Neural mechanisms of tolerance to the effects of cocaine

Chronic use of cocaine in high doses can produce tolerance as assessed by various behavioral, neurochemical, cellular and molecular measures in specific brain regions. Tolerance to cocaine is indicated by drug discrimination and intracranial self-stimulation models, which show the development of tolerance after approximately 1 week of frequent cocaine treatment, with recovery after a similar period of cocaine abstinence. Tolerance to the reinforcing properties of cocaine depends on dose, duration and frequency of cocaine self-administered by experimental animal or human subjects. The mechanism underlying this effect may involve an absolute or relative attenuation of dopamine response to cocaine challenge after frequent or repeated treatment in the nucleus accumbens (NAc). Similarly, afferent and efferent NAc circuits exhibit reduced metabolic activity, which lasts throughout the early period of withdrawal following repeated treatment. Attenuation of immediate early gene response also occurs, which might be related to a functional desensitization of dopamine D1-like receptors. Furthermore, intracellular adaptive responses to chronic cocaine exposure induce striatal dynorphin expression decreasing the behavioral potency of subsequent drug treatment. Thus, a combination of various pharmacodynamic mechanisms and the attenuation of dopamine response induced by sufficient dose, duration and frequency of cocaine exposure ultimately invoke the transient development of tolerance to the reinforcing effects of cocaine.     

Effects of in utero cocaine exposure on the expression of mRNAS encoding the dopamine transporter and the D1, D2 and D5 dopamine receptor subtypes in fetal rhesus monkey

The effects of in utero cocaine exposure on the development of the mRNAs encoding the dopamine transporter (DAT) and the D1, D2 and D5 dopamine receptor subtypes were determined in fetal monkey brains at day 45 and day 60 of gestation. Pregnant monkeys were treated with cocaine 3 mg/kg or saline i.m., four times a day from day 18 of gestation until the pregnancy was terminated at day 45 or day 60. The fetal brains were dissected, and tissue RNA extracted and quantified using ribonuclease protection assay analysis. In day 45 fetal monkeys, dopamine D1 and D2 receptor subtype mRNAs and DAT mRNA were found in low quantities both in control and cocaine-treated subjects. In day 60 fetal monkeys, D1 receptor mRNA levels were highest in the frontal cortex/striatal area, and low to moderate quantities were found in diencephalic and mesencephalic fetal brain regions. Dopamine D2 receptor mRNA levels were highest in the frontal cortex/striatal area, diencephalon and the midbrain, moderate in the brainstem and low in the caudal temporal lobe and surrounding cortical areas. Dopamine D5 receptor mRNA was expressed in low quantities throughout the day 60 fetal monkey brain, whereas DAT mRNA was found in the midbrain only. In utero cocaine exposure caused a significant increase in dopamine D1, D2 and D5 receptor subtype mRNAs in the frontal cortex/striatal area of day 60 fetal monkeys. These results support the hypothesis that dopamine synthesis and release may be reduced in cocaine-treated fetuses, which results in dopamine receptor up-regulation.     

D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum

Psychomotor stimulants such as cocaine alter gene expression in neurons of the striatum. Whereas many of these effects are mediated by D1 dopamine receptors, the involvement of other dopamine receptor subtypes or neurotransmitters is likely. To distinguish between these possibilities, regulation by cocaine of immediate-early genes and genes encoding neuropeptides was analysed in mice that lack functional D1 receptors. Gene expression was examined with in situ hybridization histochemistry. In these animals, cocaine failed to induce the immediate-early genes c-fos and zif 268. In contrast, substance P expression was abnormally increased by this drug. These results demonstrate that some of the effects of cocaine on gene regulation are mediated via D1 receptor-dependent mechanisms, as evidenced by the absence of immediate-early gene induction in D1-deficient mice, whereas others also involve additional, non-D1 receptor mechanisms, as shown for substance P expression.     

