Differential Effects Of Dopamine Research Articles

Differential effects of dopamine D1-like and D2-like receptor agonists on water drinking behaviour under thirsty conditions in mice with reduced dopamine secretion.

The mesolimbic dopamine system is important for reward-oriented behaviours, such as drinking and eating. However, the precise involvement of dopaminergic neurons and dopamine receptors in water drinking behaviour remains unclear. Here, we generated triple transgenic mice harbouring Slc6a3(DAT)-icre/ERT2, Camk2a-loxP-STOP-loxP-tetracycline transactivator and tetO-tetanus toxin constructs, in which the release of dopamine is blocked by tetanus toxin. These mice, referred to as dopamine secretion interference mice, had reduced dopamine secretion in the striatum (61.4%) and the nucleus accumbens (54.5%). They showed adequate limb strength and food consumption, similarly to control mice, but exhibited motor control impairment in a challenging rotarod test. Dopamine secretion interference mice made fewer licks and had fewer bursts than control mice during a licking test under thirsty conditions. To elucidate the influence of dopamine receptors in the altered drinking behaviour, a dopamine D1 or D2/D3 receptor agonist (A68930 or ropinirole, respectively) was administered prior to the licking microstructure analysis. Treatment with the D1 agonist restored the total number of licks but not the burst number in dopamine secretion interference mice. By contrast, the D2/3 agonist impeded water drinking behaviour in both transgenic and control mice. The present findings indicate that D1 receptor activation partially ameliorates the altered drinking behaviour of the dopamine secretion interference mice and suggest that D1 receptor activity impacts drinking under thirsty conditions.

S36. DIFFERENTIAL ENCODING OF SENSITIZATION AND CROSS SENSITIZATION TO PSYCHOSTIMULANTS AND ANTIPSYCHOTICS IN NUCLEUS ACCUMBENS D1- AND D2- RECEPTOR EXPRESSING MEDIUM SPINY NEURONS

BackgroundNearly half of all individuals diagnosed with schizophrenia abuse addictive substances such as cocaine. Currently, the neurobiological mechanisms in patients with schizophrenia that lead to cocaine abuse are unknown. A possible explanation for the co-morbidity between schizophrenia and addiction is that the rewarding properties of cocaine reverse the diminished motivational drive caused by chronic antipsychotic regimen. Moreover, chronic antipsychotic treatment can sensitize and amplify cocaine rewarding effects and exacerbate psychoses.MethodsThe rewarding properties of cocaine are attributed to the differential effects of dopamine on D1 and D2 receptor-expressing medium spiny neurons (MSNs) in the nucleus accumbens (NAc). Using in vivo Ca2+ miniature microscopic imaging, we characterize the role of D1 and D2 MSN in mono- and a cross- sensitization paradigms. D1- and D2-Cre mice were injected with a Cre dependent calcium indicator (gCaMP6f) and implanted with a gradient index (GRIN) lens above the nucleus accumbens and calcium activity was recorded using a head mounted miniature microscope. Cocaine sensitization was measured after a classic repeated cocaine regiment and antipsychotic and psychostimulant cross-sensitization was measured by a single cocaine injection after chronic pre-treatment with haloperidol.ResultsWe found that both D1-MSN and D2-MSN populations are modulated by initial cocaine experience and further modulated during the expression of cocaine sensitization. A subpopulation of D1-MSN displayed initial activation, but reduced activity during the expression of sensitization. By contrast, the majority of D2-MSNs were suppressed by initial cocaine experience, but became active during the expression of sensitization. Furthermore, activity of D1- and D2-MSNs bidirectionally related with the observed behavioral responses to cocaine. Cross-sensitization following haloperidol treatment led to increased behavioral responses to psychostimulants. Current experiments are set out to investigate the neuronal responses of D1 and D2-MSN during cross sensitization between haloperidol and cocaine.DiscussionCocaine sensitization leads to differential neuronal responses in D1- and D2-MSN and these responses are differentially correlated with the magnitude of the sensitized behavioral response. These results reveal important new insights in the neurobiological processes in the nucleus accumbens that underlie psychostimulant sensitization and provide an important new model for studying the pharmacology of antipsychotic effects on striatal function and its potential role in increasing the susceptibility of schizophrenic patients to developing drug addiction.

