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.Portions of this paper were presented at the 1992 Society for Neuroscience meetings, Anaheim, Cal., USA     

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.Portions of this paper were presented at the 1990 Society for Neuroscience meetings, St. Louis, MO, USA     

Role of D1-like receptors in amphetamine-induced behavioral sensitization: a study using D1A receptor knockout mice

RATIONALE: The role played by D(1)-like receptors in amphetamine-induced behavioral sensitization has been examined using both the D(1)-like receptor antagonist, SCH 23390, and the D(1A) receptor knockout mouse (i.e. D(1A)-deficient mice). Studies using these two approaches have provided conflicting evidence about the importance of D(1)-like receptors for amphetamine-induced behavioral sensitization. OBJECTIVE: The purpose of the present study was to determine: (a) whether D(1A)-deficient mice exhibit amphetamine-induced locomotor sensitization after 3 and 17 drug abstinence days, and (b) whether SCH 23390, which binds to both D(1A) and D(1B) receptor subtypes, blocks development of amphetamine sensitization in wild-type and D(1A)-deficient mice. METHODS: In the first experiment, adult wild-type and D(1A)-deficient mice were injected with amphetamine (0, 1, 2, 4, or 8 mg/kg, IP) for 7 consecutive days. In the second experiment, wild-type and D(1A)-deficient mice were pretreated with SCH 23390 (0, 0.15, or 0.5 mg/kg, IP) 30 min prior to being injected with amphetamine (0 or 8 mg/kg, IP). After each daily amphetamine injection, mice were placed in activity chambers where distance traveled (i.e. horizontal locomotor activity) was measured for 60 min. On the test days, which occurred after 3 or 17 drug abstinence days, mice were injected with 1 mg/kg amphetamine and locomotion was measured for 120 min. RESULTS: Both wild-type and D(1A)-deficient mice exhibited amphetamine-induced locomotor sensitization. Pretreatment with 0.5 mg/kg SCH 23390 blocked the development of locomotor sensitization in wild-type mice, but did not alter the sensitized responding of D(1A)-deficient mice. CONCLUSIONS: It appears that D(1)-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D(1A) nor D(1B) receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D(1A)-deficient mice. A possible explanation for these conflicting results is that D(1A)-deficient mice may have a compensatory mechanism (not involving D(1B) receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D(1A) receptor.     

Post-training minaprine enhances memory storage in mice: involvement of D1 and D2 dopamine receptors

Post-training administration of minaprine (2.5, 5 and 10 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in mice. Animals receiving nine daily injections of 5 mg/kg and administered a challenge dose post-training showed an improvement in memory consolidation similar to that produced by acute injection of 10 mg/kg. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during training were not affected by post-training drug administration. The effects of an acutely injected dose (10 mg/kg) of minaprine as well as those of a challenge dose (5 mg/kg) of the drug administered to repeatedly treated animals were reversed by pretreatment with either selective D₁ or D₂ dopamine receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in the effects of minaprine on memory consolidation. These results show that minaprine improves memory consolidation and that repeated drug administration leads to potentiation of this effect. Moreover, the effects of minaprine on memory consolidation are related to its dopaminergic action.     

Role of nucleus accumbens dopamine D1 and D2 receptors in instrumental and Pavlovian paradigms of conditioned reward

RATIONALE: This study investigated the role of nucleus accumbens dopamine D1 and D2 receptors in two different paradigms of conditioned reward. OBJECTIVE: We addressed the question whether accumbal dopamine is important for the motor or for the motivational components of reward. METHODS: We compared the effects of intra-accumbal infusion of the dopamine D1 receptor antagonist SCH23390 (0.3, 1.0, 3.0 microg) and the D2 receptor antagonist sulpiride (0.3, 1.0, 3.0 microg) on conditioned lever pressing for food, with the effects on the inhibition of the startle response by a conditioned reward signal. RESULTS: Both the D1 and the D2 antagonist dose-dependently attenuated conditioned lever pressing for reward under a fixed-ratio of responding and increased the consumption of freely available lab chow. However, the preference for freely available pellets, and the attenuation of the startle response in the presence of a conditioned stimulus predicting reward were not impaired by blockade of accumbal dopamine receptors. CONCLUSIONS: Our data support the idea that dopamine in the nucleus accumbens is necessary for instrumental response selection in the context of reward rather than for the mere motor performance of behavior or for the evaluation of the hedonic properties of rewarding stimuli.     

