Maternal exposure to diphenhydramine during the fetal period in rats: effects on physical and neurobehavioral development and on neurochemical parameters

Previous research from our laboratory suggested that the administration of antihistaminics (H(1) receptor antagonists) to pregnant Wistar rats throughout pregnancy altered brain sexual differentiation and dopaminergic physiology of the offspring. In the present study, we assessed the effects of 20 mg/kg diphenhydramine (DPH) administration to pregnant rats during the fetal period of pregnancy [Gestation Days (GDs) 16-21], a critical period for brain sexual differentiation and central nervous system (CNS) maturation. Maternal body weight and water and food consumption were measured during pregnancy and offspring physical and behavioral development were evaluated during lactation. Offspring open-field behavior was assessed at 21 and 100 days of age. After the final open-field test, male and female sexual behavior, stereotypy following an apomorphine challenge, striatal content of dopamine (DA), the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), serotonin (5-HT) and the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) were assessed. There were no significant treatment-related changes in maternal reproductive parameters, but DPH treatment decreased maternal body weight gain during the treatment period. Offspring physical parameters were not altered in the treated group, and no significant treatment-related changes were found in female open-field measures, sexual behavior or in striatal neurochemical measurements. However, delayed testis descent and altered patterns of sexual behavior occurred in male offspring accompanied by increased striatal DA, decreased striatal DOPAC as well as reduced DOPAC/DA, HVA/DA and 5-HIAA/5-HT ratios. Taken together, these data suggest that exposure to DPH during the fetal period of rat development altered postnatal CNS maturation and sexual development of male offspring via changes in striatal bioamine systems.     

Effects of estrogen on striatal dopamine receptor function in male and female rats

The present study compares, biochemically and behaviorally, the effect of estrogen on central dopamine (DA) function in male and female rats. Estrogen has no direct effect in vitro on DA receptors from striatal tissue of male or female rats. In vivo administration of 17β-estradiol valerate to male or long-term ovariectomized female rats significantly increases the density of the striatal DA receptors by about 20 percent. Behaviorally, normal female rats have more intense stereotypy produced by apomorphine (APO stereotypy), regardless of the phase of their estrous cycle, than normal male rats, while the density of striatal DA receptors is equal. Estrogen administration to male rats increases their APO stereotypy. Normal intact female rats have no changes in APO stereotypy after the administration of estrogen. However, ovariectomy of female rats increases APO stereotypy, and estrogen administration decreases APO stereotypy back to the levels observed in normal intact female rats. In the male rat there is a good correlation between the increased striatal DA receptor density and the increased APO stereotypy, but in the female rat factors other than striatal DA receptor density appear to the important in the regulation of APO stereotypy.     

Role of dopamine receptors in the occurrence of the behavioral motor disturbances in rats exposed to high pressure.

When human divers and experimental animals are exposed to an increasing environmental pressure, they develop the high pressure neurological syndrome (HPNS) characterized by electroencephalographic changes and sleep and behavioral disturbances. In rats, behavioral disturbances essentially include hyperlocomotor activity (HLA), tremor and myoclonia. Moreover, HLA has recently been demonstrated to be linked to a pressure-induced striatal increase of dopamine (DA). In these experiments, it was proposed to investigate in rats, at the behavioral level, the role of DA receptors in the occurrence of the pressure-induced DA disturbances. DA receptor agonists were found to induce no significant changes in the development of HLA, tremor, and myoclonia. Alternatively, HLA was found to be dramatically antagonized by the use of DA receptor antagonists (SCH 23390, sulpiride, and haloperidol), while tremor and myoclonia only decreased in SCH 23390 experiments.     

