Behavioral sensitization to dopaminergic inhibitory and stimulatory effects induced by low vs. high dose apomorphine treatments: An unconventional dose and response reversal sensitization challenge test reveals sensitization mechanisms

Low dose apomorphine treatments preferentially activate dopamine autoreceptors and inhibit dopamine neurons as well as behavior. In contrast, high doses of apomorphine induce locomotor stimulation by activating dopamine postsynaptic receptors. We compared the effects of low (0.05 mg/kg) vs. high (2.0 mg/kg) repeated apomorphine treatments (5) using paired/unpaired protocols upon the development of Pavlovian conditioned drug responses and upon drug sensitization effects. In addition to the conventional challenge test for sensitization, we also conducted a treatment reversal sensitization test in which low dose groups received the high dose treatment and vice versa. The high dose treatment produced the expected Pavlovian conditioned locomotor stimulant response as well as a sensitization effect in the high dose challenge test; but in the low dose challenge test, the effect was desensitization. The low dose apomorphine regimen induced an inhibitory sensitization effect in the low dose challenge test. In the high dose reversal challenge test, there was a sensitization effect to the locomotor stimulant effect. The low dose apomorphine treatments, however, did not produce a Pavlovian conditioned locomotor inhibitory effect. Surprisingly, the dose reversal challenge test revealed context-independent as well as context-specific sensitization/desensitization effects. These findings demonstrate that Pavlovian drug conditioned effects and drug sensitization effects are independent phenomena and that sensitization effects are not response specific. Moreover, context-specific vs. context-independent sensitization effects were protocol dependent but not drug dose dependent.     

Prenatal methamphetamine exposure affects the mesolimbic dopaminergic system and behavior in adult offspring

Methamphetamine is a commonly abused psychostimulant that causes addiction and is often abused by pregnant women. Acute or chronic administration of methamphetamine elevates the levels of the extracellular monoamine neurotransmitters, such as dopamine.The aim of the present study was to show whether prenatal exposure to methamphetamine (5 mg/kg, entire gestation) or saline in Wistar rats induces changes in dopamine levels and its metabolites in the nucleus accumbens, and in behavior (locomotor activity, rearing, and immobility) after the administration of a challenge dose of methamphetamine (1 mg/kg) or saline in male offspring.We found that adult offspring prenatally exposed to methamphetamine had higher basal levels of dopamine (about 288%), dihydroxyphenylacetic acid (about 67%) and homovanillic acid (about 74%) in nucleus accumbens. An increased basal level of dopamine corresponds to lower basal immobility in offspring prenatally exposed to methamphetamine. The acute injection of methamphetamine in adulthood increased the level of dopamine in the nucleus accumbens, which is related to an increase of locomotion and rearing (exploration). In addition, prenatally methamphetamine-exposed rats showed higher response to the challenge dose of methamphetamine, when compared to prenatally saline-exposed rats.In conclusion, rats exposed to methamphetamine in utero have shown changes in the mesolimbic dopaminergic system and were more sensitive to the administration of the acute dose of methamphetamine in adulthood.     

Effects of acute and chronic clozapine on dopaminergic function in medial prefrontal cortex of awake, freely moving rats

We previously showed that chronic administration of the clinically atypical and clinically superior antipsychotic drug clozapine selectively reduces dopamine (DA) release in the nucleus accumbens but not neostriatum, and that this effect appears mediated by anatomically selective mesolimbic DA depolarization blockade. The present study extends that research to another mesocorticolimbic DA locus, the medial prefrontal cortex. Acute clozapine challenge (5-40 mg/kg i.p.) produced dose-dependent increased extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the medial prefrontal cortex of awake, free-moving rats as measured by in vivo brain microdialysis. Chronic clozapine treatment (20 mg/kg/day for 21 days) did not significantly change basal extracellular levels of DA, DOPAC or HVA. Acute clozapine challenge on day 22 in the chronic clozapine-treated animals produced no significant differences in medial prefrontal cortex DA, DOPAC or HVA as compared to chronic vehicle-treated animals, indicating that tolerance to clozapine does not develop in the mesocortical DA system, in contrast to the mesolimbic system. The DA agonist apomorphine (100 micrograms/kg) produced decreased basal extracellular levels of DA, DOPAC and HVA in medial prefrontal cortex of both chronic clozapine-treated and chronic vehicle-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Conditioned and sensitized responses to stimulant drugs in humans

