Barbiturate dependence and drug preference

Rats were administered chronic multiple injections of amphetamine (AMPH) using dosage regimens which produce tolerance to the AMPH facilitation of self-stimulation responding, or reverse tolerance (sensitization) to the locomotor stimulant and stereotypy-producing effects of the drug. Subsequently rats were challenged with AMPH at behaviorally relevant doses and times and striatal and mesolimbic dopamine (DA) dynamics were assessed using the conversion of ³H-tyrosine to ³H-DA, and endogenous levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as indices of dopaminergic function. Acute administration of AMPH produced dose and time related changes in all indices of DA function in both the striatal and mesolimbic brain regions. Co-administration of haloperidol during chronic AMPH pretreatment prevented the appearance of most of the behavioral changes induced by chronic AMPH, suggesting an important role for DA systems. However, following chronic AMPH treatment, no additional biochemical changes in striatal or mesolimbic DA metabolism could be detected which would parallel the development of tolerance to AMPH facilitation of self-stimulation behavior or reverse tolerance to AMPH as reflected in enhanced post-stereotypy locomotor activity or a suggested increased intensity of stereotypy. Challenge with AMPH after chronic AMPH pretreatment did accelerate the changes in striatal but not mesolimbic DA metabolism, correlating with the more rapid onset of stereotypy induced by chronic AMPH. Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism.     

Biphasic effects of amphetamine on striatal dopamine dynamics

S(+)-Amphetamine (AMPH) was administered to rats over the dose range 0.15-10.0 mg/kg (1.74(3)mumoles/kg) at various times before sacrifice. 15 min before sacrifice rats received an intraventricular injection of 3H-tyrosine, and the accumulation of striatal 3H-dopamine (DA) was assessed as an index of striatal DA formation and utilization. 3H-DA formation exhibited a biphasic dose response to AMPH. At 16 and 31 min after AMPH administration, 3H-DA accumulation increased linearly in response to AMPH to a maximal rate of 200% of control values at 1.0 mg/kg, then declined to less than 50% of control values at AMPH doses of 5 and 10 mg/kg. As a function of time, low doses of AMPH (to 2.0 mg/kg)) only increased 3H-DA accumulation, whereas high doses of AMPH (greater than 2.5 mg/kg) only decreased 3H-DA accumulation. All doses of AMPH increased endogenous levels of striatal DA. The data are discussed in terms of compensatory adaptive mechanisms of the nigrostriatal dopaminergic pathway.     

Effects of REMS deprivation on striatal dopamine and acetylcholine in rats.

Changes in the concentration of striatal dopamine (DA) and acetylcholine (ACh) in rats deprived of REM sleep for 10 days were compared with those obtained after a 4 day deprivation procedure. Animals placed on small (7 cm dia.) islands surrounded by water were completely deprived of REM sleep but able to obtain some slow-wave sleep. Concentration of striatal DA was significantly increased after 4 days and 10 days of REM sleep deprivation by 73 and 133%, respectively when compared to controls. Levels of ACh in the striatum were significantly enhanced (by 28%) after 10 day, but failed to show significant change after 4 day REM sleep deprivation procedure. The short term locomotor activity was significantly higher in REM sleep-deprived animals. Our data indicate that REM sleep deprivation results in marked alterations of both cholinergic and dopaminergic mechanisms in the rat striatum.     

Naloxone reduces amphetamine-induced stimulation of locomotor activity and in vivo dopamine release in the striatum and nucleus accumbens.