Seroquel: biochemical profile of a potential atypical antipsychotic

Seroquel and the atypical antipsychotic clozapine were compared using a number of biochemical measures in rats which are indicative of potential antipsychotic activity and possible extrapyramidal side effect liability. Both in vitro and in vivo, these compounds are low potency D-2 dopamine (DA) receptor antagonists and are relatively more potent 5-HT₂ antagonists than typical antipsychotic drugs. Seroquel also exhibited low affinity for D-1 DA receptors in vitro, but D-1 receptor occupancy was not detectable in vivo. Unlike clozapine, Seroquel lacks appreciable activity at either D-1 DA or muscarinic receptors. Following IP administration, both compounds produce similar elevations in DA metabolite concentrations. Following 1 month of daily administration, at doses which produce large increases in striatal DA metabolite concentrations, both Seroquel and clozapine fail, unlike typical antipsychotics, to increase the number of striatal D-2 receptors, but do decrease the number of 5-HT₂ receptors in frontal cortex. ICI 204,636 produces a short-lasting increase in plasma prolactin levels, but these increases are much greater than those that are produced by clozapine. One day after 3 weeks of daily administration, tolerance, to the ability of Seroquel to elevate DA metabolite and plasma PRL concentrations is not observed. These biochemical observations are discussed with regard to the atypical profile of Seroquel in behavioral and electrophysiological studies.     

The intrinsic activities of the partial dopamine receptor agonists (-)-3-PPP and TDHL on pituitary dopamine receptors are lower in female than in male rats

The abilities of the mixed agonists/antagonists on dopamine (DA) receptors, (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [-)-3-PPP) and transdihydrolisuride (TDHL), to suppress serum prolactin levels in acutely hyperprolactinemic male and female rats were investigated. gamma-Butyrolactone was used to deplete endogenous DA and raise serum prolactin concentrations. Both (-)-3-PPP and TDHL were found to cause sexually differentiated responses: (-)-3-PPP reduced serum prolactin levels dose dependently and effectively in males but caused only a modest decrease of prolactin release in females. Moreover, (-)-3-PPP antagonized the prolactin-suppressing effects induced by the DA receptor agonist (+)-3-PPP in females. Likewise TDHL decreased prolactin secretion markedly in males while it had only slight effects in females. It can be concluded from these results that the intrinsic activities of the partial DA agonists (-)-3-PPP and TDHL are lower in female than in male rats, suggesting a reduced responsiveness of hypophyseal DA receptors in females. Since DA levels in the pituitary portal circulation are higher in female than in male rats, this study gives further support to the hypothesis claiming an inverse relationship between the intrinsic activity of a mixed agonist/antagonist and the degree of previous stimulation of its receptor.     

Effects of postnatal PCP treatment on locomotor behavior and striatal D2 receptor

Exposing the developing brain to the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has been shown to cause deficits in neurobehavioral functions, particularly on learning and memory and seizure sensitivity. Besides acting as a noncompetitive NMDA antagonist, PCP at high doses is known to affect the dopaminergic system. The present study assessed the effect of postnatal PCP treatment on locomotor activity and striatal dopamine (DA) D(2) receptor. Male and female rat pups were injected intraperitoneally (i.p.) with one of three doses of PCP (1, 3 and 5 mg/kg) or saline from postnatal day (PD) 5 to PD 15. Control and PCP-treated rats were given a challenge dose of PCP (10 mg/kg) as adults, and their locomotor behaviors--locomotion, stereotypy and ataxia--were scored. Postnatal PCP treatment did not have any significant effect in either sex on any of the PCP-induced locomotor behavioral paradigms studied. Separate groups of male and female rats were treated daily with saline or PCP (5 mg/kg i.p.) from PD 5 to PD 15 and sacrificed either as juveniles (PD 21) or adults, and D(2) receptor binding was measured in their striata. Striatal D(2) receptor density in juvenile and adult male postnatal PCP-treated rats did not differ from saline-treated controls. Adult female PCP-treated rats showed a slight but significant reduction in the maximal binding of striatal D(2) receptors. There was no effect of postnatal PCP on striatal D(2) receptor binding in female juvenile rats. These results support the hypothesis that blocking the developing NMDA receptor minimally affects PCP-induced locomotor behavior and the striatal D(2) receptor.     

