Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model.

Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some central DA receptors, FR discrimination training could be a useful adjunct to PD replacement therapy and that the neostriatal DA-repleting action of training in 6-OHDA-treated rats depend on the age at which 6-OHDA is administered.

Behavioral effects of 3 alpha-androstanediol. I: Modulation of sexual receptivity and promotion of GABA-stimulated chloride flux.

Pregnane neurosteroids may initiate sexual receptivity not only via actions at intracellular receptors, but by affecting gamma-aminobutyric acid (GABA) receptor complexes (GBRs). To investigate whether GBR-mediated actions of an androgenic neurosteroid 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-androstanediol; 3 alpha-Diol) may influence the expression of sexual behavior, ovariectomized (ovx) rats received daily injections of 3 alpha-Diol (0.6, 3.0, 6.0 and 7.5 mg/kg) or vehicle (10% (v/v) ethanol in propylene glycol) at 10.00 h, and s.c. injections of estradiol-17 beta (E2: 1 microgram/0.2 ml in 10% ethanol) at 13.00 h and 19.00 h. Progesterone (P: 0.5, 1.0, 2.0 and 4.0 mg/kg) or sesame-oil vehicle was given at 12.30 h on the day following two days of 3 alpha-Diol and E2 treatment. In Expt. 1, levels of sexual receptivity were measured at 18.00-19.00 h, 56-57 h after the first injection of 3 alpha-Diol and 4 h after P or vehicle injection. 3 alpha-Androstanediol (6.0 mg/kg) attenuated sexual behavior (lordosis quotient, lordosis rating) and facilitated aggressive/rejection behaviors following 0.0, 1.0, 2.0 and 4.0 mg/kg P. The highest dosage of 3 alpha-Diol (7.5 mg/kg) facilitated sexual behavior and inhibited aggression behaviors following 0.0, 1.0, 2.0 and 4.0 mg/kg P. In Expt. 2, GABA-stimulated chloride flux was greater in cortical synaptoneurosomes of animals that received hormone treatments associated with inhibited receptivity (E2 + P + 3 alpha-Diol 3.0 mg/kg) than following treatments that facilitated receptivity (E2 + P and E2 + P + 3 alpha-Diol 7.5 mg/kg) or unreceptive ovx animals. In Expt. 3, circulating concentrations of 3 alpha-Diol resulting from the 0.0, 3.0 and 7.5 mg/kg s.c. doses administered to E2- and P-primed animals was measured by radioimmunoassay. Circulating levels of 3 alpha-Diol at the completion of behavioral testing were comparable to those previously ascertained across the estrous cycle. These data indicate that 3 alpha-Diol influences the expression of E2 and P-induced receptivity, and suggest that 3 alpha-Diol, like other neurosteroids, may exert its effects on sexual behavior by actions at GBRs.

Progesterone and 3 alpha-androstanediol conjugated to bovine serum albumin affects estrous behavior when applied to the MBH and POA.

Ovariectomized rats with cannula over the medial basal hypothalamus (MBH) received implants of 3 alpha-diol conjugated to bovine serum albumin (BSA; 3 alpha-diol:BSA), free 3 alpha-diol diluted with BSA (3 alpha-diol&BSA), progesterone (P) conjugated to BSA (P:BSA), free P diluted with BSA (P&BSA), or BSA alone. 3 alpha-diol:BSA or 3 alpha-diol&BSA facilitated receptivity within 90 min. Other estradiol-treated rats received steroid implants in the preoptic area (POA); those receiving P:BSA or P&BSA showed significant elevations in lordosis in 5 min. When systemic P was given, 3 alpha-diol:BSA and 3 alpha-diol&BSA applied to the MBH or POA inhibited receptivity. When 3 alpha-diol was given systemically, 3 alpha-diol:BSA implants to the MBH and POA produced facilitatory effects. These data suggest 3 alpha-diol can act at the membrane and that these effects are influenced by circulating steroids; yet membrane-mediated actions do not account for all of P-facilitated sexual behavior in the MBH and POA.

Analgesic effects of the neurosteroid 3 alpha-androstanediol.

The efficacy of 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-Androstanediol; 3 alpha-Diol) and 4-pregnen-3,20-dione (progesterone; P) in promoting analgesia was investigated. Ovariectomized rats received daily injections of 3 alpha-Diol (0.6, 3.0, 6.0 and 7.5 mg/kg) or vehicle and twice daily injections of estradiol-17 beta (E2: 1 microgram) for 2 days. Progesterone (0.5, 1.0, 2.0 and 4.0 mg/kg) or its vehicle was given on the third day and nociceptive testing using the radiant heat tailflick method was carried out 4 h later. In Expt. 1, P and 3 alpha-Diol both produced analgesia and had biphasic dose-response effects when administered singly. 3 alpha-Diol (3.0 mg/kg) elevated tailflick latencies in E2-primed animals above those following vehicle, 6.0 or 7.5 mg/kg 3 alpha-Diol; 6.0 and 7.5 mg/kg produced elevations that were greater than vehicle but less than 3.0 mg/kg. Progesterone (0.5 and 1.0 mg/kg) also elevated tailflick latencies above vehicle controls, while 2.0 and 4.0 mg/kg produced intermediate effects. In Expt. 2, 3 alpha-Diol (3 alpha-Diol:BSA) and P (P:BSA) conjugated to bovine serum albumin (BSA) were applied to the medial basal hypothalamus (MBH) and preoptic area (POA) to ascertain whether the steroids' analgesic actions were mediated by membrane actions in these sites. Free P and P:BSA both increased tailflick latencies when applied to the MBH, while 3 alpha-Diol and 3 alpha-Diol:BSA elevated latencies when applied to the POA, suggesting the steroids' effects occur in part at the neuronal membrane. In Expt. 3, free P or P:BSA applied to the MBH did not increase tailflick latencies if systemic P was given concurrently. Similarly, free 3 alpha-Diol and 3 alpha-Diol:BSA implants into the POA failed to increase tailflick latencies if s.c. 3 alpha-Diol was co-administered. These data indicate that P and 3 alpha-Diol at moderate doses have analgesic effects in part via membrane actions within the MBH and POA, respectively.