This study tested the possibility that naloxone (NX), an opioid antagonist, reduces the behavioral effects of amphetamine (AMPH) in rats by attenuating the dopaminergic response to AMPH. In the first experiment, adult, male rats were injected SC with either NX (5.0 mg/kg) or saline and 30 min later received doses of AMPH (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) cumulatively at 30-min intervals. Gross locomotor counts following AMPH administration were significantly lower for rats pretreated with NX than for rats pretreated with saline. In the second experiment, the same drug treatments were given while performing microdialysis in either the striatum (STR) or nucleus accumbens (NACC). STR rats treated with vehicle showed a larger percentage increase in DA levels following AMPH treatment than did NACC rats treated with vehicle. NX pretreatment did not affect dopamine concentrations in either brain region. However, compared to pretreatment with saline pretreatment with NX significantly decreased the dopaminergic response to AMPH in the STR. There was no difference between the two groups in the peak dopaminergic response to AMPH in the NACC, but there was a significant AMPH x treatment x time interaction due to differences between the groups during the later portion of the response to 6.4 mg/kg AMPH. There was also a difference in locomotor activity following AMPH treatment between NX- and saline-treated subjects during dialysis. These findings suggest that a decrease in the dopaminergic response to AMPH is the mechanism by which NX attenuates behavioral stimulant effects of AMPH. In addition, there is a difference between the STR and NACC in dopaminergic responsiveness to AMPH.     

Alterations in striatal acetylcholine,acetylcholine esterase and dopamine after methadone replacement in morphine-dependent rats

Chronic treatment of rats with morphine was found to produced a significant increase in endogenous ACh and DA as well as a decrease in AChE activity of rat striatum. Narcotic withdrawal for 48 hr resulted in a reversal of morphine-induced changes in striatal ACh levels and AChE activity whereas the enhanced striatal DA remained unaltered. Methadone replacement failed to affect the changes in striatal ACh and AChE activity but abolished the increases in striatal DA seen in morphine-withdrawn rats. Our results suggest that ‘morphine addiction’ in rats may involve alterations in the cholinergic and dopaminergic mechanisms of the striatum and that methadone replacement influences primarily the changes in the dopaminergic system produced by chronic morphine and its subsequent withdrawal.     

Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists

The disruption of prepulse inhibition (PPI) in rats by dopamine (DA) agonists is used to study the neural basis of strain differences in dopaminergic function. We reported that, compared to Long-Evans (LEH) rats, Sprague-Dawley (SDH) rats are more sensitive to the PPI-disruptive effects of the direct D1/D2 agonist apomorphine (APO) and the indirect DA agonist d-amphetamine (AMPH). This strain difference is heritable, with PPI drug sensitivity following a generational pattern (SDH>N2>F1>LEH) suggestive of additive effects of multiple genes. Here, we assessed the neurochemical bases for these heritable strain differences by measuring tissue levels of dopamine, serotonin (5HT) and their respective metabolites in several forebrain regions after vehicle, APO or AMPH administration. SDH rats were more sensitive than LEH rats to the PPI-disruptive effects of both APO (0.5 mg/kg) and AMPH (4.5 mg/kg). Several significant SDH vs. LEH strain differences in regional neurochemical levels were detected, as were drug effects on these chemicals. However, SDH, LEH and F1 rats did not exhibit differential drug sensitivity in any neurochemical indices measures. These findings suggest that inherited differences in the dopaminergic regulation of sensorimotor gating do not likely reflect differences in presynaptic forebrain dopaminergic or serotonergic processes.     

Repeated stress increases locomotor response to amphetamine

Adult male rats submitted to mild, 20 min electric foot shock sessions for 10 days displayed an enhanced locomotor response to 0.75 mg/kg (+)amphetamine 24 h after the last shock session, when compared to non-stressed controls. This effect was still present in rats specifically deprived of their forebrain noradrenergic innervation, suggesting the involvement of a dopaminergic mechanism. Cortical and limbic dopamine turnover which increased immediately after acute and repeated foot shocks returned to normal 24 h later, at the time of the pharmacological testing. This fact indicates that a permanent modification of the basal DA activity is not responsible for the above effect apomorphine was enhanced in experimental animals, while hypoactivity resulting from the injection of 0.05 mg/kg apomorphine was similar in control and shocked rats. This latter result suggests the existence of an increased postsynaptic DA sensitivity as a result of repeated stress.     

Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion

The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this is accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release. In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines). However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later. Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization). Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days. This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios. These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH 'challenge.' In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity. It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH 'runs' common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity.     

Striatal dopamine activity and unilateral barpressing in rats

A micro-punch tissue assay was used to measure changes in dopamine content at twenty-six sites within the striatum of rats trained to barpress exclusively with one forepaw for food pellets. Analysis of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was carried out using HPLC with electrochemical detection. The barpress group had a significantly higher DOPAC/DA ratio in both the contralateral and ipsilateral hemispheres when compared to feeding and homecage controls. The DOPAC/DA ratio is considered to be a measure of dopaminergic neuronal activity, thus suggesting a bilateral activation of the neostriatal dopaminergic afferents as a result of the motor performance. Topographical analysis within the barpress group revealed an anterior-posterior, medial-lateral gradient of dopaminergic activity with the posterior and lateral sites showing the greatest increases over the controls. The results of this experiment indicate that localized changes in neuronal activity can be monitored with the micro-punch assay-HPLC/EC technique and that voluntary motor behavior produces an activation of the striatal dopamine system.     

Effects of prenatal exposure to deltamethrin on forced swimming behavior, motor activity, and striatal dopamine levels in male and female rats

The effects of prenatal exposure of rat pups to 0.08 mg/kg deltamethrin (DTM) on physical, reflex and behavioral developmental parameters, on forced swimming and open-field behaviors, and on striatal monoamine levels at 60 days of age were observed. Maternal and offspring body weight, physical and reflex development were unaffected by the exposure to the pesticide. At 21 days of age, open-field locomotion frequency and immobility duration of male and female offspring were not different between control and exposed animals. However, male rearing frequency was increased in experimental animals. A decreased immobility latency to float and in general activity after the swimming test in male offspring was observed at adult age; no interference was detected in the float duration during the swimming test. In addition, these animals presented higher striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels without modification in dopamine (DA) levels and an increased DOPAC/DA ratio. These data indicate a higher activity of the dopaminergic system in these animals. Noradrenaline (NA) levels were increased, while MHPG levels were not detectable in the system studied. Serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, as well as the homovanillic acid (HVA)/DA ratio, were not modified by the exposure to the pesticide. No changes were observed in swimming and open-field behaviors nor were there any changes in striatal monoamines or their metabolites in the female experimental group. In relation to the pesticide formula, the present data showing that prenatal exposure to DTM alters latency to float and the activity of striatal dopaminergic system might reflect a persistent effect of the pesticide on animal motor activity, mainly in males. On the other hand, the decrease in general activity observed in experimental male rats suggests higher levels of emotionality induced by previous exposure to the swimming behavior test in relation to control animals. Data gathered in the present study may be important for the assessment of the safety of pyrethroid insecticides.     

Influence of hypophysectomy on dopamine receptors and dopaminergic behaviors

Hypophysectomy (Hypox) has been proposed to alter the behavioral and biochemical indices of striatal dopamine (DA) function. Since the regulation of striatal DA receptors by hormones may involve the pituitary, it was relevant to reevaluate the effects of Hypox in male and female rats. Behaviorally, dopaminergic agonists exerted enhanced activity in Hypox male and female rats. It has been suggested that these changes are due to altered metabolism since no increase in the DA receptor populations was observed. Dopaminergic antagonists showed equivalent behavioral actions in male and female rats, whether intact or Hypox. Biochemically, neither the density nor the affinity of the striatal DA receptors is altered by Hypox in female rats for 1-2 weeks or male rats for 5-6 weeks. However, in female rats at 5-6 weeks after Hypox there is a significant decrease in receptor number. This decrease in density is not reflected in behavioral changes to either DA receptor agonists or antagonists. Therefore, all dopaminergic behavioral changes do not result from alterations in DA receptors and changes in DA receptors do not necessarily dictate altered behavioral responses to dopaminergic agents.     

