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.

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.

Repeated treatments with 7-OH-DPAT: context-independent behavioral sensitization and conditioned hyperactivity.

The primary objective of this study was to determine whether the expression of behavioral sensitization to the putative dopamine D3 receptor agonist 7-OH-DPAT is context dependent. Three groups (n = 8 each) of male Wistar rats (250-350 g) were given nine injections (at 48-h intervals) of 7-OH-DPAT (1.0 mg/kg, SC) or vehicle 15 min before and after activity testing. The paired group received 7-OH-DPAT before activity testing and vehicle after testing. The unpaired group received vehicle before and 7-OH-DPAT after testing, and the vehicle control group received two vehicle injections. Locomotor activity was measured in photocell arenas for 2 h. After the first seven sessions, all rats were tested for activity following a vehicle injection to test for possible conditioning effects. Prior to the 11th session, all rats were given a challenge injection of 7-OH-DPAT (1.0 mg/kg, SC) to test for sensitization. Major findings were as follows: (a) the 7-OH-DPAT/paired group displayed a progressively greater increase in locomotor activity with repeated treatments; (b) the 7-OH-DPAT/paired group was significantly more active than either the vehicle control group or the 7-OH-DPAT/unpaired group during the vehicle test session; and (c) after the 7-OH-DPAT challenge injection, the paired and unpaired 7-OH-DPAT groups were significantly, and equally, more active than the vehicle control group. In contrast to previous findings with the D2-type dopamine agonists bromocriptine and quinpirole, these results suggest that the expression of behavioral sensitization to 7-OH-DPAT is not context dependent. Moreover, these results suggest that the apparent conditioned hyperactivity and context dependency often observed after repeated dopamine agonist treatments may not be related to the same associative and/or nonassociative mechanisms.

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.

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.

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.

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.

Cocaine-induced behavioral sensitization: effects of haloperidol and SCH 23390 treatments.

The objective of this study was to determine whether the development of behavioral sensitization to cocaine could be prevented by high doses of the dopamine receptor antagonists haloperidol and SCH 23390. In two experiments, male Wistar rats were injected daily for 4 days with either cocaine (15 mg/kg, IP) or vehicle in combination with haloperidol (1.0 mg/kg, IP), SCH 23390 (0.5 mg/kg, SC), or vehicle. After the daily injections, the rats were tested for locomotor activity in photocell arenas. At 24 h after the last preexposure 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 compared to vehicle treatments (i.e., sensitization). Moreover, the acute activating effects of cocaine over days were blocked by both haloperidol and SCH 23390. The coadministration of haloperidol, but not SCH 23390, blocked the development of behavioral sensitization to cocaine. That is, after the cocaine challenge injection, rats pretreated with SCH 23390 and cocaine did not differ from rats preexposed only to cocaine, whereas rats pretreated with haloperidol and cocaine did not differ from rats pretreated only with vehicle. Pretreatment with haloperidol or SCH 23390 without cocaine enhanced the locomotor-activating effects of the subsequent cocaine challenge injection. These findings suggest that cocaine-induced behavioral sensitization may develop as a result of repeated dopamine D1- or D2-type receptor stimulation, and that brief dopamine antagonist treatments enhance subsequent behavioral sensitivity to cocaine.

Repeated quinpirole treatment: locomotor activity, dopamine synthesis, and effects of selective dopamine antagonists.

Repeated treatment with the non-selective dopamine agonist apomorphine results in behavioral sensitization and enhanced dopamine synthesis in dopamine projection fields. To examine the role of D2-type dopamine receptors in modulating these effects, the present experiment assessed the effects of repeated treatment with the D2-type agonist quinpirole on locomotor activity and dopamine synthesis. In the first experiment, rats were treated with vehicle or one of two doses (0.3 or 3.0 mg/kg) of quinpirole for 8 days. Daily measures of locomotor activity revealed an initial suppression of activity produced by quinpirole which dissipated over the 8 days of treatment. A trend for an increase in activity for 3.0 mg/kg quinpirole compared to vehicle was obtained on day 8. Twenty-four hours after cessation of treatment, dopamine synthesis, measured as accumulation of 3,4-dihydroxyphenylalanine (DOPA) after treatment with the DOPA decarboxylase inhibitor NSD-1015, was enhanced in the striatum, but not nucleus accumbens-olfactory tubercle (NAOT) or ventral mesencephalon (VM). In Experiment 2, rats were treated for 8 days with vehicle, 3.0 mg/kg quinpirole or the D1 antagonist SCH 23390 (0.5 mg/kg) in a two (vehicle or quinpirole) x two (vehicle or SCH 23390) design. Quinpirole-alone treatment resulted in a reduction of the locomotor suppressant effects of the drug. SCH 23390-alone and quinpirole-SCH 23390 combined treatment resulted in decreased activity compared to the vehicle control group that did not change across days. DOPA accumulation was enhanced in the striatum and NAOT after quinpirole treatment; however, SCH 23390 had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: assessment of the role of D1 dopamine receptor stimulation.

Previous research has revealed a role of repeated D1 dopamine receptor stimulation in the development of behavioral sensitization to the D1/D2 agonist apomorphine. The present experiments assessed the role of repeated D1 receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D1 stimulation on dopamine synthesis, rats were injected with the D1 agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD-1015. DOPA accumulation, assessed in striatal, nucleus accumbens-olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D1 agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine-treated rats, but not the SKF 38393-treated rats, across the 10 days. On day 11, all rats were injected with NSD-1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and [3H]SCH 23390 binding to D1 receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

Effect of forebrain dopamine depletion on novelty-induced place preference behavior in rats.

Novelty-induced place preference behavior of rats was studied in two experiments. In the first experiment, separate groups of animals were habituated to a distinct environment 30 min daily for either zero, one, two, four or eight days. On the day following the last habituation day, animals were allowed 15 min free access to both the habituated (familiar) and a distinct novel environment. The results revealed a significant novelty preference in the two-, four- and eight-day habituation groups. In these same animals, the rate of horizontal and vertical activity was lower in the novel environment relative to the familiar environment. The influence of forebrain dopamine (DA) projections on novelty preference behavior was studied in the second experiment. Animals were given an injection of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens or were given sham surgery, and then they were given four habituation days to one environment. Novelty-induced place preference was blocked in the lesioned animals, as the amount of time spent in the novel and familiar environments was not significantly different. Lesioned animals also failed to show a difference in locomotor activity between the novel and familiar environments. Subsequent assay data revealed that the 6-OHDA lesion reduced DA levels in the nucleus accumbens, anterior striatum and olfactory tubercles by over 65% as compared to sham surgery. These results suggest that novelty preference behavior may be mediated by a central DA pathway similar to that involved in other types of reinforcing stimuli, such as food, water and drugs of abuse.

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.

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.

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.