A novel IV cocaine self-administration procedure in rats: differential effects of dopamine, serotonin, and GABA drug pre-treatments on cocaine consumption and maximal price paid

Behavior occurring during cocaine self-administration can be classified as either consummatory or appetitive. These two concepts are usually addressed independently using separate reinforcement schedules. For example, appetitive behavior can be assessed with a progressive ratio schedule, whereas consummatory behavior is typically measured using a fixed ratio schedule. Depending on the schedule used, it is often difficult to determine whether a particular drug pretreatment is affecting self-administration through an effect on appetitive responding, consummatory responding, or perhaps both. In the present study, we tested the effect of pretreating rats with four different drugs on appetitive and consummatory behaviors. We recently developed a technique that provides an independent assessment of both behavioral concepts within the same experimental session. In this threshold procedure, rats are offered a descending series of 11 unit doses (422-1.3 μg/injection) during consecutive timed intervals under a fixed-ratio schedule. Consummatory behavior can be analyzed by assessing intake at high unit doses; an estimate of appetitive responding can be determined from responding occurring at the threshold dose. Applying behavioral economics to these data provides dependent measures of consumption when minimally constrained by price and the maximal price paid (P (max)) for cocaine. Haloperidol increased cocaine consumption when minimally constrained by price but decreased P (max). In contrast, D: -amphetamine increased P (max). Fluoxetine decreased P (max) and consumption when minimally constrained by price. Baclofen selectively decreased P (max). These data suggest that drug pretreatments can alter consummatory and appetitive behavior differently because each concept involves distinct neural mechanisms.

Differential effects of dopamine and opioid receptor blockade on motivated Coca-Cola drinking behavior and associated changes in brain, skin and muscle temperatures

Although pharmacological blockade of both dopamine (DA) and opiate receptors has an inhibiting effect on appetitive motivated behaviors, it is still unclear which physiological mechanisms affected by these treatments underlie the behavioral deficit. To clarify this issue, we examined how pharmacological blockade of either DA (SCH23390+eticlopride at 0.2 mg/kg each) or opioid receptors (naloxone 1 mg/kg) affects motor activity and temperature fluctuations in the nucleus accumbens (NAcc), temporal muscle, and facial skin associated with motivated Coca-Cola drinking behavior in rats. In drug-free conditions, presentation of a cup containing 5 ml of Coca-Cola induced locomotor activation and rapid NAcc temperature increases, which both transiently decreased during drinking, and phasically increased again after the cup was emptied. Muscle temperatures followed this pattern, but increases were weaker and more delayed than those in the NAcc. Skin temperature rapidly dropped after cup presentation, remained at low levels during consumption, and slowly restored during post-consumption behavioral activation. By itself, DA receptor blockade induced robust decrease in spontaneous locomotion, moderate increases in brain and muscle temperatures, and a relative increase in skin temperatures, suggesting metabolic activation coupled with adynamia. Following this treatment (∼180 min), motor activation to cup presentation and Coca-Cola consumption were absent, but rats showed NAcc and muscle temperature increases following cup presentation comparable to control. Therefore, DA receptor blockade does not affect significantly central and peripheral autonomic responses to appetitive stimuli, but eliminates their behavior-activating effects, thus disrupting appetitive behavior and blocking consumption. Naloxone alone slightly decreased brain and muscle temperatures and increased skin temperatures, pointing at the enhanced heat loss and possible minor inhibition of basal metabolic activity. This treatment (∼60 min) had minimal effects on the latencies of drinking, but increased its total duration, with licking interrupted by pauses and retreats. This behavioral attenuation was coupled with weaker than in control locomotor activation and diminished temperature fluctuations in each recording location. Therefore, attenuation of normal behavioral and physiological responses to appetitive stimuli appears to underlie modest inhibiting effects of opiate receptor blockade on motivated behavior and consumption.

