Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats.

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.

Conditioning and experiential factors affecting the development of sensitization to apomorphine.

In 3 experiments, the role of conditioning and experiential factors in producing behavioral sensitization to apomorphine (APO) was examined. In each experiment, male rats received intermittent injections of APO (5.0 mg/kg s.c.) or vehicle (VEH) and were tested for locomotor activity in photocell arenas. Activity test experience was paired or unpaired with drug exposure or not given. After the pretreatment phase in each experiment, all rats were tested for activity after an APO injection. The results indicated that behavioral sensitization to APO develops with repeated treatments in the absence of drug-associated contextual environmental stimuli. The magnitude of the sensitization effect observed, however, was always greater in rats for which specific environmental cues were reliably associated with drug exposure. These findings indicate that behavioral sensitization to APO develops through both associational and non-associational mechanisms.

Latent sensitization to apomorphine following repeated low doses.

In two experiments, the effect of repeated injections of apomorphine on locomotor activity of rats was determined. In each experiment, different groups of rats were injected with either apomorphine (0.2, 1.0, or 5.0 mg/kg) or vehicle at either 24 or 72 hr intervals and tested for locomotor activity in photocell arenas. In Experiment 2, following 13 treatment sessions with various doses, all groups were first tested for activity following a 5.0 mg/kg dose of apomorphine and then given vehicle only prior to the final activity test session. Major findings were as follows: (a) repeated injections of 1.0 and 5.0 mg/kg apomorphine produced a progressively greater increase in activity with each injection (i.e., sensitization); (b) injections of 0.2 mg/kg of apomorphine produced a slight inhibition of activity, which did not change with repeated injections; (c) prior treatment with 0.2 mg/kg of apomorphine resulted in a significantly greater activity increase following a 5.0 mg/kg dose of apomorphine than did prior vehicle treatments; and (d) chronic pretreatment of rats with apomorphine did not affect their activity level following a vehicle injection. These findings suggest that sensitization to apomorphine is a graded, rather than an all or none, phenomenon dependent on the dose of apomorphine repeatedly administered. In addition, these results are inconsistent with autoreceptor tolerance and conditioning explanations of dopamine agonist-induced sensitization effects.

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.

Effects of daily SKF 38393, quinpirole, and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine.

In three experiments, male Wistar rats (250-350 g) were injected (SC) daily with the D1-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D2-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D1-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8-10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D1 receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D2 receptor stimulation also contributes to the effect.

Selective antagonism of dopamine D1 and D2 receptors does not block the development of behavioral sensitization to cocaine.

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by either D1 or D2 selective dopamine receptor antagonists. Male Wistar rats were treated daily for 7 days with either cocaine (15 mg/kg, IP) or vehicle in combination with the D1 dopamine antagonist SCH 23390 (0.3 mg/kg, SC), the D2 dopamine antagonist sulpiride (100 mg/kg, IP), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. Twenty-four hours after the last pre-exposure test session, all rats were given a challenge injection of cocaine (15 mg/kg, IP) and tested for activity. Cocaine treatments produced a greater relative increase in locomotor activity with repeated exposure (i.e. sensitization). Moreover, this increase in cocaine-induced locomotor activity was attenuated by both SCH 23390 and sulpiride. In contrast, neither sulpiride nor SCH 23390 blocked the development of behavioral sensitization to cocaine. That is, rats pretreated with sulpiride or SCH 23390 and cocaine did not differ from rats pre-exposed only to cocaine when given a cocaine challenge injection. These results suggest that behavioral sensitization to cocaine may develop through either D1 or D2 dopamine receptor stimulation or possibly through stimulation of some non-dopaminergic receptor.

Effects of selective dopamine D1- and D2-type receptor antagonists on the development of behavioral sensitization to 7-OH-DPAT.

The primary objective of this study was to determine whether the development of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT could be prevented by either selective D1-type or D2-type dopamine receptor antagonists. In three experiments, male Wistar rats (250-350 g) were given seven to nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle in combination with the D2-type dopamine antagonist eticlopride (0.3 mg/kg, SC), the D1-type dopamine antagonist SCH 23390 (0.1 or 0.2 mg/kg, SC), or vehicle. After the injections, the rats were tested for locomotor activity in photocell arenas for 2 h. In the first two experiments, after seven injections, all rats were tested for activity following vehicle injections to test for possible conditioning effects. In each experiment, after the last pre-exposure session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) and tested for activity. Major findings were as follows: a) 7-OH-DPAT treatments produced a progressively greater increase in locomotor activity with repeated treatment; b) concurrent treatment with eticlopride or SCH 23390 (0.1 and 0.2 mg/kg) blocked the acute locomotor-activating effects of 7-OH-DPAT across days; c) eticlopride, but not SCH 23390, completely blocked the development of behavioral sensitization to 7-OH-DPAT. Although the low dose of SCH 23390 (0.1 mg/kg) produced a partial attenuation of sensitization, the higher dose (0.2 mg/kg) of SCH 23390 appeared to augment, rather than block, sensitization to 7-OH-DPAT; d) rats previously treated with SCH 23390 (0.2 mg/kg, but not 0.1 mg/kg) without 7-OH-DPAT displayed a hyperactive response to the 7-OH-DPAT challenge injection; and e) after vehicle injections, rats previously given 7-OH-DPAT, SCH 23390, or eticlopride either alone or in combination were more active than vehicle control rats. These findings suggest that the neurochemical mechanisms mediating the development of behavioral sensitization to 7-OH-DPAT may differ from those of other dopamine D2-type agonists such as quinpirole or bromocriptine. Moreover, these results demonstrate that hyperactivity responses following vehicle injections in drug-pretreated animals do not necessarily reflect conditioning mechanisms.