Resolved cis- and trans-2-amino-5-methoxy-1-methyltetralins: central dopamine receptor agonists and antagonists

A series of 35 stereochemically well-defined C1-methyl-substituted derivatives of the potent dopamine (DA) receptor agonist 5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-DPAT) have been synthesized. The compounds were tested for central DA receptor agonistic and antagonistic activity, by use of biochemical and behavioral tests in rats. In addition, the compounds were tested for in vivo interactions with 5,6-dihydroxy-2-(di-n-propylamino)tetralin (DiPr-5,6-ADTN). On the basis of pharmacological activity profiles, the active compounds have been classified into four groups: classical pre- and postsynaptic DA receptor agonists, DA receptor agonists with preferential action at presynaptic receptors, pre- and postsynaptic DA receptor antagonists, and DA receptor antagonists with preferential action at presynaptic receptors. Results obtained indicate that both 2R and 2S enantiomers of C5-oxygenated 2-aminotetralins may be able to bind to DA receptors but that only 2S antipodes are able to activate the receptors. O-Methylation of the C5-oxygenated (1S,2R)-2-amino-1-methyltetralin derivatives tends to increase their DA receptor antagonistic activity, whereas decrease of the size of the N-substituent(s) from n-propyl to ethyl or methyl appears to increase their activity at postsynaptic DA receptors.     

Absence of postsynaptic DA2 dopamine receptors in the dog renal vasculature.

In experiments designed to look for functional postsynaptic DA2 dopamine receptors in the dog renal vasculature, the vascular effects of two selective DA2 receptor agonists, bromocriptine and quinpirole, were studied in pentobarbital-anesthetized dogs. Intra-arterial (i.a.) injections of bromocriptine reduced renal blood flow before and after blockade of alpha-adrenoceptors. I.a. quinpirole produced dose-related increases in renal blood flow which were not altered by blockade of alpha- or beta-adrenoceptors or DA1 dopamine receptors. Neither of the selective DA2 dopamine receptor antagonists, domperidone or YM 09151-2, altered the renal vascular effects of quinpirole, but these were reduced by combined H1 and H2 histamine receptor blockade. The results of these experiments do not support the existence of postsynaptic DA2 dopamine receptors mediating vasodilation in the canine renal vasculature.     

Effect of desipramine during infancy and preweanling on dorsal striatal dopamine D1 and D2 receptor binding in adolescence in the rat.

Desipramine, a monoamine uptake inhibiting antidepressant, was given once a day sc from the 6th to the 22nd postnatal days, which is during infancy and preweanling in ontogenesis, to rats and its effects on dorsal striatal dopamine D1 and D2 receptor binding in adolescence were examined. The rats were decapitated, their dorsal striata were dissected on approximately the 34th postnatal day, and the maximal densities (Bmax) and affinities (Kd) of dopamine D1 and D2 receptors were assayed using [3H] SCH 23390 and [3H] spiperone as ligands. Desipramine did not affect the densities or affinities of dopamine D1 or D2 receptor binding, and tended to increase the D1/D2 density ratio. The Bmax of dopamine D2 receptors was higher in male than in female rats (p<0.01), the D1/D2 Bmax ratio tended to be lower in male than in female rats (p<0.07), and the Kd for D1 receptors tended to be lower in male than in female rats (p<0.05). There was no interaction between treatment and gender. We conclude that desipramine given at infancy and preweanling increases the susceptibility of adolescent rats to behavioral effects of dopamine agonists with an optimal, and relatively high SCH 23390/spiperone binding site density ratio. Furthermore, gender differences in dorsal striatal spiperone binding site densities, SCH 23390/spiperone density ratio, and SCH 23390 affinities may render male rats more vulnerable than female rats to expression of excessive stereotyped behavior.     