Differential effects of dopamine D 2 and GABA A receptor antagonists on dopamine neurons between the anterior and posterior ventral tegmental area of female Wistar rats

Previous findings indicated differences in neuronal circuitries mediating drug reinforcement between the anterior and posterior ventral tegmental area (VTA). The objective of the present study was to examine the effects of the dopamine D 2 antagonist sulpiride and the GABA A antagonist picrotoxin administered in the anterior and posterior VTA on the activity of mesoaccumbal dopamine neurons in female Wistar rats. Sulpiride and picrotoxin were administered in the anterior and posterior VTA. Extracellular dopamine levels were measured in sub-regions of the VTA and nucleus accumbens (ACB). Reverse-microdialysis of sulpiride (100 µM) into the posterior VTA increased extracellular dopamine levels locally (80% above baseline) and in the ACB shell and core (70% above baseline), whereas reverse-microdialysis into the anterior VTA produced a much smaller effect locally (30% above baseline) and in the ACB shell and core. In contrast, microinjection of picrotoxin (80 and 160 µM) into the anterior, but not posterior VTA, increased dopamine release in the ACB shell. The results suggest that dopamine neurons in the posterior VTA, compared to the anterior VTA, may be under greater D 2 receptor-mediated tonic inhibition, whereas dopamine neurons in the anterior VTA, compared to the posterior VTA, may be under greater GABA A receptor-mediated tonic inhibition.

Differential effects of dopamine and AMPA receptor antagonists on the expression of conditioned avoidance responding in rats.

AMPA receptor antagonists disrupt avoidance responding, but their day-to-day effect on this behavior has not been elucidated. This study compared the multisession effect of the AMPA/kainate receptor antagonist CNQX with that of the typical antipsychotic haloperidol on the expression of avoidance responding. Rats (N = 199) were trained to move to safety on presentation of a tone in one-way active conditioned avoidance and were tested across 5 sessions. Intracerebroventricular (icv) injection of CNQX (20-min injection-test interval) produced a dose-dependent, immediate block of avoidance responding, compared with the extinction-like decline of avoidance responding produced by haloperidol (intraperitoneal [ip], 60-min injection-test interval; icv, 60 but not 20-min injection-test interval). Previous exposure to CNQX significantly reduced its efficacy, illustrating that its effects may not be specific to the conditioned safety-related stimuli that control responding in conditioned avoidance, as proposed for antidopaminergic compounds. The new multisession profile of disrupted avoidance responding illustrated by CNQX suggests different roles for glutamatergic and dopaminergic neurotransmission in conditioned avoidance responding. Results are consistent with a role for AMPA receptors in maintaining the expression of learning.

Differential effects of dopamine on pain-related electric activities in normal rats and morphinistic rats

To investigate the influence of dopamine (DA) and DA receptor's antagonist on the transmission of noxious information in the central nervous system of normal rats or morphinistic rats. The influence of DA on the electric activity of the pain-excited neuron (PEN) in the caudate nucleus (Cd) of normal rats or morphinistic rats was recorded after the sciatic nerve was noxiously stimulated. DA shortened the average latency of the evoked discharge of PEN in the Cd of normal rats, indicating that DA could increase the activity of PEN and pain sensitivity in normal rats. This effect could be inhibited by Droperidol. DA increased the average latency of the evoked discharge of PEN in the Cd of morphinistic rats, indicating that DA could inhibit the activity of PEN and pain sensitivity in morphinistic rats. The responses to painful stimulation were completely opposite between normal rats and morphinistic rats after the intracerebroventricular injection of DA.