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. Received: 28 May 1997/Final version: 2 April 1998     

Subthalamic high frequency stimulation induced rotations are differentially mediated by D1 and D2 receptors

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has clinically emerged as a promising approach in the treatment of Parkinson's disease, epilepsy, dystonia as well as compulsive and possibly other mood disorders. The underlying mechanisms are incompletely understood, but are definitely related to high frequency and likely to involve the dopamine (DA)-system. To further test this hypothesis the present study investigated the modulation of STN-HFS-induced circling by systemic and intracerebral injection of drugs acting on DA receptors in naive freely moving rats. Within this experimental setup, unilateral STN-HFS alone induced intensity-dependent circling. Systemic injections of selective D1- (SCH-23390) and D2-((-)-sulpiride) antagonists as well as the mixed D1 and D2 agonist apomorphine dose-dependently reduced STN-HFS-induced rotational behavior. Intracerebral microinjections of (-)-sulpiride but not SCH-23390 decreased circling when injected intrastriatally and increased the number of rotations when injected intranigrally (pars reticulata (SNr)). These data reveal that STN-HFS-induced contralateral circling is differentially modulated by D1 and D2 receptors. While D2 receptor-mediated effects involve the dorso-/ventrolateral striatum and the SNr, D1 receptors probably exert their actions via brain areas outside the striatum and SNr. These findings suggest the nigrostriatal DA-system to be specifically involved in the mediation of STN-HFS-induced motor effects.     

Effects of blockade of central dopamine D1 and D2 receptors on thermoregulation,metabolic rate and running performance

To assess the effects of a blockade of central D₁- and D₂-dopaminergic receptors on metabolic rate, heat balance and running performance, 10 nmol (2 μl) of a solution of the D₁ antagonist SCH-23390 hydrochloride (SCH,n= 6), D₂ antagonist eticlopride hydrochloride (Eti, n = 6), or 2 μl of 0.15 MNaCl (SAL, n = 6) was injected intracerebroventricularly into Wistar rats before the animals began graded running until fatigue (starting at i0 m/min, increasing by 1 m/min increment every 3 min until fatigue, 5% inclination). Oxygen consumption and body temperature were recorded at rest, during exercise and following 30 min of recovery. Control experiments with injection of two doses (10 and 20 nmol/rat) of either SCH or Eti solution were carried out in resting rats as well. Body heating rate, heat storage, workload and mechanical efficiency were calculated. Although SCH and Eti treatments did not induce thermal effects in resting animals, they markedly reduced running performance (–83%, SCH; -59% Eti, p < 0.05) and decreased maximal oxygen uptake (–79%, SCH; -45%, Eti, p < 0.05) in running rats. In addition, these treatments induced a higher body heating rate and persistent hyperthermia during the recovery period. Our data demonstrate that the alteration in dopamine transmission induced by the central blockade of dopamine- D₁ and D₂ receptors impairs running performance by decreasing the tolerance to heat storage. This blockade also impairs the dissipation of exercise-induced heat and metabolic rate recovery during the post-exercise period. Our results provide evidence that central activation of either dopamine- Di or D₂ receptors is essential for heat balance and exercise performance.     

Effects of dopamine receptor antagonists on sucrose consumption and preference

Effects of the dopamine D2 receptor antagonist sulpiride and the D1 antagonist SCH-23390 were examined, in rats, in two-bottle preference tests (sucrose versus water) and in single-bottle tests, at different sucrose concentrations. Both drugs decreased sucrose intake in single bottle tests, at low sucrose concentrations, but had no effect at high concentrations; reducing drive level had exactly the opposite pattern of effects. In two-bottle tests, both drugs reduced preference for the weakest sucrose concetration (0.7%) but increased preference for the strongest concentration (34%). The effects of antagonizing either subtype of DA receptor appear to be similar to those of reducing the concentration of sucrose.     

