Effects of apomorphine and haloperidol on response suppression learning of young chicks

In four experiments, the effects of augmenting or blocking dopamine receptor activity on response suppression learning of Colburn X Colburn chicks were determined. In each experiment, 4-day-old chicks were trained to key peck for heat reward and then tested for response suppression learning by using either a response-contingent punishment or an extinction-punishment task. Before response suppression testing, different groups of chicks were injected ip with apomorphine (1.0, 2.0, or 4.0 mg/kg) either alone or after pretreatment with haloperidol (0.5 or 1.0 mg/kg). Regardless of the response suppression task used, chicks injected with apomorphine had difficulty inhibiting their responding; whereas, chicks injected with haloperidol, either alone or before apomorphine treatment, responded on fewer trials than saline-treated chicks. During extinction testing, 4-day-old chicks given only apomorphine showed the typical suppressive effect of punishment on responding rather than the paradoxical punishment-induced increase in responding found in normal 1-day-old chicks. These results indicate that activation of dopamine receptors retards response suppression learning of the 4-day-old chick, but functional changes in central dopaminergic mechanisms are not primarily responsible for the normal age-dependent improvement in response suppression learning of the young chick.     

The effects of apomorphine and haloperidol on memory consolidation in the day-old chick

Apomorphine was found to disrupt memory consolidation in a dose-dependent manner on chicks trained on a 1-trial passive avoidance task with a strong aversant experience. Chicks injected with 4.0 mg/kg apomorphine displayed memory deficits at 180 min after learning and showed marked behavioral disturbances, including increased locomotion and increased pecking at the feet of conspecifics. Pretreatment with the dopamine antagonist haloperidol eliminated the memory disturbance induced by apomorphine and facilitated consolidation of memory in chicks given a weak (20% vol/vol methyl anthralinate) training experience. Time-of-retention data suggested that the memory disruption occurred from 120 min after learning, leading to the suggestion that dopamine-related modulation of the training experience may be involved in late-memory formation processes.     

Cocaine-induced effects on isolation stress in neonatal rats.

The effects of cocaine administration on isolation-induced vocalizations and activity levels in 10-day-old rat pups were examined. Day 10 pups given cocaine (1.25, 2.5, 5, 10, & 20 mg/kg ip) vocalized significantly less than their caffeine- (10 mg/kg) and saline-administered siblings during a 5-min isolation period. Cocaine- and caffeine-administered pups also demonstrated a significant increase in overall activity compared with controls. In addition, intraperitoneal administration of the dopamine antagonist haloperidol (0.5 & 1.0 mg/kg) before 1.25 and 2.5 mg/kg cocaine produced a significant elevation in vocalizations compared with saline pretreatment, which indicates a blocking of cocaine's effect on calling behavior. These results suggest that the endogenous dopamine system involved with reinforcement and reward may quell the stress of isolation in the infant rat.     

Presynaptic autoinhibition of the electrically evoked dopamine release studied in the rat olfactory tubercle by in vivo electrochemistry.

Evoked dopamine release was monitored in vivo from the olfactory tubercle of anaesthetized rats by differential pulse amperometry combined with carbon fibre electrodes which, in most cases, were electrochemically treated. Dopamine release was evoked by electrical stimulation of the ascending dopaminergic pathway. The dopamine release evoked by burst stimulation (20 s with a mean frequency of 6 Hz) was dose-dependently decreased by D,L-apomorphine (25-800 micrograms/kg, s.c.) or by quinpirole (50 micrograms/kg, s.c.) while the opposite effect was observed with haloperidol (12.5 micrograms/kg-0.5 mg/kg, s.c.) or with D,L-sulpiride (2-200 mg/kg, s.c.). Neither the D1 agonist SKF 38393 (10 mg/kg, s.c.) nor the D1 antagonist SCH 23390 (0.5 mg/kg, s.c.) affected the evoked dopamine release. Moreover, sulpiride competitively antagonized the effects of apomorphine. The relative amplitude of the apomorphine inhibition was inversely correlated with the stimulation frequency (6 or 9 Hz). The increase induced either by haloperidol or by sulpiride was positively related to the stimulation frequency (from 3 to 9 Hz) and reached a stable value (+700% of the pre-drug-evoked dopamine release) with higher frequencies (from 9 to 20 Hz). This increase also depended on the duration of the stimulation: both single-train (10 pulses) or burst stimulations for 20 s, whose frequency inside the trains was in both cases 14 Hz, evoked a dopamine release which was minimally affected by sulpiride or haloperidol. In conclusion, in physiological conditions the amplitude of the impulse flow-dependent dopamine release is regulated by the extrasynaptic extracellular dopamine concentration which varies from 10 to 100 nM. This presynaptic autoinhibition is mediated by autoreceptors of the D2 type and is involved in the nonlinear relationship between impulse flow and dopamine release.     