Differential effects of dopamine and psychoactive drugs on dopamine transporter phosphorylation and regulation

The dopamine transporter (DAT) is a phosphoprotein whose activity and phosphorylation state are acutely regulated by both protein kinase C (PKC) and substrate transport. DAT is a major site of action for psychostimulant and therapeutic drugs that either block transport or are transported substrates, but the effects of such drugs on DAT phosphorylation and regulation are not well understood. To examine these issues we subjected rDAT LLC-PK 1 cells to acute in vitro pretreatments with the endogenous, psychostimulant, and therapeutic compounds dopamine (DA), (−)-cocaine, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane (β-CFT), GBR 12909, mazindol, and methylphenidate (MPH), in the presence or absence of the PKC activator phorbol 12 myristate 13 acetate (PMA), followed by analysis of DAT metabolic phosphorylation and transport activity. Basal phosphorylation of DAT was not affected by any of the uptake blockers tested, and PMA-stimulated phosphorylation was not affected by cocaine, β-CFT, mazindol or MPH, but was strongly suppressed by GBR 12909. Pretreatment of cells with cocaine or MPH had no effect on subsequent DA transport activity or the extent of PMA-induced transport down-regulation, whereas GBR 12909 inhibited PMA-induced DAT internalization. These findings indicate that these DAT phosphorylation and down-regulation properties are unaffected by some classes of uptake blocking drugs, but that differential regulatory effects may be exerted by GBR compounds. Pretreatment of cells with DA had no obvious effect on basal or PMA-stimulated DAT phosphorylation but led to cocaine-blockable transport down-regulation. DA-induced down-regulation was blocked by the PKC inhibitor bisindoylmaleimide I and was not additive with down-regulation induced by PMA, consistent with PKC serving as a common step and point of integration for these DA and PMA induced processes. The results of this study provide information on the potential for endogenous and psychoactive compounds to modulate or be modulated by DAT phosphorylation-mediated regulatory mechanisms that may contribute to drug behavioral or therapeutic properties.

Differential effect of dopamine on mitosis in early postnatal albino and pigmented rat retinae

Insufficient levels of L-DOPA, released from the retinal pigment epithelium (RPE), in albino animals are considered responsible for the abnormal development of the underlying neural retina. L-DOPA normalizes retinal neurogenesis by reducing levels of cell proliferation either by acting on the cells directly or by being converted into dopamine. Here we report the effects of dopamine on mitosis in early postnatal neural retinae from albino and pigmented rats, using 4D (x, y, z and time) confocal microscopy. Exogenous dopamine significantly prolongs mitosis in retinae from albino, but not pigmented, animals. As fewer cells move into and divide in the ventricular zone (VZ) in the presence of dopamine, we conclude that the overall cell cycle is affected. The D1 receptor blocker, SCH 23390, inhibits these effects. Thus, the differential effects of dopamine on neural retinae from pigmented and albino rats in vitro must result from the activation of D1 receptors, which are present in the retina from birth. Immunohistochemical labeling of D1 receptors shows that the pattern of their distribution is similar between pigmentation phenotypes, but levels of expression may be elevated in albinos. Labeling is most intense in the inner plexiform layer but is present throughout the neuroblastic layer. These findings are discussed in light of previous reports of reduced catecholamine levels in the albino retina.

Differential effects of dopamine on a potassium current in cultured rutabaga and wild‐type Drosophila cells

AbstractThe rutabaga mutation which has a low intracellular cyclic adenosine monophosphate (cAMP) concentration is defective in short‐term memory. The aim of this study was to compare modulation effects of dopamine on the delayed‐rectifier potassium current (IKDR) in rutabaga and wild‐type Drosophila neurons. The conventional whole‐cell patch‐clamp technique was applied to cultured Drosophila neurons derived from embryonic neuroblasts. IKDR was measured from cultured (2 days) wild‐type and rutabaga neurons. IKDR was smaller in rutabaga neurons (373 ± 38 pA) than in wild‐type neurons (519 ± 40 pA) but there was no difference in IKDR activation in wild‐type inactivation between the two genotypes. We examined the effects of dopamine on IKDR in wild‐type and rutabaga neurons. IKDR was measured from neurons before and after addition of dopamine to the external solution. Dopamine application reduced IKDR in wild‐type neurons but did not significantly affect IKDR in rutabaga neurons (single‐cell studies). In the presence of dopamine there was no difference in IKDR between wild‐type (344 ± 29 pA) and rutabaga (338 ± 27pA) neurons (population studies). These results indicate that dopamine differentially affects the delayed‐rectifier channel in wild‐type and rutabaga neurons. This can alter neuronal excitability in rutabaga and may affect the processing of neural signals necessary for learning and memory.