D1 receptors mediate dopamine action in the fetal suprachiasmatic nuclei: studies of mice with targeted deletion of the D1 dopamine receptor gene

Studies in rodents suggest the presence of a dopaminergic system that influences the function of a biological clock in the hypothalamic suprachiasmatic nuclei (SCN). To provide insights into mechanisms of dopamine action in the SCN, we studied transgenic mice that had either one allele (+?-) or both alleles (-/-) of the D1 dopamine receptor gene deleted, along with normal (+/+) littermates. As expected, receptor labelling autoradiography studies using [125I]SCH 23982 showed a complete absence of D1 dopamine receptor binding sites in the SCN of -/- animals. When pregnant mice from +?- x +?- matings were injected with the D1 receptor agonist SKF 38393, or the dopamine reuptake blocker GBR 12909 at day 19 of gestation, c-fos mRNA expression was observed in the SCN of +/+ fetuses. In contrast, c-fos mRNA induction was not seen in -/- or +?- litter mates. Injection of cocaine into pregnant dams also resulted in robust SCN c-fos mRNA expression in +/+ mice. Increases in SCN c-fos mRNA expression were also seen in +?- and -/- mice suggesting that cocaine action in the SCN involves both D1 receptor-dependent and -independent mechanisms. Collectively, our studies of transgenic mice deficient in D1 receptors support the presence of a functional dopaminergic system in the fetal SCN. We also identify D1 receptors as the prominent transducer of dopamine action in the fetal SCN.     

Striatal dopaminergic abnormalities in human cocaine users

OBJECTIVE: Previous human postmortem experiments have shown an abnormally high number of dopamine uptake sites in the striatum of chronic cocaine users, which might contribute to cocaine withdrawal symptoms such as depression and suicidality. Previous inconsistencies in results were perhaps related to selective radioligand affinity changes or a coexisting loss of dopamine neurons. METHOD: In the present study, binding of the cocaine analog [3H]WIN 35428 to the dopamine transporter was assayed in postmortem striatal samples from 15 cocaine-using subjects and 15 matched comparison subjects to determine whether there were differences in number of binding sites or in affinity. Binding to the vesicular monoamine transporter, a measure of total dopaminergic terminals, was also assessed by using the radioligand (+)-[3H]dihydrotetrabenazine (DTBZ). RESULTS: Striatal [3H]WIN 35428 binding sites were significantly more numerous in the cocaine users: the mean Bmax value was 9.0 fmol bound/microg protein (SD = 2.8) for the cocaine users but only 6.0 (SD = 1.7) for the comparison subjects. Severity of chronic cocaine use was significantly related to [3H]WIN 35428 binding level. [3H]DTBZ binding was significantly lower in the cocaine users (mean = 330 nCi/mg, SD = 42) than in the comparison subjects (mean = 374, SD = 68). CONCLUSIONS: The present results confirm that cocaine users have a high number of dopamine transporter binding sites on dopaminergic neurons, despite an apparent low number of total dopamine terminals. These abnormalities may contribute to the abnormalities in subjective experience and behavior characteristic of chronic cocaine abusers.     

PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects

OBJECTIVE: Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge. METHOD: Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers. RESULTS: All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site. CONCLUSIONS: These results support the concept of dopamine system involvement in human cocaine abuse.     

Continuous cocaine induces persisting alterations in dopamine overflow in caudate following perfusion with a D1 agonist

The present study examined whether exposure to 5 days of continuous cocaine in rats would produce any persisting alterations of the decrease in striatal dopamine (DA) overflow produced by local infusion of a D1 receptor agonist. Using a microdialysis probe in striatum, changes in DA, DA metabolites, and GABA were assessed 14 to 21 days following a 5-day continuous cocaine treatment. There were no differences in baseline levels of DA and it's metabolites. SKF 38393 (10(-6) infusion into the striatum decreased striatal DA levels in the controls and this effect was attenuated in cocaine-pretreated rats. This result, together with other observations, supports the hypothesis of a persistently altered D1-mediated negative feedback produced by previous exposure to continuous cocaine.     