Short- and long-term heterologous sensitization of adenylate cyclase by D4 dopamine receptors

The D₄ dopamine receptor, a member of the D₂-like dopamine receptor family, may be important in the etiology and treatment of schizophrenia. The present study was designed to examine the effects of dopamine agonist exposure on adenylate cyclase activity in HEK293 cells stably expressing recombinant-D₄ receptors. Two hour pretreatment with dopamine receptor agonists resulted in heterologous sensitization of forskolin-stimulated cyclic AMP accumulation in intact cells expressing the D_4.2, D_4.4, or D_4.7 dopamine receptor variant. The potency and efficacy of dopamine for sensitization of cyclic AMP accumulation was comparable at all D₄ receptor variants. D₄ dopamine receptor-mediated sensitization was blocked by the D₄ antagonist, clozapine, and prevented by overnight pretreatment with pertussis toxin, implying a role for G_i/G_o proteins in heterologous sensitization. Further, long-term (18 h) agonist exposure resulted in a greater degree of sensitization of forskolin-stimulated cyclic AMP accumulation in both intact cells and membrane preparations of cells expressing the D₄ receptor, compared to 2 h agonist exposure, without altering the density of the receptors. In addition, long-term agonist exposure decreased the abundance of G_iα without altering the abundance of G_sα, whereas short-term agonist treatment had no effect on the immunoreactivity of either G protein. In summary, long-term agonist-induced sensitization of adenylate cyclase by the D₄ receptor may involve mechanisms that do not contribute to short-term sensitization. Received: 26 March 1998/Final version: 6 May 1998     

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D₃ versus D₂ dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01–0.1 mg/kg), the preferential D₂ agonist, bromocriptine (1–10 mg/kg) and the selective D₃ agonists, 7-OH-DPAT (0.003–0.1 mg/kg), PD 128907 (0.1–3 mg/kg), (+)3PPP (0.3–3 mg/kg), quinelorane (0.0001–0.003 mg/kg) and quinpirole (0.003–0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D₃ but not D₂ responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D₂/D₃ dopamine antagonists, haloperidol (0.1–0.4 mg/kg) and tiapride (10–60 mg/ kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission. Received: 25 January 1998/Final version: 24 April 1998     

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists: relevance to cocaine sensitization

The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D₂ autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D₁ receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D₁ class receptor agonist SKF 38393, the DA D₂ class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D₁ receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D₁ responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D₁ receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization. Received: 23 February 1998/Final version: 2 April 1998     

Effects of selective D-1 and D-2 dopamine antagonists on development of methamphetamine-induced behavioral sensitization

The present study examined effects of selective antagonists of D-1 and D-2 dopamine receptors on the development of behavioral sensitization produced by repeated methamphetamine (MAP) administration. Male Sprague-Dawley rats were divided into four groups. Each group received a daily injection of saline (control group), 4 mg/kg MAP (MAP group), 1 mg/kg YM-09151-2 plus 4 mg/kg MAP (YM+MAP group) or 0.5 mg/kg SCH 23390 plus 4 mg/kg MAP (SCH+MAP group) for 14 days. During daily injection for 14 days, the MAP group exhibited a progressive augmentation in locomotor and stereotyped behavior, whereas the progression of such behaviors in the YM+MAP and SCH+MAP group was completely prevented. After an abstinence period of 7 days, all groups received a challenge of 2 mg/kg MAP. The MAP challenge reproduced hyperlocomotion and intense stereotyped behavior only in the MAP group. However, neither the YM+MAP group nor the SCH+MAP group showed sterotypy. The manner in which both groups showed only hyperlocomotion was similar to that observed in the control group. These results indicate that both selective D-1 antagonists and selective D-2 antagonists not only reverse MAP-induced motor effects at each injection but also prevent the development of behavioral sensitization induced by repeated MAP administration.     

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats

RATIONALE: D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). OBJECTIVES: The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. METHODS: Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. RESULTS: SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. CONCLUSIONS: While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.     

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration ofd-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2:d-amphetamine, 0.25 µg/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not primed with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration ofd-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a fulld-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses ofd-amphetamine. In experiment 2c, the infusate (1 µgd-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbicstriatal systems, with particular reference to the mesoaccumbens dopamine projection.     