Differential effects of dopamine on two frog melanotrope cell subpopulations.

The frog intermediate lobe consists of a single endocrine cell type, the melanotrope cells, which are under the tonic inhibitory control of dopamine. Separation of dispersed pars intermedia cells in a Percoll density gradient has revealed the existence of two melanotrope cell subpopulations, referred to as high-density (HD) and low-density (LD) cells. The aim of the present study was to investigate the effects of dopamine on each of these melanotrope cell subsets. Increasing doses of dopamine, ranging from 10(-9)-10(-6) M, inhibited the release of alpha-melanocyte-stimulating hormone (alpha-MSH) in LD (but not in HD) melanotrope cells. In addition, dopamine provoked a significant reduction of the rate of acetylation of alpha-MSH in LD cells but not in HD cells. Similarly, dopamine significantly decreased the accumulation of POMC messenger RNA in LD cells, whereas it did not affect POMC gene expression in the HD melanotrope subset. On the other hand, microfluorimetric studies revealed that dopamine induced a significant reduction of KCl-stimulated cytosolic free calcium concentration in both LD and HD cells. The present study provides additional evidence for functional heterogeneity of melanotrope cells in the frog pars intermedia. Because dopamine plays a pivotal role in the regulation of alpha-MSH secretion, these data suggest the involvement of cell heterogeneity in the physiological process of background color adaptation in amphibians.

Differential Effects of Dopamine on Two Frog Melanotrope Cell Subpopulations

Differential Effects of Dopamine on Two Frog Melanotrope Cell Subpopulations

Iontophoresis in the neostriatum of awake, unrestrained rats: Differential effects of dopamine, glutamate and ascorbate on motor- and nonmotor-related neurons

The neostriatum and its major afferent transmitters, dopamine and glutamate, play a critical role in behavior, but relatively little information is available on their postsynaptic effects in behaving animals. As a first step in addressing this shortcoming, single-unit electrophysiology was combined with iontophoresis in the neostriatum of awake, unrestrained rats. Relative to periods of quiet rest, most neurons (58 of 77) changed discharge rate in close temporal association with movement, while the remainder showed no such relationship. When animals resumed a resting posture, iontophoretic current-response curves were established for dopamine and glutamate as well as for ascorbate, a modulator of neostriatal function released from glutamatergic terminals. Application of either glutamate or ascorbate produced current-dependent increases in activity in all neurons, although this effect was somewhat less pronounced for nonmotor cells. In both types of neurons, the excitatory effect of ascorbate either diminished or shifted to an inhibition at high ejection currents. Dopamine, on the other hand, routinely excited motor-related, but inhibited nonmotor-related neurons. Further assessment of motor-related neurons revealed that in most cases the excitatory effects of either glutamate or dopamine alone were supra-additive when these compounds were either administered together or co-administered with ascorbate. Our results suggest that the response of neostriatal neurons to glutamate or dopamine depends, at least in part, on the motor responsiveness of these cells. Motor-related neurons, moreover, respond to the co-administration of glutamate and dopamine with synergistic increases in firing rate. Ascorbate also influences neostriatal activity, but the postsynaptic action of this substance cannot be explained as a simple interaction with either glutamatergic or dopaminergic mechanisms.

Differential effects of dopamine D 2 agonist quinpirole upon the dorsal immobility response in rats

The effects of various dose levels of systemically injected quinpirole upon the dorsal immobility response (DIR) over a time course was investigated in male rats. A low dose of quinpirole (0.01 mg/kg) significantly attenuated the duration of the DIR following the 10-min interval, whereas the highest dose (1.0 mg/kg) had a biphasic effect so that at the 10-min interval the duration of the DIR was significantly potentiated and at the 60-min interval the duration of the DIR was significantly attenuated. The intermediate dose (0.1 mg/kg) had intermediate behavioral effects. The data support the growing evidence that quinpirole has differential effects upon behavior over time as a function of the dose levels. The present data were discussed in reference to presynaptic and postsynaptic dopamine D 2 receptor theory.