In vivo amygdala dopamine levels modulate cocaine self-administration behaviour in the rat: D1 dopamine receptor involvement

Nucleus accumbens dopamine is often hypothesized as the critical factor for modulating cocaine self-administration. In the current study we examined the extent to which dopamine in the amygdala could contribute to cocaine intake behaviour and modify nucleus accumbens dopamine levels. Rats were trained to self-administer intravenous cocaine (1.5 mg/kg/injection) under a fixed-ratio reinforcement schedule in daily 3 h operant training sessions. In the first in vivo microdialysis experiment, extracellular dopamine levels were found to be increased 200% of baseline in the amygdala and by 400% in the nucleus accumbens. Although cocaine induced similar profiles of dopamine overflow in the two mesolimbic areas, in the nucleus accumbens the latency of the dopaminergic response was shorter (three- to four-fold) during both initiation and termination of the cocaine self-administration session than in the amygdala. Despite achieving a stable self-regulated pattern of cocaine intake and high dopamine concentrations in the nucleus accumbens, a unilateral injection of the D1 receptor antagonist SCH 23390 (0.5 or 1.5 microg) into the amygdala was still able to increase the rate of cocaine intake. This behavioural effect was accompanied by a dose-dependent increase in nucleus accumbens dopamine levels; at the highest SCH 23390 concentration cocaine intake was increased by 400% and dopamine levels were potentiated by an additional 400%. In vivo autoradiography using [3H]SCH 23390 showed that D1 receptor sites contributing to the behavioural and subsequent neurochemical effects were predominantly localized to the amygdala and not the nucleus accumbens. Altogether these results point to a significant contribution of in vivo amygdala D1 dopamine transmission to cocaine self-administration behaviour.     

Regulation of the Na+/K(+)-ATPase pump in vitro after long-term exposure to cocaine: role of serotonin

Long-term exposure to cocaine can cause persistent behavioral changes and alterations in neuronal function. One cocaine-regulated mRNA in the rat brain is the beta-1 subunit of the Na+/K(+)-ATPase pump. We examined both Na+/K(+)-ATPase function and expression after cocaine treatment of pheochromocytoma cells. One-hour exposure to cocaine did not alter Na+/K(+)-ATPase activity, as measured by the ouabain-sensitive component of rubidium uptake. Four days of cocaine resulted in an approximately 30% decrease in Na+/K(+)-ATPase activity. Western blot analyses demonstrated an approximately 25% decrease in levels of the beta-1 isoform, without changes in pump total alpha subunit levels. Treatment with dopamine type 1 or type 2 receptor agonists for the same period did not affect Na+/K(+)-ATPase activity. The serotonin-selective reuptake inhibitor paroxetine caused an approximately 45% decrease in rubidium uptake after 4 days, whereas pump function was not altered after treatment with either the dopamine-selective reuptake blocker nomifensine or the norepinephrine-selective reuptake blocker desipramine. Chronic treatment with both cocaine and LY 278,584, a serotonin type 3 receptor antagonist, did not replicate the cocaine-associated decrease in pump function. Long-term cocaine exposure regulates expression and function of the Na+/K(+)-ATPase pump in neuronal-like cells; this regulation is mediated in part via the serotonin type 3 receptor. Similar Na+/K(+)-ATPase pump regulation in vivo may selectively alter neuronal function in the mammalian brain.     

Effect of chronic treatment with typical and atypical neuroleptics on the expression of dopamine D2 and D3 receptors in rat brain

The effect of chronic treatment (21 days) with typical and atypical neuroleptics on the expression of striatal and limbic D2 and D3 dopamine receptors was investigated in rat brain by in situ hybridization and receptor autoradiography. Haloperidol and sulpiride increased D2 receptor expression in striatal and limbic areas. In contrast, clozapine had no effect on D2 receptor expression. Haloperidol decreased D3 receptor expression in limbic areas, with the exception of the islands of Calleja where an increase occurred. Sulpiride and clozapine increased D3 receptor expression in limbic and striatal regions but decreased D3 receptor expression in the islands of Calleja. This study demonstrates that chronic treatment with typical and atypical neuroleptics produces different regionally specific changes in limbic and striatal D2 and D3 receptor expression. The alterations in dopamine receptor expression were different for each drug, but a distinction between the effects of atypical and typical neuroleptics could be made. Comparison of mRNA levels in animals which were not withdrawn from drug treatment with those that were withdrawn, demonstrated that some changes in receptor expression occurred during drug treatment, whilst others only manifested when drug treatment had ceased. The different regulation of dopamine D2 and D3 receptor expression by typical and atypical neuroleptics may have relevance to the ability of these drugs to cause extrapyramidal side-effects.     