Dissociation of immunosuppression by chlorpromazine and trifluoperazine from pharmacologic activities as dopamine antagonists.

Neuroleptic compounds may affect the immune system through a variety of mechanisms. Most possess a complex pharmacology, which makes specific, causal relationships difficult to discern. In this study, a series of experiments was performed to examine the effects of dopamine antagonists on a battery of immunologic parameters. Mitogen-induced lymphocyte proliferation in vitro was inhibited by haloperidol, chlorpromazine, and trifluoperazine at 10, 1 and 1 microM concentrations, respectively. Sulpiride and metoclopramide had no direct effect in vitro. In vivo lymphocyte proliferation was significantly reduced by chlorpromazine at the highest tested doses (12.5 and 15 mg/kg) and by trifluoperazine at the highest tested dose (30 mg/kg). All other dopamine antagonists had no significant effect on in vivo lymphocyte proliferation. A murine graft vs host (GVH) response was unaffected by haloperidol, sulpiride, and metoclopramide. Chlorpromazine and trifluoperazine exhibited significant inhibition of the GVH response at the highest doses only (15 and 30 mg/kg, respectively). In a picryl chloride induced delayed type hypersensitivity (DTH) assay, haloperidol, metoclopramide, and sulpiride had no effect. However, both chlorpromazine and trifluoperazine significantly reduced DTH-induced paw swelling at the higher doses (7.5 mg/kg, and 10 and 30 micrograms/kg, respectively). These studies indicate that the more specific dopamine antagonists (e.g. sulpiride, metoclopramide, and haloperidol) do not share the immunologic profiles of chlorpromazine and trifluoperazine, suggesting that these effects of chlorpromazine and trifluoperazine are not related to their dopamine antagonist properties.     

Picrotoxin enhances latent extinction of conditioned fear

Male CD1 mice received 20 pairings of tone and footshock (FS) or tone alone in an arm of a Y-maze on Day 1. On Day 2 either extinction (tone alone) or no extinction was followed immediately by saline or picrotoxin (0.5 or 1.0 mg/kg ip). Nonextinguished groups received only saline or picrotoxin (1.0 mg/kg ip) on Day 2. Other groups received saline or picrotoxin (1.0 mg/kg) 2 hr after extinction. On Day 3 all mice were placed in the Y-maze (with doors to all 3 alleys open), and total alley entries during a 2-min test session were recorded. Day 1 FS training resulted in reduced alley entries during the test session. Day 2 extinction session significantly attenuated the effects of the FS training. Day 3 performance of mice given picrotoxin (1.0 but not 0.5 mg/kg) immediately postextinction was comparable to that of mice not given FS on Day 1. The findings suggest that picrotoxin enhanced extinction of conditioned fear.     

P-chlorophenylalanine attenuates tonic immobility duration in chickens

The results of two experiments demonstrated a dose-dependent reduction in tonic immobility (TI) duration by p-chlorophenylalanine (PCPA) in White Leghorn cockerels. In Experiment 1, five-day old chicks were given five intraperitoneal injections of either saline or 75 or 150 mg/kg of PCPA at a rate of one injection a day for five days. The effects of these injections were evaluated one day after the last injection. A total of 750 mg/kg of PCPA significantly reduced TI duration but 375 mg/kg did not. In Experiment 2, chicks were given either two saline injections, two 375 mg/kg PCPA injections, or one 375 mg/kg PCPA injection and one saline injection. The effects of these injections were evaluated either one or three days after injections. A total of 750 mg/kg of PCPA significantly reduced TI both one and three days after injections but 375 mg/kg of PCPA did not. Previous failures to obtain significant PCPA effects on TI may reflect insufficient drug amounts.     