Administration of the D1-like dopamine receptor antagonist SCH-23390 into the medial nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug-seeking behavior in rats

Rationale. A growing literature indicates that increased dopamine transmission in the nucleus accumbens contributes to priming-induced reinstatement of cocaine-seeking behavior. Objectives. The present experiments were designed to assess the role of D₁-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug seeking. Methods. Rats were trained to lever press for cocaine using a fixed ratio (FR) 5 schedule of reinforcement. Drug-seeking was measured by active lever presses during daily 2-h sessions. After approximately 30 days of cocaine self-administration, the animals underwent an extinction phase during which cocaine was replaced with saline. Daily extinction sessions were conducted until responding was consistently less than 10% of the response rate maintained by cocaine self-administration. After the extinction phase, priming-induced reinstatement of cocaine-seeking behavior was assessed. Results. Cocaine dose-dependently reinstated cocaine seeking, with robust drug seeking at 10 mg/kg cocaine. Administration of the D₁-like dopamine receptor antagonist, SCH-23390 (0.1–1.0 μg), directly into the medial nucleus accumbens shell dose-dependently attenuated drug seeking induced by 10 mg/kg cocaine. Microinjection of 1.0 μg SCH-23390 into either the nucleus accumbens core or lateral septum had no influence on cocaine-seeking behavior. Conclusions. These results indicate that stimulation of D₁-like dopamine receptors in the medial nucleus accumbens shell contributes to drug-induced reinstatement of cocaine-seeking behavior.     

Age-related changes in human D1 dopamine receptors measured by positron emission tomography

The effects of age on the binding parameters of¹¹C-SCH23390, the highly selective ligand for central D1 dopamine receptors, at specific binding sites in the brain were studied. Seventeen healthy male volunteers (20–72 years old) participated. Regional radioactivity in the brain was followed for 40 min by positron emission tomography (PET). A high accumulation of radioactivity was observed in the striatum and there was a conspicuous accumulation in the neocortex. A two-compartment model was used to obtain quantitative estimates of rate constants of association (k₃) and dissociation (k₄). The binding potential (k₃/k₄) of the dopamine D1 receptors in the striatum and frontal cortex decreased by 35% and 39%, respectively, with age. The value of k₃ decreased by 58% in the striatum and 83% in the frontal cortex, whereas the value of k₄ decreased by 35% in the striatum and 72% in the frontal cortex with age.     

Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose,injection schedule,and test context

Rationale  Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically characterized. Objective  The aim of the present studies was to characterize the development and expression of ethanol sensitization in female Swiss mice by examining (1) the doses of ethanol that induce behavioral sensitization, (2) the doses of acute ethanol challenges that are necessary to express behavioral sensitization, (3) the effects of the intervals between administrations, and (4) the context dependency of ethanol sensitization. Materials and methods  Mice were i.p. injected for 8 days with various ethanol doses, and locomotion was recorded for 5 min. Two days after the last sensitization session, ethanol sensitization was tested in 30-min test sessions. Results  Mice repeatedly injected with 2.5 g/kg ethanol showed a progressive (200–300%) increase in locomotor activity. In response to a 2.5 g/kg ethanol challenge, the mice repeatedly treated with doses above 1.5 g/kg showed a significant sensitization. Following the induction of sensitization with the maximally effective sensitizing dose (2.5 g/kg), mice showed greater activation after challenges with 1.5, 2.0, 2.5, and 3.0 g/kg ethanol. The intervals (24, 48, or 96 h) between ethanol injections did not affect the induction or expression of sensitization. Finally, sensitization to 2.5 g/kg ethanol was expressed regardless of the context in which it was induced. Conclusions  Female Swiss mice develop a robust context-independent sensitization after repeated ethanol injections at all doses above 1.5 g/kg, including highly sedative doses such as 4 g/kg.     

Reversal of antidepressant action by dopamine antagonists in an animal model of depression

Rats subjected chronically (12 weeks) to a variety of mild, unpredictable stressors showed a reduced consumption of sucrose or a sucrose/saccharin mixture in two-bottle consumption tests (sweet solution versus water). The deficit was apparent within 2 weeks of stress; normal behaviour was restored by chronic (7 weeks) treatment with the tricyclic antidepressants desmethylimipramine (DMI) or amitriptyline (AMI). Acute administration of the dopamine D1 receptor antagonist SCH-23390 1 week after withdrawal, or the dopamine D2 receptor antagonist sulpiride 2 weeks after withdrawal, were without effect in vehicle-treated stressed animals, and in non-stressed animals. However, the DA antagonists selectively reversed the improvement of performance in DMI- or AMI-treated stressed animals. This suggests that an increase in functional activity at DA synapses is the mechanism of action of DMI and AMI in this model.