Cocaine, dopamine and the endogenous opioid system

Cocaine addiction and opiate addiction are both major health problems in the United States today. Prospective studies from our Laboratory, which were able to detect the advent of the HIV-1 epidemic in parenteral drug abusers in New York City beginning around 1978, also showed that, from the beginning of the AIDS epidemic, cocaine abuse was a very important co-factor significantly increasing the risk for developing cocaine dependency. Fundamental studies from many laboratories including our own have shown that cocaine has profound effects on dopaminergic function, primarily from its well-established primary action of blocking the reuptake of dopamine from the synaptic cleft, an action of cocaine directed at the specific dopamine transporter. It has also been well-established by others that cocaine similarly blocks the reuptake of serotonin and norepinephrine. However, recent studies from our laboratory have shown that chronic cocaine administration profoundly disrupts the endogenous opioid system. Extensive studies have been conducted using an animal model which we have developed in our laboratory, the "binge" pattern cocaine administration model. Findings from these studies have led us to recognize the profound disruption of both dynorphin gene expression and kappa opioid receptor gene expression in a setting of chronic cocaine administration and, in turn, have led us to question a possible role of disruption of this system in the acquisition and persistence of cocaine addiction. These findings may have significance for the development of new pharmacotherapeutic agents which may be directed to specific components of the endogenous opioid system and, in particular, possibly the kappa opioid receptor system. Therefore, we have initiated studies to examine further the role of the dynorphin peptide-kappa opioid receptor system in normal physiologic function in humans.     

Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration

The present experiment examined whether ondansetron, co-administered with continuous cocaine, would block the down regulation of accumbens 5-HT3 receptors. Rats were exposed to a 14-day pretreatment regimen that involved the continuous infusion of 40 mg kg(-1) day(-1) cocaine or 0.9% saline via a subcutaneously implanted osmotic minipump. In addition to the continuous cocaine or saline administration, all subjects received daily subcutaneous (s.c.) injections of either vehicle or 0.1 mg kg(-1) ondansetron for the entire 14-day pretreatment regimen. The rats were then withdrawn from this pretreatment regimen for seven days, and slices from the nucleus accumbens obtained. The slices were perfused with 25 mM K+ in the absence and presence of 0, 12.5, 25, or 50 microM m-Chlorophenyl-biguanide HCl (mCPBG). The efflux samples were assayed for dopamine content by high pressure liquid chromatography (HPLC) with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-induce dopamine overflow compared to saline control rats. In addition, the rats that received ondansetron and cocaine during the 14-day pretreatment period, the ability of mCPBG to enhance K+ stimulated dopamine release was not significantly different from the saline control subjects. For all groups except the cocaine alone group, the effects of mCPBG on K+ stimulated dopamine release were Ca2+ dependent, suggesting that these effects are receptor mediated. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and that this down-regulation can be blocked by chronic ondansetron administration. Hence, a functional down regulation of accumbens 5-HT3 receptors represents a significant contribution to the tolerance induced by continuous cocaine administration.     

Specific reductions of striatal prodynorphin and D1 dopamine receptor messenger RNAs during cocaine abstinence

It is well established that the opioid neuropeptide and dopamine systems are altered following the use of cocaine. However very little information is available about their possible involvement during cocaine abstinence. In the present study, the mRNA expression of the dopamine receptors, D1 and D2, and the opioid peptides, prodynorphin and proenkephalin, were analyzed in the rat striatum using in situ hybridization histochemistry. Saline or cocaine (30 mg/kg, i.p.) were administered to rats once daily for 1 or 10 days. To examine cocaine abstinence, animals were treated for 10 days as described followed by a 10-day drug free period. Acute and intermittent cocaine administration elevated the prodynorphin mRNA expression in the dorsal striatum, consistent with previous reports, while the abstinent phase resulted in a significant reduction of prodynorphin mRNA levels in the ventrorostral striatum. The D1-receptor mRNA was decreased in the caudorostral striatum during cocaine withdrawal, a finding opposite to the increase observed following a single injection of the drug. Proenkephalin and the D2-receptor mRNAs were not altered during cocaine abstinence, though proenkephalin was elevated following acute but not repeated cocaine administration. These results show long-term suppression on prodynorphin and D1-receptor systems in specific striatal populations localized mainly in rostral areas during withdrawal from cocaine.     