Indirect dopamine agonists augment the locomotor activating effects of the kappa-opioid receptor agonist U-50,488 in preweanling rats

kappa-Opioid receptor agonists (e.g., enadoline or U-50,488) increase the locomotor activity of preweanling rats, while the same drugs depress the locomotor activity of adults. Curiously, direct stimulation of dopamine (DA) D2-like receptors fully attenuates the U-50,488-induced locomotor activity of preweanling rats. The purpose of the present study was to determine whether indirect DA agonists (i.e., cocaine, methylphenidate, and amphetamine) would also attenuate U-50,488's behavioral effects. In two experiments, 17-day-old rats were injected with saline or U-50,488 (5 mg/kg, sc) and locomotor activity and stereotyped sniffing were assessed. After 20 min, the saline- and U-50,488-pretreated rats were injected with saline, cocaine (5, 10, or 20 mg/kg, i.p.), methylphenidate (10 or 20 mg/kg, i.p.), amphetamine (2.5 or 5 mg/kg, i.p.), or the direct D2-like receptor agonist NPA (1 mg/kg, i.p.). As expected, U-50,488 dramatically enhanced the locomotor activity of 17-day-old rats, while attenuating the stereotyped sniffing caused by indirect and direct DA agonists. All three indirect DA agonists augmented U-50,488's locomotor activating effects across the initial 10 min of testing and then activity declined to U-50,488 control values. Direct stimulation of DA receptors produced nearly opposite effects because NPA attenuated U-50,488-induced locomotor activity across the entire testing session. It is uncertain why direct and indirect DA agonists affected U-50,488-induced locomotor activity differently, but the relative amount of DA D1-like receptor activation is probably not responsible.     

Lack of task specificity and absence of posttraining effects of atropine on learning

Three experiments are reported whose purpose was to examine the effect of the cholinergic antagonist atropine on the acquisition of different learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions; on the retention of performance acquired in the absence of the drug; and on memory consolidation immediately after daily training trials. In Experiment 1, atropine sulfate (10 or 50 mg/kg, ip), injected 30 min prior to training, severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Experiment 2, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in rats previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects or gross sensorimotor impairments. In Experiment 3, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in rats that were trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypothesis that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Furthermore, these results point to dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes.     

多巴胺受体阻滞剂协调吗啡镇痛及其镇痛机制分析

目的:观察低剂量多巴胺受体阻滞剂氟哌啶醇与阈下镇痛剂量吗啡合用对抗热刺激和醋酸致小鼠痛反应的作用,并初步分析其协同镇痛作用的主导机制。方法:采用热板法测试给予氟哌啶醇(0.3125mg/kg,0.625mg/kg,1.25mg/kg)、吗啡(3.125mg/kg,6.25mg/kg,12.5mg/kg)和氟哌啶醇(0.3125mg/kg)与吗啡(3.125mg/kg)合用,对热刺激致小鼠痛反应的变化及苯丙胺(10mg/kg)和纳洛酮(5.0mg/kg)对其合用小鼠痛反应的影响。采用扭体法测试给予氟哌啶醇(0.625mg/kg,1.25mg/kg,2.5mg/kg)、吗啡(1.25mg/kg,2.5mg/kg,5.0mg/kg)及氟哌啶醇(0.625mg/kg)与吗啡(1.25mg/kg)合用,对醋酸(0.7%,0.1mL/10g,ip)诱致小鼠扭体出现潜伏期、20min内扭体反应次数的影响。结果:氟哌啶醇与吗啡合用明显提高小鼠对热刺激致痛的痛阈,显著延长醋酸致小鼠扭体反应潜伏期和抑制扭体反应次数;纳洛酮可取消两者合用的协同镇痛效应,而苯丙胺无明显影响。结论:多巴胺受体阻滞剂氟哌啶醇与吗啡合用可产生协同镇痛作用,而吗啡在协同镇痛中起主导作用。     

Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release.