Serotonergic innervation of the rat caudate following a neonatal 6-hydroxydopamine lesion: an anatomical, biochemical and pharmacological study

6-Hydroxydopamine (6-OHDA) treatment of neonatal rats resulted in a dose-related loss of striatal dopamine (DA). These reductions corresponded closely with the loss of tyrosine hydroxylase-containing terminals at this brain site. Striatal serotonin (5-HT) concentration increased only after DA was maximally depleted by the highest dose of 6-OHDA. Quantitative immunohistochemistry revealed that the increased 5-HT content after neonatal 6-OHDA lesioning was due to a proliferation of 5-HT nerve terminals. The density of immunoreactive 5-HT-containing terminals appeared to increase more than did the 5-HT content. The present study examined whether 5-HT hyperinnervation was playing a role in behavioral responses induced by D1-DA agonists and antagonists in neonatally lesioned rats, because reports have suggested that these drugs may interact with 5-HT receptors. However, SCH-23390, the D1-DA antagonist (0.3 mg/kg), did not alter behavioral responses to 5-HTP and SKF-38393 (3 mg/kg), a D1-DA agonist did not produce any signs of activating 5-HT receptors in 5,7-DHT-lesioned rats. These data indicate that these compounds affecting D1-DA receptors do not have a significant effect on 5-HT function at doses which have maximal effects on D1-DA receptor function. Pretreatment with the 5-HT antagonist methysergide did not produce a change in apomorphine-induced locomotion and did not antagonize the self-mutilation or the other behaviors produced by L-DOPA or SKF-38393 in neonatally lesioned rats, suggesting that 5-HT hyperinnervation is not responsible for these drug-induced changes in neonatal 6-OHDA-lesioned rats.     

Independent mediation of unconditioned motor behavior by striatal D1 and D2 receptors in rats depleted of dopamine as neonates

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D₁ and D₂ receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at the level of striatal DA terminals and their targets. The ability of bilateral intrastriatal injections (0.5 µl) of DA receptor antagonists to induce motoric deficits was determined in adult rats treated with vehicle or 6-OHDA (100 µg, intraventricular) on postnatal day 3. Administration of the D₁-like antagonist SCH 23390 (0.5–2.0 µg) or the D₂-like antagonist clebopride (1.0–4.0 µg) induced dose-dependent akinesia, catalepsy, and somatosensory neglect in vehicle-treated controls. In contrast, neither antagonist produced deficits in rats depleted of forebrain DA as neonates. However,combined administration of SCH 23390+clebopride induced similar akinesia, catalepsy, and somatosensory neglect in both controls and DA depleted animals. Animals depleted of DA were more sensitive than controls to the low doses of this combined D₁+D₂ antagonism. These results demonstrate that activation of striatal DA receptors remains necessary for unconditioned motor behavior in rats depleted of DA as neonates. However, the specific contributions of D₁- and D₂-like receptors to these behaviors differ between intact animals and those depleted of DA as neonates. The ability of endogenous DA acting at either D₁ or D₂ receptors to support spontaneous motor behavior in rats depleted of DA as neonates may contribute to their relative sparing from parkinsonian deficits.     

Dopaminergic modulation of oscillatory network inhibition in the rat basolateral amygdala depends on initial activity state

The amygdala receives dopaminergic innervation, and dopamine (DA) enhances various activities in cognitive and emotional behaviors. Periodic bursts of spontaneous inhibitory postsynaptic currents (IPSCs) with a low (<1 Hz) inter-event frequency have been observed in projection neurons of the basolateral nucleus of the amygdala (BL). Blockade of ionotropic glutamate receptors or GABA_A receptors abolishes these oscillatory IPSC bursts in the BL, suggesting that the activity has a network origin. Here, we investigated dopaminergic modulation of the oscillatory network inhibition in rat brain slices. We evaluated the effects of DA receptor agonists and antagonists on the network inhibition; the resultant changes were quantified by integrated power spectral density (0.1-3.0 Hz). DA enhanced the power when its initial activity was low, but reduced it when the activity was initially robust. These changes in the power were accompanied by changes in burst IPSC amplitude. D1-like receptor agonist SKF 38393, or DA together with the D2-like receptor antagonist sulpiride, reproduced DA’s facilitatory actions. D2-like receptor agonist quinpirole did not change the periodic IPSC burst activity of the high baseline power, though D₄ receptor agonist PD 168077, or DA together with the D1-like receptor antagonist SCH 23390, reduced its activity. These results suggest that: 1) dopaminergic modulation of the oscillatory network inhibition depends on its initial activity; and 2) facilitatory and suppressing effects of DA in the BL are mediated by D1-like receptors and D₄ receptors, respectively.     