D 1 and D 2 Dopamine Receptor-regulated Gene Expression of Striatonigral and Striatopallidal Neurons

The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.

Differential effects of dopamine on glucoregulatory hormones in rats

The effect of dopamine at different doses on serum concentrations of insulin, glucose and corticosterone and on plasma glucagon concentration was investigated in rats. Dopamine was given intravenously over 6 h with infusion rates of 2.5, 7.5, 15, and 60 μg/kg · min and in combination with phentolamine. Serum insulin concentration was unchanged at low doses of dopamine. It was significantly increased from 6.0 ± 0.7 ng/ml to 13.7 ± 2.3 ng/ml ( P < 0.01) when 7.5 μg/kg · min of dopamine were used, whereas it was significantly depressed to 3.96 ± 0.89 and to 4.0 ± 0.34 ng/ml ( P < 0.01), respectively, at the high doses of dopamine. This latter effect could be reversed to 6.7 ± 1.19 ng/ml and inverted to 9.2 ± 1.7 ng/ml ( P < 0.01) by simultaneously applied phentolamine at appropriate dosages. Serum glucose levels were markedly elevated from 154 ± 7 to 234 ± 42 mg/dl ( P < 0.01) by the higher doses of dopamine. A significant alteration of glucagon plasma concentrations from 18.9 ± 2.8 to 42.3 ± 14 pg/ml ( P < 0.01) was elicited only by 7.5 μg/kg · min of dopamine. The data clearly demonstrate that exogenous dopamine acts differently on glucose homeostasis according to the dosage. The study provides strong evidence that dopamine decreases insulin levels via α-adrenergic receptor stimulation. This effect may contribute to the deterioration of glucose homeostasis with high doses of dopamine.

Differential effects of dopamine D-1 and D-2 receptor agonists on eeg activity and behaviour in the rabbit

SKF 38393, a selective agonist for dopamine D-1 receptors, LY 171555, a selective agonist for D-2 receptors and apomorphine, an agonist for both receptor sites, all induced activation of the electrical activity of the brain (EEG) in the rabbit. While SKF 38393 induced EEG changes without concomitant signs of stereotyped behaviour, the injection of both LY 171555 and apomorphine also elicited marked behavioural effects, mostly stereotyped mouth and head movements. The EEG effects of SKF 38393 were prevented by SCH 23390 (0.003 mg/kg i.V.), but not by (−)-sulpiride (6.2–25 mg/kg i.V.). Haloperidol attenuated the effects induced by SKF 38393 only at a dose (1 mg/kg) that induced EEG changes of its own. Similarly, effects of apomorphine on both EEG and behaviour were prevented by SCH 23390 and to a lesser extent by haloperidol, but not influenced by (−)-sulpiride. Different patterns of interactions were observed when D-2 receptors were selectively stimulated by LY 171555. Behavioural effects induced by LY 171555 were fully inhibited by both (−)-sulpiride (6.2–12.5 mg/kg i.v.) and haloperidol (0.1–0.3 mg/kg i.v.). The drug SCH 23390 attenuated some behavioural components at 0.3 mg/kg (i.v.), a dose at least 100-fold that effective on the EEG effects induced by SKF 38393. However, all these antagonists exerted weak or no effects on EEG activation induced by LY 171555 and did not restore the control patterns at any doses examined. These data indicate that the population of D-1 receptors is strongly involved in the regulation of EEG and behavioural arousal, while D-2 receptors appear to be mostly involved in mediating stereotyped movements. Based on the findings with apomorphine, it is also suggested that D-1 and D-2 receptors are functionally inter-related, with D-1 receptors playing a prominent role in the modulation of the EEG and in behavioural arousal.