Cortical acetylcholine, under resting and stimulated conditions, was measured in frontoparietal and prefrontal cortex using in vivo microdialysis in freely-moving rats. Cortical acetylcholine efflux was stimulated by systemic administration of the benzodiazepine receptor partial inverse agonist FG 7142. Administration of FG 7142 (8.0 mg/kg; i.p.) significantly elevated acetylcholine efflux in both cortical regions (150-250% relative to baseline) for 30 min after drug administration. The ability of endogenous dopamine to regulate cortical acetylcholine efflux under resting or stimulated conditions and the relative contributions of D1- and D2-like dopamine receptor activation was also assessed. In a first series of experiments, systemic administration of the antipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142-stimulated acetylcholine efflux in frontoparietal, cortex while the D1-like antagonist, SCH 23390 (0.1, 0.3 mg/kg), was less effective in attenuating stimulated acetylcholine efflux. In a second series of experiments, the effects of infusions of these antagonists and of the D2-like antagonist sulpiride (10, 100 microM) into the nucleus accumbens were assessed. Infusions of haloperidol and sulpiride significantly blocked FG 7142-stimulated acetylcholine efflux while SCH 23390 did not. By contrast, a third series of experiments demonstrated that perfusion of these antagonists (100 microM) locally into the cortex (through the probe) did not affect FG 7142-stimulated acetylcholine efflux. Moreover, none of these dopamine receptor antagonists, whether administered systemically or perfused into the nucleus accumbens or cortex, affected basal cortical acetylcholine efflux. These results reveal similarities in stimulated cortical acetylcholine release across frontal cortical regions and suggest a prominent role for D2-mediated accumbens dopamine transmission in the regulation of cortical acetylcholine release. The findings provide evidence in support of a neural substrate that links dysregulation of mesolimbic dopaminergic transmission to changes in cortical cholinergic transmission. Dysregulation within this circuit is hypothesized to contribute to the etiology of disorders such as schizophrenia, dementia and drug abuse.     

Effects of haloperidol, a dopamine D2-like receptor antagonist, on reward-related behaviors in laying hens

In order to investigate the involvement of dopaminergic transmission in the regulation of reward-related behaviors in laying hens, the effects of systemic injections of dopamine D2-like receptor antagonist haloperidol (0.3, 0.5, 1.0 and 2.0 mg/kg s.c.) 30 min prior to a conditioned cue signaling a reward were tested and compared to the effects of a saline injection. Head movements and latency to initiate display of anticipatory behavior were significantly affected by 0.3 and 0.5 mg/kg haloperidol, respectively. More hens were found lying down resting prior to the cue at 0.5 mg/kg and higher doses, and increased latency to peck at reward and shorter duration of anticipatory behavior was significant at 2.0 mg/kg. The findings are consistent with the involvement of dopamine in control of reward-related behaviors in laying hens. It is suggested that the lowest dose of haloperidol (0.3 mg/kg) affects reward-related behaviors, whereas the effects of higher doses of haloperidol could be confounded by sedative effects. A high inter- and intra observer agreement in the assessment of head movements together with their dopamine dependency further suggest that this behavior in classical conditioning paradigm represents an indicator of the state of the reward system in laying hens that can be assessed with good reliability.     

Posttraining administration of gastrin-releasing peptide improves memory loss in scopolamine- and hypoxia-induced amnesic mice

We examined memory improvement with respect to the effects of gastrin-releasing peptide (GRP) in male C57BL/6J mice under conditions of experimentally induced amnesia. GRP was administered following training in a one-trial passive avoidance test. In Experiment 1, the drug scopolamine (1 or 2 mg/kg, ip) was used to induce amnesia prior to training, and GRP (32 nmol/kg, ip) or saline (control) was administered immediately after training. Results indicate that GRP at this dose improved memory only when the dosage of scopolamine was relatively low (1 mg/kg). In Experiment 2, CO2-induced amnesia was employed. Mice were placed in a chamber filled with CO2 or air (control) immediately after acquisition training. Subsequently, they were administered either saline or GRP (32 nmol/kg, ip). Significantly longer light-dark latency was observed in all mice that received GRP (both experimental and control groups). In total, our results indicate that the effect of GRP at this dose on the improvement of impaired memory is dependent on the degree of impairment. Furthermore, because CO2-induced hypoxia is known to decrease acetylcholine release in the brain, our results also suggest that GRP and its receptor may interact with the cholinergic system in the central nervous system.     