Increased conditioned fear response and altered balance of dopamine in the shell and core of the nucleus accumbens during amphetamine withdrawal

It has been suggested that neuroadaptations within the nucleus accumbens (NAC) dopaminergic (DA) projection contribute to the negative affect associated with psychostimulant withdrawal. The present study assessed the effects of amphetamine (AMPH) withdrawal on behavioral and NAC DA responses to conditioned fear stress. Animals injected with escalating-dose AMPH (1-5mg/kg, three injections/day, 6 days) or saline (SAL) acquired a tone-shock association on withdrawal day 3 and were tested for extinction of conditioned freezing to the tone on withdrawal day 4. Extracellular levels of NAC shell and core DA were monitored using in vivo microdialysis on both days. AMPH-withdrawn animals exhibited more conditioned freezing than SAL animals during both acquisition and extinction. During acquisition, DA increased more in the shell than the core of the NAC in both AMPH and SAL groups. During extinction to the tone, shell DA increased in SAL- but not AMPH-treated animals, whereas core DA activity was greater in AMPH than SAL animals. These data demonstrate that AMPH withdrawal alters the balance between shell and core DA transmission while increasing the behavioral expression of conditioned fear. Such drug-induced neuroadaptations in the NAC stress response may be involved in the exacerbation of negative emotions associated with drug withdrawal and stimulant-induced psychosis.     

Time-course of the effects of ovarian steroids on the activity of limbic and striatal dopaminergic neurons in female rat brain

This paper studies the time-course of the effects of pharmacological administrations of ovarian steroids on the functional state of dopaminergic terminals in the striatum and the limbic forebrain, using the ratio between the contents of dopamine (DA) and its metabolite, L-3,4 dihydroxyphenylacetic acid (DOPAC), as an index of nerve activity. Estradiol produced an increase in the dopaminergic activity of both limbic and striatal neurons, reflected in the high DOPAC/DA ratio observed in both areas. This estrogenic effect was only observed at 4 hours, disappearing in the subsequent times studied. The effect was antagonized by progesterone in both tissues, since a single injection of this steroid to estrogen-pretreated rats restored to control values the estradiol-induced increase, suggesting the existence of negative interactions between both steroids. Furthermore, treatment with progesterone produced also a late decrease of the DOPAC/DA ratio in the striatum, which was observed only in the animals nonpretreated with estrogens.     

Behavioural and biochemical effects of subchronic treatment with raclopride in the rat: tolerance and brain monoamine receptor sensitivity

Male Sprague-Dawley rats were treated with the dopamine (DA) D2 receptor blocking agent raclopride 0.5 or 8.0 mg kg-1 subcutaneously (1.0 and 16.0 mumol kg-1, respectively), twice daily for 21 days. The animals treated with raclopride gained weight at the same rate as saline controls, and gross observation did not indicate any behavioural abnormalities due to the subchronic raclopride treatment. Possible changes in brain DA receptor sensitivity due to prolonged blockade of DA receptors were evaluated in behavioural and biochemical models. There were no effects on locomotor activity, as observed by means of photobeam-equipped activity cages, 24 hr or 72 hr after withdrawal of 0.5 or 8.0 mg kg-1 subchronic raclopride treatment. Twenty-four hr after withdrawal of the raclopride treatment there was an increased post-synaptic DA receptor sensitivity as evidenced by increased behavioural and biochemical responses to apomorphine, and by an attenuated response to acute raclopride treatment, 0.1 mg kg-1. Thus, there was an increase in locomotor activity by the apomorphine treatment in animals pretreated with the 8 mg kg-1 dose, as compared to the response obtained in saline controls. Furthermore, the suppression of locomotor activity in saline controls produced by acute raclopride treatment was dose-dependently antagonized by the raclopride pretreatment and this also applied to the increase in striatal DOPAC levels produced by acute raclopride treatment. Finally, there was an increased DA receptor sensitivity presynaptically as evidenced by an enhanced effect on striatal DOPA levels by apomorphine in rats treated with NSD 1015 and reserpine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation

The dopamine transporter, DAT, is a primary regulator of dopamine (DA) signaling at the synapse. Persistent stimulation with the substrate amphetamine (AMPH) promotes DAT internalization. AMPH rapidly elicits DA efflux, yet its effect on DAT trafficking at short times is unknown. We examined the rapid effect of AMPH on DAT trafficking in rat striatal synaptosomes using biotinylation to label surface DAT. Within 30s of treatment with 3 microM AMPH, synaptosomal DAT surface expression increased to 163% of control and remained elevated through at least 1 min before returning to control levels at 2.5 min. The increase in surface DAT was cocaine-sensitive but was not produced by DA itself. A 1-min preincubation with AMPH did not alter [(3)H]DA uptake, but did result in a higher basal DA efflux and efflux elicited in the presence of AMPH as compared to vehicle pretreatment. Reversible biotinylation experiments demonstrated that the AMPH-stimulated rise in surface DAT is due to an increase in the delivery of DAT to the plasmalemmal membrane rather than a reduction of the endocytic process. These studies suggest that AMPH has a biphasic effect on DAT trafficking and acts rapidly to regulate DAT in the plasmalemmal membrane.     

Elevated neuronal nitric oxide synthase expression in chronic haloperidol-treated rats

Long-term administration of neuroleptic drugs, such as haloperidol, in the management of psychiatric disorders may adversely cause an irreversible neurological syndrome of tardive dyskinesia, which is associated with dopamine (DA(2)) receptor supersensitivity in the basal ganglia. Recent studies also indirectly suggest an involvement of nitric oxide synthase (NOS) in dopaminergic supersensitivity; however, chronic neuroleptic effects on neuronal NOS (nNOS) expression in the basal ganglia have not been reported. In this investigation, we treated rats with saline or haloperidol (1 mg/kg, s.c.) daily for 21 days. Five days later, we detected a significant increase of NOS activity in the striatum of haloperidol-treated rats when compared to saline controls. This effect was associated with elevated levels of nNOS mRNA and protein expression in the striatum, but not in the nucleus accumbens, as evidenced by the use of in situ hybridization, Western blot and immunohistochemical techniques. The involvement of the nNOS system after chronic haloperidol treatment coincides with increases of striatal DA(2) receptor sites, calmodulin kinase II activity, animal locomotor and stereotypy behaviors. This study suggests an integral role between nNOS, DA(2) receptor and calmodulin system in the development of dopaminergic behavioral supersensitivity resulting from chronic neuroleptic drug treatment. Furthermore, the toxic effect of chronic haloperidol on NOS system selectivity takes place in the neostriatum.     

Lack of effect of some dopamine and non-dopamine receptor ligands on amphetamine-induced changes in the rat brain neuropeptide Y system

None of the receptor ligands studied: the dopamine D2 antagonist eticlopride, D2/D3 antagonist haloperidol, alpha1-adrenergic antagonist prazosin, N-methyl-D-aspartate antagonist MK-801, 5-HT2/D2 antagonist mianserin, D2/D3 agonist quinpirole and alpha2-adrenergic agonist clonidine co-administrated with repeated amphetamine (AMPH) injections blocked the AMPH-induced decrease in the striatal and nucleus accumbens neuropeptide Y (NPY) levels. Only the D1/D5 receptor antagonist SCH 23390 insignificantly attenuated this effect what suggests that these dopamine receptor subtypes may partially mediate AMPH effect on NPY. Moreover, the results of multiple administrations of the receptor ligands to control rats indicate that the NPY systems in both structures under study are modulated in the same manner by dopaminergic activity and differentially by adrenergic, N-methyl-D-aspartate and serotonergic activity.     

