels.

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