Strychnine increases acoustic startle amplitude but does not alter short-term or long-term habituation

Theories of habituation have included an increase in postsynaptic inhibition as one possible mechanism underlying response decrement following repetitive stimulus presentation. In this study, the glycine antagonist strychnine (1.0 mg/kg, ip, 10 min pretreatment) was used to investigate the involvement of glycinergic neurons in the development and/or expression of short-term (within-session) habituation (Experiment 1) and long-term (between-sessions) habituation (Experiments 2 and 3) of the acoustic startle response in rats. Over a range of eliciting-stimulus intensities (95, 105, and 115 dB) and interstimulus intervals (3, 7, 13, and 27 s), strychnine markedly increased startle amplitude, relative to water injection, whereas it failed to attenuate the rate of within-session habituation (Experiment 1). In Experiment 2, rats that were exposed to daily sessions of startle-eliciting stimuli for 4 days and then tested on the fifth day showed lower overall levels of startle amplitude, relative to rats that had not received prior habituation training. Strychnine injected prior to the test session again increased startle amplitude but did not block the expression of between-sessions habituation. In Experiment 3, rats that were injected with either strychnine or water prior to each of three daily habituation training sessions and subsequently tested on Day 4 showed similar between-sessions habituation, relative to untrained rats that had received daily injections in the animal room. In summary, strychnine increased startle amplitude without affecting either within-session or between-sessions habituation of acoustic startle. These results emphasize the need to discern between drug effects on response amplitude per se and effects on response habituation. Furthermore, the data indicate that a buildup of inhibition in glycinergic neurons does not explain either within-session or between-sessions habituation of acoustic startle in rats. These results are discussed in light of current theories of habituation.     

Dopamine manipulations limited to preexposure are sufficient to modulate latent inhibition

Four experiments are reported that demonstrated that dopamine (DA) transmission is involved in the acquisition of latent inhibition (LI) of a conditioned taste aversion. LI refers to weaker conditioning as a consequence of nonreinforced preexposure (PE) of the future conditioned stimulus. Although it is known to depend on DA transmission during the conditioning phase, it is usually thought that the cognitive processes involved in the establishment of LI (during the PE phase) are DA independent. Either amphetamine (AMPH; 0.5 or 1.0 mg/kg) or haloperidol (HAL; 0.1 mg/kg) were injected before 1 or all of the 3 PE sessions. AMPH blocked the acquisition of LI if it was injected before each or before only the last PE session and HAL potentiated LI. ((c) 2006 APA, all rights reserved).     

Synergistic interaction between mazindol, an anorectic drug, and swim-stress on analgesic responses in the formalin test in mice

The present study examined the interaction between mazindol (MZ), an anorectic drug extensively used in Brazil and opioid/non-opioid endogenous analgesic systems activated by swim-stress. Further, the role of opioid, dopamine and N-methyl-D-aspartate (NMDA) receptors in mediating the analgesic effect was evaluated. The stress-induced analgesia of a 3-min swimming at 32 degrees C (opioid/non-opioid) and 20 degrees C (non-opioid) were assessed using the formalin test. Male Swiss mice were intraperitoneally injected with naloxone (1.0 mg/kg), sulpiride (3.0 mg/kg), MK-801 (0.075 mg/kg) or saline/vehicle 15 min prior, and with MZ (0.5 mg/kg) or saline/vehicle 5 min prior to swimming. The dose of MZ (0.5 mg/kg) did not cause analgesic effect, however, the association of MZ and swim-stress at both temperatures displayed synergistic interaction on analgesia that was blocked by sulpiride and MK-801 but not by naloxone. The present results suggest that MZ and swim-stress acted synergistically on analgesic responses, involving mainly the non-opioid component and possibly mediated by dopamine D2 receptors and NMDA receptors.     

Norepinephrine and dopamine in the developing chick brain

Appearance, concentration, and distribution of catecholamines (dopamine and norepinephrine) in embryonic and postnatal chick brain regions were studied. The highest amount of DA was found in cerebral hemispheres and increased gradually to adult levels, whereas in other parts of the brain the concentrations of DA fluctuated during the post-hatch period. The remainder contained the largest amount of NE, whereas the cerebral hemispheres contained relatively small amounts of NE. Relatively high amounts of NE were found in the cerebellum. A single dose of L-3, 4-dihydroxyphenylalanine (DOPA) injected into the 3-day-old embryo had no significant effect upon the levels of DA and NE either in the embryonic stages or in the postnatal period. In the 7-day-old chick, combined treatment of JB-516 (catron) and L-DOPA (IP) induced about a 10-fold and 2-fold increase of the brain level of DA and NE respectively about 30 min after injection, and these levels decreased rather rapidly within 2 hr. A group of chicks injected with DOPA at the 3-day-old embryonic stage and a group injected with saline were exposed one month post-hatch to three visual discrimination tasks. There was no significant difference in the performance between these two groups.     