Differential effects of dopamine D 1 and D 2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse : Implications for the roles of D 1 and D 2 receptors

A system combining visual recording of rearing and grooming, with automatic measurement of slow and fast components of locomotion, was examined for its suitability as a means of studying the effects on behaviour of conventional and novel dopaminergic drugs in the mouse. Amphetamine (0.1–10 mg kg ) selectively stimulated fast movements and affected rearing bimodally. Apomorphine (0.01–5 mg kg ) influenced locomotion polyphasically, depressing fast movements and enhancing slow ones, and producing parallel changes in rearing. Both drugs reduced grooming monotonically. A dose of apomorphine (25 μg kg ) which is considered to act presynaptically produced haloperidol-resistant sedation, while a larger dose (0.5 mg kg ; with postsynaptic actions) evoked head-down sniffing and ponderous walking that were partially prevented by pretreatment with 0.05 mg kg haloperidol (D 2 blocker), but not 0.01 mg kg SCH 23390 (D 1 blocker). The behavioural effects of haloperidol (0.2–0.4 mg kg ) and SCH 23390 (0.05 mg kg ) were indistinguishable; both drugs caused sedation and inhibited all forms of motor activity. Small doses of SCH 23390 (2–10 μg kg ) and large doses of the D 1 agonist SKF 38393 (3–10 mg kg ) evoked excessive grooming. The drug SKF 38393 (1–30 mg kg ) had no other effects on motor behaviour, whereas the whole spectrum of pre- and postsynaptic motor responses produced by apomorphine could be duplicated with the D 2 agonist RU24213 (0.05–15 mg kg ). The differential sensitivity of fast and slow components of locomotion to treatment with drug suggests these are qualitatively distinct responses. The results implicate D 2 receptors in the mechanisms of locomotion and rearing, and D 1 receptors in the expression of grooming.

Resumption of prolactin secretion after dopaminergic inhibition: differential effects of dopamine and its agonists.

The recovery of prolactin (PRL) secretion following dopaminergic inhibition was studied in vitro using pituitary monolayer cultures. PRL secretion over 4 h was inhibited comparably by 10(-6) M dopamine (DA), 10(-7) M apomorphine (APO), and 10(-10) M bromocriptine (45%, 42%, 51%, respectively) with reciprocal increases in intracellular hormone content. After drug removal, the PRL secretion rate in the cultures that had been treated with DA was 208% of the control cultures by the 2nd h but returned to control values by 4 h, whereas the secretion rate after APO was 131-142% of control throughout the 4-h recovery period. In contrast, PRL secretion remained significantly less than control 20 h after the removal of bromocriptine. Although haloperidol (10(-7) M) prevented the inhibitory action of bromocriptine when added simultaneously, the addition of haloperidol did not restore PRL secretion when added in the posttreatment period. Thus, DA and APO inhibition of PRL release is readily reversible and is followed by early PRL hypersecretion. However, bromocriptine's effects are sustained and once started are not reversed by DA antagonists.

Dopaminergic mechanisms and luteinizing hormone (LH) secretion. II. Differential effects of dopamine and bromocriptine on LH release in normal women.

After our observation of the failure of bromocriptine to inhibit LH secretion in hyperprolactinemic women, we have investigated the effects of bromocriptine and dopamine (DA) on LH secretion in normal ovulatory women within 5 days of the midcycle LH peak. Both bromocriptine (2.5 mg, orally) and DA (4 micrograms/kg . min, iv) for 4 h lowered serum PRL levels by more than 80%. Bromocriptine was ineffective in suppressing LH secretion and, in fact, resulted in a slight but significant stimulation, while, in contrast, DA was effective in lowering circulating LH levels by approximately 30% and reducing spontaneous LH fluctuations. The dissociation of the effects of these two dopaminergic agents on LH secretion may be explained by the existence of multiple DA receptors. The slight stimulatory effect of bromocriptine might be due to a preferential presynaptic action of bromocriptine inhibiting endogenous DA secretion in the hypothalamus and thus reducing this catecholamine's tonic inhibitory influence on LH secretion.