Behavioral sensitization to beta-phenylethylamine (PEA): enduring modifications of specific dopaminergic neuron systems in the rat

Repeated daily administration of an endogenous trace amine, beta-phenylethylamine (PEA), produces behavioral sensitization such that the intensity of PEA-induced stereotyped behaviors in rats increases gradually during the treatment, and a challenge injection with PEA reinstates the enhanced stereotypy even long after withdrawal. In the present study, we examined the neurochemical changes in the central dopaminergic neuron systems in the rat for 7 drug-free days after repeated treatment with PEA (50 mg/kg, IP day for 14 or 28 days). During withdrawal, a decrease in steady-state levels of tissue dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), was found in the mesolimbic DA nerve terminal areas of the rat brain receiving repeated PEA treatment. Fifteen minutes after challenge administration of PEA at varying doses from 6.3 to 75 mg/kg, the rats with repeated PEA treatment required smaller doses of PEA challenge than the rats with acute PEA treatment in order to obtain a significant decrease in striatal DOPAC content compared to the saline control in each treatment group. These results imply that the behavioral sensitization to PEA is accompanied by enduring modifications of the specific dopaminergic neuron systems in the rat brain. This suggestion was strongly supported by the results of the study using in vivo intracerebral dialysis, which indicated that 25 mg/kg PEA challenge elicited a remarkable increase in the extracellular DA concentrations in striatal perfusates collected from the PEA-pretreated rats, in accordance with the intensity of stereotyped behaviors. These findings argue that the hyper-responsiveness to PEA of the striatal dopaminergic neuron systems persists long after withdrawal from repeated treatment with PEA.     

Pharmacological reactivity to cocaine in adult rats undernourished at perinatal age: behavioral and neurochemical correlates

The influence of neuronal alterations induced by early undernutrition on the stimulant effect of cocaine was assessed in adult rats submitted to a protein deprivation schedule at perinatal age. To evaluate the sensitization phenomenon induced by repeated cocaine administration, different groups of control (C) and deprived (D) rats received a daily injection of cocaine (5, 10 or 15 mg/kg, i.p.) for 16 days. Behavioral parameters were assessed every two days in an open-field. Dose-response curves obtained with different doses of cocaine used revealed a shift to the left in the locomotor activity curves of D rats compared to controls. Thus, D animals showed a clear behavioral sensitization to the lower dose of cocaine, whereas this phenomenon was only observed in C rats for the higher dose used. To correlate this differential development of sensitization with neurochemical parameters, we assessed extracellular dopamine (DA) levels in nucleus accumbens (core and shell) and in the dorsal caudate-putamen, using a microdialysis technique. A challenge with cocaine in cocaine pre-exposed animals produced a different increase in DA output only in nucleus accumbens "core" of D animals. Comparable DA levels were observed in nucleus accumbens shell and in dorsal caudate-putamen of both groups. These results demonstrate that D rats had a lower threshold developing a progressive behavioral sensitization following repeated cocaine administration, as well as higher responsiveness of the nucleus accumbens (core) expressed by increased DA release.     

Effects of postpuberal castration on dopamine receptor sensitivity in the male rat brain

In order to study the effects of castration of brain dopamine (DA) receptor sensitivity, the effects of apomorphine on locomotor activity and striatal DA synthesis, as assessed by the dihydroxyphenylalanine (DOPA) accumulation after NSD-1015 treatment, were examined in normal and castrated male Sprague-Dawley rats pretreated with reserpine (5 mg/kg-18 hrs). There was an enhanced locomotor response to apomorphine (0.05-0.1 mg/kg) in castrated animals, as compared to sham operated controls. Furthermore, the increase in DOPA accumulation produced by the reserpine treatment was antagonized to a greater extent by apomorphine in the castrated animals. These results indicate an enhanced DA receptor sensitivity at both pre- and post-synaptic sites.