Dopaminergic modulation of transcallosal activity of cat motor cortical neurons

The effects of dopamine (DA) and its antagonists on the transcallosal activity of pyramidal tract neurons (PTNs) and non-PTNs in the anesthetized cat motor cortex were studied with iontophoretic applications; dopamine, SCH 23390 (D1 antagonist), sulpiride (D2 antagonist) and haloperidol. Neuronal activity was recorded with a multi-barreled glass microelectrode. Transcallosal neuronal activity was evoked by stimulation of the contralateral motor cortex. The number of spikes thus activated was counted for the control and test conditions after application of each drug: (1) dopamine application decreased the number of spikes evoked by transcallosal stimulation; (2) application of SCH 23390, sulpiride and haloperidol restored these decreased spike numbers to the control level; (3) latency of neuronal response to transcallosal stimulation was not affected by the application of either DA, SCH 23390, sulpiride or haloperidol; and (4) there was no significant difference between PTNs and non-PTNs in the manner of response to DA and its antagonist applications. Our conclusion is that dopamine modulated the transcallosal neuronal response in the cat motor cortex in a suppressive manner. This fact suggested that interhemispheric neuronal communications could be subjected to suppressive modification by the dopaminergic system.     

Clozapine and PD149163 elevate prepulse inhibition in Brown Norway rats

Unmedicated schizophrenia patients exhibit deficits in prepulse inhibition (PPI) of the acoustic startle response. Similar deficits can be induced in rodents via a variety of manipulations and these deficits can be reversed by antipsychotics. Brown Norway (BN) rats exhibit natural PPI deficits under certain parametric conditions. We treated BN rats with haloperidol or clozapine to determine if the BN rat is a useful animal model with predictive validity for the effects of antipsychotics. In addition, we also tested PD149163, a neurotensin-1 receptor agonist, which has been shown to exhibit antipsychotic-like effects in several other animal models. BN rats received subcutaneous injections of either saline or one of two doses of haloperidol (0.5 mg/kg, 1.0 mg/kg), clozapine (7.5 mg/kg, 10 mg/kg) or PD149163 (1.0 mg/kg, 2.0 mg/kg). PPI was measured in startle chambers 30 min after injection. Systemic clozapine and PD149163 but not haloperidol facilitated PPI in BN rats (p < .001). This drug response profile suggests that the BN rat may be useful for detecting atypical antipsychotics and antipsychotics with novel mechanisms of action. The results also add to the evidence suggesting that PD149163 may have antipsychotic properties.     

Effects of salvinorin A on locomotor sensitization to D2/D3 dopamine agonist quinpirole

Locomotor sensitization induced by the dopamine agonist quinpirole can be potentiated by co-treatment with the synthetic kappa opioid agonist U69593. The identification of salvinorin A, an active component of the psychotropic sage Salvia divinorum, as a structurally different agonist of kappa-opioid receptors raised the question of whether this compound would similarly potentiate sensitization to quinpirole. Rats were co-treated with 0.5 mg/kg quinpirole and either salvinorin A (0.04, 0.4 or 2.0 mg/kg) or U69593 (0.3 mg/kg). Control groups were co-treated with vehicle and saline, vehicle and quinpirole (0.5 mg/kg), or saline and salvinorin A (0.4 mg/kg). Rats were injected biweekly for a total of 10 injections and locomotor activity measured after each treatment. Results showed that the highest dose of salvinorin A potentiated sensitization to quinpirole as did U69593, the middle salvinorin A dose had no effect on quinpirole sensitization, and the lowest dose of salvinorin A attenuated sensitization to quinpirole. These findings indicate that structural differences between salvinorin A and U69593 do not affect the potentiation of quinpirole sensitization. Moreover, the opposite effects of high and low salvinorin A doses suggest that salvinorin A can produce bidirectional modulation of sensitization to dopamine agonists.