Repeated neonatal maternal separation alters intravenous cocaine self-administration in adult rats

Behavioural responses to psychostimulant drugs can be profoundly affected by early environmental influences. The aim of this study was to describe the effects of repeated brief separations of rat pups from their dams during the early neonatal period on cocaine self-administration behaviour as adults. Lister hooded rats exposed to a repeated maternal separation procedure (REMS) showed altered acquisition and maintenance of cocaine self-administration as adults, the effects being dose and gender-dependent. Overall, the patterns of acquisition of self-administration across three doses of cocaine (0.05, 0.08 and 0.5 mg/injection) suggested a rightward shift in the acquisition dose-effect functions for the REMS animals relative to control animals. At 0.05 mg/injection, there was a retarded acquisition of cocaine self-administration in male and female neonatally separated rats. At 0.08 mg/injection there was a facilitated acquisition in female neonatally separated subjects. After establishment of stable self-administration of the training dose, in the same cohort of subjects, rightward and downward shifts in the cocaine self-administration dose-effect functions were determined for female and male REMS subjects, respectively, relative to their controls. The dose-effect function for both female groups was shifted to the left of that of the respective male groups, although the lighter body weights of the females meant that they administered a higher unit dose per unit body weight than the males. Whereas male REMS subjects tended to self-administer less cocaine than the controls at the dose eliciting maximal responding (0.03 mg/injection) and to make fewer lever responses overall at each dose tested, female REMS subjects self-administered significantly more cocaine than their respective controls at a dose of 0.03 mg/injection. There was no differential sensitivity to the rate-altering effects of the selective dopamine D2 receptor antagonist, eticlopride, or to the selective dopamine D1 receptor antagonist, SCH 23390. These data provide further evidence that altered early environment affects drug-taking behaviour in a developmentally specific and gender-specific manner, with the effects of neonatal separation contrasting with previously published data on the effects of post-weaning isolation rearing.     

Specificity of the high-mannose recognition site between Enterobacter cloacae pili adhesin and HT-29 cell membranes

Dopamine D2 receptor agonists are commonly used in the control of PRL-secreting adenomas, and the sensitivity of dopamine agonists during long term therapy is exquisite. However, the molecular mechanisms responsible for the maintenance of this cellular sensitivity to dopamine agonists remain poorly understood. In the present study, we examined the agonist-induced regulation of the human D2L receptor expressed to a specific activity of approximately 1 pmol receptor/mg protein in Sf9 insect cells. Treatment of D2L receptor-expressing cells with dopamine for up to 3 h resulted in no detectable change in the ligand-binding properties of the receptor and a approximately 120-fold reduction in the potency, but not the efficacy, of D2L receptors to mediate dopamine inhibition of forskolin-stimulated adenylyl cyclase activity. This resistance of the D2L receptor to agonist-induced desensitization was accompanied by a approximately 28% translocation of intracellular D2L receptors to the cell surface, as quantified by cellular fractionation and radioligand binding and visualized by whole cell immunocytochemical staining and confocal microscopy. Immunoblot analysis of the P2 membrane fraction revealed that surface D2L receptors comprised monomers and dimers. Treatment of D2L receptor-expressing cells with the protein synthesis inhibitor cycloheximide significantly reduced the basal expression level of receptors, but did not block the agonist-induced up-regulation of receptors. Longer periods of dopamine exposure for 24 h brought about a small increase in surface receptor density. However, when these studies were conducted in the presence of cycloheximide, receptor density was marginally reduced, suggesting that receptor synthesis accounts for the maintenance of cellular receptor density under these conditions. We conclude that the resistance of the D2L receptor-coupled adenylyl cyclase system to agonist-induced desensitization is attributed to the up-regulation of surface receptors after the translocation of existing intracellular receptors and de novo receptor synthesis.     