Stimulus and response factors affecting the development of behavioral sensitization to apomorphine.

The present study was designed to assess the role of stimulus and response factors in the context-dependency of behavioral sensitization to the direct dopamine agonist apomorphine. In two experiments, male Wistar rats were given repeated injections of the direct dopamine agonist, apomorphine (5 mg/kg, s.c.), or vehicle at 24- to 72-h intervals and tested for locomotor activity for 30 min in either an openfield activity drum or a running wheel. In experiment 1, after eight activity sessions in either the activity drum or running wheel, one-half of the rats in each drug condition (apomorphine or vehicle) were tested in the alternate activity test environment. In both activity test environments, apomorphine produced progressively greater levels of locomotor activity with repeated treatment (i.e., sensitization). Moreover, sensitization to apomorphine transferred completely across test environments. That is, rats given apomorphine associated with one test environment (e.g., wheel) displayed equivalent sensitization when tested in the alternate environment (e.g., drum). Thus, changing external stimulus cues associated with repeated drug exposure did not affect the expression of sensitization. In experiment 2, rats were given either apomorphine or vehicle daily and tested for activity in a running wheel. For one-half the rats in each drug condition, the running wheel was free to move, but for the remainder the wheel was immobilized. After nine training sessions, all rats were given an apomorphine challenge injection and tested in a mobile wheel. After the challenge injection of apomorphine, rats previously treated with apomorphine and trained in the mobile wheel were significantly more active than rats previously treated with vehicle. In contrast, rats given equivalent apomorphine treatments and trained in the immobile wheel did not differ in activity from rats previously given only vehicle. Since the external stimulus cues associated with drug exposure for the mobile and immobile wheel groups were the same, this finding suggests that environmental factors affecting response expression are critical to the development of behavioral sensitization to apomorphine.

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine.

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D1 or D2 selective dopamine antagonists. In three experiments, male rats received 10-21 daily injections of a selective D1 (SCH 23390; 0 or 0.5 mg/kg IP) or D2 (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D1 receptors.

Repeated 7-OH-DPAT treatments: behavioral sensitization, dopamine synthesis and subsequent sensitivity to apomorphine and cocaine.

Male Wistar rats (250-350 g) were injected (SC) daily with the putative selective dopamine D3 receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D2/D3 dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity.

Factors affecting the measurement of classically conditioned fear in rats following exposure to escapable versus inescapable signaled shock.

Three experiments are reported in which rats first received 50 escapable or inescapable signaled-shock trials. Experiment 1 (n = 22) employed an acquired-drive paradigm and found inescapable shock subjects learned a hurdle-jump response to escape the signal less rapidly than did escapable-shock subjects. Experiment 2 (n = 24) employed a conditioned emotional response paradigm and found inescapable-shock subjects suppressed more when the signal was introduced in the appetitive bar-pressing task. Both experiments measured spontaneous activity immediately following conditioning and found no group differences. Experiment 3 (n = 39) employed the same activity task and found no difference between escapable- and inescapable-shock groups when the signal was introduced into the activity task. Both groups displayed less activity than a nonshock control group during the signal. The results suggest that lack of control over the shock in the conditioning phase did not result in an increase of conditioned fear. The results are discussed in terms of a learned active-inactive predisposition to respond.

Effect of 6-hydroxydopamine or repeated amphetamine treatment on mesencephalic mRNA levels for AMPA glutamate receptor subunits in the rat.

Expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subunit mRNAs were assayed in the ventral mesencephalon of rats that received either a unilateral microinjection of the dopamine neurotoxin 6-hydroxydopamine (6-OHDA; Experiment 1) or repeated treatment with amphetamine (Experiment 2). GluR2 levels were decreased 1 and 3 days after the lesion, and GluR1 and GluR3 levels also showed a transient decrease at 1 day after the lesion. Repeated amphetamine treatment did not significantly alter GluR1-4 levels measured 30 min after the third or tenth amphetamine injection, even though locomotor sensitization was obtained. Thus, while the present results indicate that AMPA receptor subunits are associated with dopamine-containing cell bodies in the ventral mesencephalon, these transcripts may not be responsible for the development of amphetamine sensitization.