Differential affinity of dopaminergic agonists and antagonists for D1 and D2 dopamine receptors in rat striatum

Dopamine (DA) receptors have been classified into two types, D1 and D2, on the basis of their pharmacological specifities and localization. We now report that lesions of striatal dopaminergic neurons by kainic acid (KA) injection or cerebral neocortex (CN) ablation, differentially affect the potency of DA agonists and antagonists in displacing 3H-spiroperidol specific binding. In particular, agonists show a preferential affinity in displacing 3H-spiroperidol from those receptors situated on intrastriatal neurons, following CN lesion. On the other hand, antagonists show a higher displacing activity for those receptors mainly located on cortical terminals following KA lesion. These data support the hypothesis of the existence of different types of DA receptors with a differential anatomical location.     

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.     

Estrogen treatment enhances dopamine receptor sensitivity in the rat striatum

Estrogen (125 μg/rat) was administered, subcutaneously, to male rats six days before measurements were made. Estrogen treatment increased the number of dopamine receptor sites labeled by [³H]spiroperidol in vitro and the intensity of stereotypy induced by dopamine agonists in vivo. These two measures suggest that estrogen administration significantly influences the number of striatal DA receptors and a response to in vivo striatal DA receptors stimulation.     

The effect of drugs altering striatal dopamine levels on apomorphine induced stereotypy

Drugs that increase or decrease striatal dopamine levels appear to affect apomorphine induced stereotypy. This finding was unexpected, as it has previously been maintained that drugs which exert any action on striatal DA terminals exclusively would affect only indirect dopaminergic agonists, as opposed to apomorphine which induces stereotypy by acting directly on postsynaptic dopamine receptors. Specifically, inhibiting intrastriatal dopamine levels inhibits this behavior. This effect is explained in terms of apomorphine having a greater intrinsic activity and agonist affinity for striatal dopamine receptors than dopamine itself. Thus, dopamine and drugs which promote its release, may diminish the central behavioral effects induced by apomorphine relative to drugs which inhibit dopamine release centrally.     

Muscarinic receptor-mediated regulation of OM-853-enhanced dopamine release in striatum of rat

The effect of OM-853, a new vincamine analogue, on cerebral dopaminergic neurons was investigated in male Wistar rats. The administration of OM-853 (200 mg/kg p.o.) induced facilitation of the metabolic turnover of dopamine (DA) in all brain areas except the cerebral cortex. Addition of OM-853 enhanced the release of [3H]DA from striatal slices; this release was antagonized by atropine (10(-7) M). However, pretreatment with scopolamine (0.5 mg/kg s.c.) inhibited the enhancement of striatal DA turnover induced by OM-853 administration. OM-853 (10(-4) M) inhibited [3H]quinuclidinyl benzilate binding to muscarinic cholinergic receptors in a striatal particulate fraction more potently than carbachol (10(-4) M). These results suggest that OM-853 may induce facilitation of striatal DA turnover by enhancing DA release via the stimulation of muscarinic cholinergic receptor.     

Nigrostriatal dopaminergic denervation enhances dopamine D(4) receptor binding in rat caudate-putamen.

Radioligand binding to dopamine (DA) D(4) receptors was examined in adult rat forebrain 5 weeks after unilateral 6-hydroxydopamine (6-OHDA) lesioning of substantia nigra to remove ascending nigrostriatal dopaminergic projections. D(4) receptor binding was increased by up to 47% in denervated caudate-putamen (CPu) in rats that rotated away from the lesioned side with apomorphine challenge, with lesser changes in rats that failed to rotate with apomorphine. Functional significance of D(4) receptor upregulation induced by the lesions was investigated by examining behavioral effects of the highly selective D(4) agonist CP-226,269 and antagonist CP-293,019. Neither agent induced rotation at doses as high as 30 mg/kg ip. Pretreatment with the D(4) antagonist CP-293,019 did not affect rotation induced by either a D(1)-like (SKF-38393) or D(2)-like receptor (quinpirole) agonist. These findings provide the first evidence that D(4) receptors can be upregulated by nigrostriatal dopaminergic denervation. They also suggest that, unlike D(1) and D(2) receptors, D(4) receptors do not play a pivotal role in rotational behavior in rats with unilateral dopaminergic lesions.     