Alterations in locomotor activity during chronic cocaine administration: effect on dopamine receptors and interaction with opioids

Chronic cocaine administration can produce tolerance or sensitization to locomotor activating effects, depending on the treatment paradigm. The effects of chronic, continuous cocaine were measured on locomotor activity for 1 hr daily for 7 days. Cocaine produced significant increases in locomotor activity 4 hr after osmotic minipumps were implanted, and an even higher level of activity after 24 hr. This was likely a rapid sensitization to the locomotor activating effects of cocaine, because neither brain nor plasma levels of cocaine were significantly altered over the treatment period. By day 4, activity levels diminished, but remained significantly higher than in saline-treated animals. Twenty-four hr after pump removal, there were no changes in dopamine D1 or D2 receptor binding, or in dopamine-stimulation of adenylyl cyclase activity in either caudate putamen or nucleus accumbens of cocaine-treated animals. Chronic naltrexone produced a slight, nonsignificant decrease in locomotor activity and when combined with cocaine, produced the same pattern of activity as cocaine alone, but with slightly less stimulation on all days. Morphine produced a smaller increase in activity than cocaine that remained constant throughout the treatment week. Cocaine with morphine was additive, producing greater activity and less tolerance than cocaine alone. Thus, continuous cocaine administration produces a rapid sensitization that is lost over the course of the treatment period, yet does not produce any immediate alterations in dopamine receptors or regulation of adenylyl cyclase. The pattern of behavior is not altered by an opioid antagonist, while the sensitization period appears to be prolonged in the presence of an opioid agonist.     

The effects of cocaine, amphetamine, and the dopamine D1 receptor agonist SKF 38393 on fear extinction as measured with potentiated startle: implications for psychomotor stimulant psychosis

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) D1 receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions.     

Effects of dopamine D1 and D2 receptor antagonists on cocaine-induced place preference conditioning in preweanling rats

The effects of dopamine D1 and D2 receptor antagonists on the reward processes of 10- and 17-day-old rats were assessed using the conditioned place preference paradigm. Conditioning and testing were conducted in a three-compartment chamber, with each end compartment having its own distinct tactile and odor cues (almond and lemon). During six experiments, 10- and 17-day-old rats (age at initial conditioning) were injected intraperitoneally with either saline, the dopamine D1 receptor antagonist R(+/-)-SCH 23390 hydrochloride (0.01-1.0 mg/kg), or the dopamine D2 receptor antagonists (+/-)-sulpiride (1-100 mg/kg) or S(-)-eticlopride hydrochloride (0.1-0.5 mg/kg) 30 min prior to being injected with cocaine hydrochloride (20 mg/kg) or saline. After the latter injections, rats were immediately confined in the lemon-scented (nonpreferred) compartment for 30 min. On the alternate conditioning day, rats were injected with saline and confined in the almond-scented compartment. On the third day (i.e., the test day), rats were given saline and allowed free access to the entire chamber for 15 min. The results showed that the dopamine D1 receptor antagonist SCH 23390 blocked the cocaine-induced place preference conditioning of both 10- and 17-day-old rats. Surprisingly, the dopamine D2 receptor antagonists sulpiride and eticlopride blocked the place preference conditioning of 10-day-old rats, while leaving the 17-day-old rats unaffected. These results indicate that dopamine D1 receptors are critically involved in the reward processes of preweanling rats, but that the importance of dopamine D2 receptors changes across ontogeny.     

Limitations to the generality of cocaine locomotor sensitization.

Repeated exposure to cocaine often leads to tolerance to effects on operant behavior, whereas sensitization often develops to effects on locomotor activity. The purpose of the present set of experiments was to examine if locomotor sensitization to cocaine would develop in the presence or absence of an operant contingency in rats. In Experiment 1, rats lever pressed on an FR schedule of reinforcement, and were administered chronic cocaine. Tolerance to effects of cocaine on lever pressing developed in most subjects. No subjects developed locomotor sensitization even when the operant contingency was removed. Experiment 2 examined effects of chronic cocaine administration in rats with no exposure to an operant contingency. Tolerance developed to locomotor effects of cocaine in some subjects, but none developed sensitization. In Experiment 3, rats were exposed to a shorter drug regimen, and given time off before a sensitization-test session. Some, but not all subjects showed locomotor sensitization during the test session. The present results, therefore, show that locomotor sensitization to cocaine is not an inevitable consequence of repeated exposure to the drug. (PsycINFO Database Record (c) 2010 APA, all rights reserved)