Scopolamine disrupts leverpress shock escape learning in rats.

Five groups of rats were tested on a discrete-trial leverpress shock escape task 30 min following an intraperitoneal injection of either 0 (saline), 0.2, 1.0, or 5.0 mg/kg scopolamine hydrobromide, or 5.0 mg/kg methylscopolamine hydrobromide. The results indicated that scopolamine, but not methylscopolamine, disrupted escape performance and this disruption was dose-related. These findings are consistent with both disinhibition and reduced freezing explanations of anticholinergic effects and support the view that reduced acetylcholine is involved in the behavioral effects of septal lesions.

The effects of apomorphine on leverpress shock escape learning in rats.

Four groups of rats (n = 10 each) were tested on a discrete trial leverpress shock escape task 15 min following an intraperitoneal injection of either 0 (saline), 0.5, 1.0, or 2.0 mg/kg apomorphine hydrochloride. The results indicated that all doses of apomorphine produced a severe disruption in escape performance. This disruption was temporary, however, as all apomorphine groups were responding as quickly as the saline control rats by the end of the training session. A comparison of the effects of apomorphine with the previously reported effects of scopolamine and septal lesions on shock escape learning revealed both similarities and differences. These findings suggest that a septal lesion-induced reduction of acetylcholine levels does not simply "unleash" an antagonistic dopaminergic system.

The effect of para-chlorophenylalanine and scopolamine on passive avoidance in chicks.

Four-day-old Vantress x Arbor Acre chicks were treated for key-peck passive avoidance (PA) learning following intraperitoneal injections of parachlorophenylalanine (PCPA) and/or scopolamine. In Experiment 1, chicks were pre-treated with either three or five injections of PCPA (150 mg/kg) or saline across th first three posthatch days and then tested for PA learning on the fourth posthatch day. In Experiment 2, chicks were first pre-treated with three injections of PCPA (150 mg/kg) or saline, and then injected with either scopolamine (0.5 mg/kg) or saline 20 min prior to PA testing on the fourth posthatch day. Major findings were: (a) Chicks pre-treated with PCPA did not significantly differ from saline control chicks in either the acquisition or maintenance of response suppression during PA testing; (b) chicks injected with scopolamine were significantly disrupted in PA learning as compared to saline control chicks; and (c) PCPA pre-treatment did not significantly affect the scopolamine-induced disruption of PA learning. These findings, therefore, suggest that cholinergic, but not serotonergic, mechanisms are involved in PA learning of the young chick.

Effects of repeated apomorphine and haloperidol treatments on subsequent behavioral sensitivity to apomorphine.

In a 2 x 2 factorial design, four groups of rats (n = 10 each) were injected daily with haloperidol (0.5 mg/kg IP) or its injection vehicle and apomorphine (1.0 mg/kg SC) or its vehicle for 21 consecutive days. Then, following a six-day drug-free rest interval, all rats were tested for locomotor activity in photocell arenas after an apomorphine injection on four additional days. Major findings were as follows: (a) rats pretreated with apomorphine were significantly more active following an apomorphine injection than rats pretreated with vehicle; (b) the development of sensitization to apomorphine was completely blocked by the concurrent administration of haloperidol during the pretreatment phase; and (c) pretreatment of rats with haloperidol alone did not affect subsequent sensitivity to apomorphine. These results suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine receptors.

Locomotor activity and stereotypy in rats following repeated apomorphine treatments at 1-, 3-, or 7-day intervals.

In two experiments, the effects of repeated intermittent administration of a relatively high dose of apomorphine (5 mg/kg) on locomotor activity and/or stereotypic behavior in rats was determined. In Experiment 1, male rats were given ten subcutaneous (SC) injections of apomorphine or vehicle and tested for locomotor activity and stereotypy. The first nine injection test sessions were given at 3-day intervals and the tenth injection test session was given 18 days following the ninth session. In Experiment 2, male rats were tested for locomotor activity following ten SC injections of apomorphine or vehicle with either a one- or seven-day interval between injections. Major findings were as follows: a) apomorphine produced progressively greater increases in locomotor activity with each succeeding injection (i.e., sensitization); b) sensitization to the locomotor activity stimulating effects of apomorphine developed with interinjection intervals of one, three, and seven days; c) the sensitization effect was maintained over the 18-day drug-free break; and d) the effect of apomorphine on stereotypic behavior did not significantly change with repeated injections. These findings indicate that even a single dose of apomorphine induces relatively long-lasting neurobiological changes. Moreover, these findings are consistent with the view that separate neural pathways mediate locomotor activity and stereotypy in rats.