Dissociation of the striatal D-2 dopamine receptor from adenylyl cyclase following 6-hydroxydopamine-induced denervation.

Intracellular cyclic AMP accumulation following exposure to dopamine (DA) agonists and and antagonists was measured in striatal slices from rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway and which showed contralateral circling to apomorphine. Both DA (10-320 microM) and the D-1 agonist SKF 38393 (0.1-32 microM) increased cyclic AMP accumulation in striatal slices from the lesioned and intact hemispheres. The EC50 for DA to increase cyclic AMP accumulation in slices was greater in the 6-OHDA-lesioned striata compared to the intact striatum, but the EC50 for SKF 38393 was not affected. The D-1 antagonist SCH 23390 (10 microM) completely inhibited the ability of DA and SKF 38393 to increase cyclic AMP accumulation in striatal slices from both denervated and intact sides of the brain. In slices from the intact hemisphere the increase in DA-induced cyclic AMP accumulation was enhanced by the D-2 antagonist (+/-)-sulpiride (50 microM) but (+/-)-sulpiride had no effect on the DA response in slices from the lesioned side. Similarly, the ability of SKF 38393 to enhance cyclic AMP accumulation was blocked by the D-2 agonist quinpirole (10 microM) in striatal slices from the intact hemisphere but not in tissue from the lesioned side. The density of striatal D-1 and D-2 receptors assessed by [3H]SCH 23390 and [3H]spiperone binding did not differ between the hemispheres although there was an increase in the affinity of D-1 receptors for [3H]SCH 23390 in the lesioned striatum. After striatal deafferentiation there appears to be an uncoupling of the "inhibitory" D-2 receptor from the D-1 receptor-associated adenylyl cyclase.     

Pharmacological activity profiles of dopamine D-1 and D-2 reception agonists and antagonists on striatal neuronal activity and the response to dexamphetamine in freely moving rats

1. The effects of dopamine D-1 and D-2 receptor agonists and antagonists were investigated by recording extracellular striatal action potentials in freely moving rats. Dopamine receptor antagonist effects were also evaluated on dexamphetamine-induced excitation of striatal neurons. 2. Striatal neurons responded to SKF 38393, a D-1 agonist, with dose-dependent reductions in activity. At a 2.0 mg/kg dose neuronal activity decreased to 50% of control values. 3. The D-1 antagonist, SCH 23390, at a dose of 4.0 mg/kg decreased striatal neuronal activity by more than 50% and also effectively blocked the effects of 2.5 mg/kg dexamphetamine. 4. LY 171555, a D-2 agonist, at 1.0 or 2.5 mg/kg, did not significantly increase striatal neuronal activity. Although behavioral activation was noted, the neuronal response at the high dose was biphasic with inhibition predominant. 5. The D-2 antagonists haloperidol and sulpiride decreased striatal neuronal activity in a dose-dependent manner and also effectively antagonized the effects of dexamphetamine. The D-2 antagonist, RO 22-1319, at a dose of 2.0 mg/kg completely antagonized increases in striatal neuronal activity after dexamphetamine. 6. These findings suggest that dexamphetamine-induced increases in striatal neuronal activity are due to either stimulation of both D-1 and D-2 receptors, or alternatively, a third dopamine receptor subtype sensitive to both D-1 and D-2 antagonists but not agonists. Furthermore, the concept of specific D-1 and D-2 receptor agonists may require revision as neither SKF 38393 or LY 171555 increased striatal neuronal activity.