Differential effects of 7-OH-DPAT on the development of behavioral sensitization to apomorphine and cocaine.

The primary objective of this study was to determine whether concurrent treatments with a low dose of the dopamine D(3)-preferring receptor agonist 7-OH-DPAT would attenuate the development of behavioral sensitization to the indirect dopamine receptor agonist, cocaine, or the direct dopamine receptor agonist, apomorphine. In two experiments, male Wistar rats (250-350 g) were given seven daily injections of 7-OH-DPAT (0.05 mg/kg sc) or vehicle in combination with either cocaine (15 mg/kg ip), apomorphine (1.0 mg/kg sc), or vehicle. After the injections, the rats were tested for activity in photocell arenas for 40 min, and three measures of motor behavior (distance traveled, rearing, and stereotypy) were recorded at 10-min intervals. A total of 24 h after the last preexposure session, all rats were given a challenge injection of either cocaine (10.0 mg/kg ip, Experiment 1) or apomorphine (1.0 mg/kg sc, Experiment 2) and tested for activity. Major findings were as follows: (a) 7-OH-DPAT treatments alone suppressed all measures of locomotor activity and did not affect subsequent behavioral sensitivity to either cocaine or apomorphine; (b) cocaine treatments acutely increased all measures of activity, and repeated treatments produced behavioral sensitization to the horizontal locomotor-activating effects of cocaine; (c) apomorphine treatments alone increased horizontal activity and stereotypy but completely abolished rearing behavior; (d) like cocaine, repeated treatments with apomorphine induced behavioral sensitization; (e) concurrent treatments of 7-OH-DPAT with cocaine acutely attenuated cocaine-induced increases in motor behavior but enhanced the development of behavioral sensitization to cocaine; and (f) concurrent 7-OH-DPAT treatments did not significantly affect either the acute or chronic effects of apomorphine. It is evident from these results that concurrent treatment with 7-OH-DPAT does not block the development of behavioral sensitization to either cocaine or apomorphine. Moreover, the differential acute and chronic effects of 7-OH-DPAT on cocaine- and apomorphine-induced hyperactivity appear to be mediated by dopamine autoreceptor stimulation.

Effects of apomorphine on novelty-induced place preference behavior in rats.

Adult male rats were exposed to one of two different stimulus compartments by being placed into the compartment for 30 min on each of eight consecutive days. Following this exposure, each rat was administered 0, 0.05, 0.1, 0.5 or 5.0 mg/kg apomorphine. Thirty min after injection, each animal was given free-choice access to the familiar (exposed) compartment and to the novel (nonexposed) compartment. As expected, saline-injected control animals displayed a preference for the novel compartment. This novelty preference was disrupted in animals given either 0.05 or 0.1 mg/kg apomorphine, but not in animals given either 0.5 or 5.0 mg/kg apomorphine. The disruption in novelty preference by the low doses of apomorphine did not reflect a disruption of locomotor activity, as there was no direct relationship between the preference for novelty and the rate of horizontal or vertical activity among the different treatment groups. Instead, the low doses of apomorphine may have inhibited dopamine function by blocking presynaptic autoreceptors selectively, and thus the reinforcing effect of the novel stimulation may have been attenuated.

Locomotor activity and dopamine synthesis following 1 and 15 days of withdrawal from repeated apomorphine treatments.

In two experiments, the effects of repeated apomorphine treatments on locomotor activity and terminal field dopamine synthesis was assessed after either a 1- or 15-day withdrawal period. In the first experiment, rats (n = 11/group) were treated with apomorphine (1.0 mg/kg, s.e.) or vehicle and tested for locomotor activity daily for 10 days. Fifteen days after the last repeated treatment, all rats received 1.0 mg/kg apomorphine and were tested for locomotor activity. Locomotor sensitization developed over the 10 day period and was still evident after the 15-day withdrawal period. In the second experiment rats (n = 11/group) were treated with apomorphine (1.0 mg/kg, s.c.) or vehicle and tested for locomotor activity daily for 10 days. Dopamine synthesis was assessed following 1 or 15 days of withdrawal by measuring dihydroxyphenylalanine (DOPA) accumulation (after DOPA decarboxylase inhibition with NSD-1015) in striatum and nucleus accumbens-olfactory tuberele. As in the first experiment, rats treated with repeated apomorphine showed locomotor sensitization over the 10 days, relative to controls. Dopamine synthesis was reliably enhanced in the striatum, but not nucleus accumbens-olfactory tuberele, following both 1- and 15-day withdrawal periods. These results indicate that enhanced basal dopamine synthesis following repeated apomorphine treatments, similar to locomotor sensitization, is a persistent phenomenon.