In animal models considerable evidence suggests that increased motivation to seek and ingest drugs of abuse are related to conditioned and sensitized activations of the mesolimbic dopamine (DA) system. Direct evidence for these phenomena in humans, though, is sparse. However, recent studies support the following. First, the acute administration of drugs of abuse across pharmacological classes increases extracellular DA levels within the human ventral striatum. Second, individual differences in the magnitude of this response correlate with rewarding effects of the drugs and the personality trait of novelty seeking. Third, transiently diminishing DA transmission in humans decreases drug craving, the propensity to preferentially respond to reward-paired stimuli, and the ability to sustain responding for future drug reward. Finally, very recent studies suggest that repeated exposure to stimulant drugs, either on the street or in the laboratory, can lead to conditioned and sensitized behavioral responses and DA release. In contrast to these findings, though, in individuals with a long history of substance abuse, drug-induced DA release is decreased. This diminished DA release could reflect two different phenomena. First, it is possible that drug withdrawal related decrements in DA cell function persist longer than previously suspected. Second, drug-paired stimuli may gain marked conditioned control over the release of DA and the expression of sensitization leading to reduced DA release when drug-related cues are absent. Based on these observations a two-factor hypothesis of the role of DA in drug abuse is proposed. In the presence of drug cues, conditioned and sensitized DA release would occur leading to focused drug-seeking behavior. In comparison, in the absence of drug-related stimuli DA function would be reduced, diminishing the ability of individuals to sustain goal-directed behavior and long-term objectives. This conditioned control of the expression of sensitized DA release could aggravate susceptibility to relapse, narrow the range of interests and perturb decision-making, accounting for a wide range of addiction related phenomena.     

Changes in apomorphine pharmacodynamics following repeated treatment in 6-hydroxydopamine-lesioned rats

Rats with 6-OHDA lesions were repeatedly treated with apomorphine and dose-response relationships compared before and after treatment to better understand the pharmacological mechanisms which result in sensitization. A progressive increase in the magnitude and duration of rotational behavior was observed following repeated treatment and was associated with a nonparallel (upward) shift in apomorphine dose-response curves. These changes are inconsistent with simple shifts in drug potency, and instead are more consistent with changes in the ability of apomorphine to stimulate postsynaptic, striatal efferent pathways which result from repeated drug administration.     

Continuous dopaminergic stimulation reduces risk of motor complications in parkinsonian primates

Levodopa or short-acting dopamine (DA) agonist treatment of advanced parkinsonian patients exposes striatal DA receptors to non-physiologic intermittent stimulation that contributes to the development of dyskinesias and other motor complications. To determine whether continuous dopaminergic stimulation can delay or prevent onset of motor complications, four MPTP-lesioned, levodopa-naive cynomolgus monkeys were implanted subcutaneously with apomorphine containing ethylene vinyl acetate rods. Three other MPTP-lesioned monkeys received daily injections of apomorphine. Animals receiving apomorphine rods showed improved motor function ('ON' state) within 1 day of implantation, and remained continually 'ON' for the duration of treatment (up to 6 months) without developing dyskinesias. Injected animals also showed similar improvement in motor function after each apomorphine injection. However, these primates remained 'ON' for only 90 min and within 7-10 days all developed severe dyskinesias. Implanted monkeys evidenced local irritation, which was alleviated by steroid co-therapy.     

Tyrosine hydroxylase, aromatic -amino acid decarboxylase and dopamine metabolism after chronic treatment with dopaminergic drugs

Mice were treated with dopamine (DA) receptor agonist and antagonist drugs: Agonists: (±)-SKF 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) [DA D₁-like]; bromocriptine, [DA D₂ selective]; quinpirole, [DA D₂/D₃ preferring]; (±)-7-hydroxy-dipropylamino-tetralin (7-OH-DPAT), [DA D₃/D₂ preferring], Antagonists: R(+)-SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), [DA D₁-like]; and haloperidol, [DA D₂-like]. All drugs were administered intraperitoneally, two injections daily 8 h apart for 30 days. Aromatic -amino acid decarboxylase (AAAD) and tyrosine hydroxylase (TH) activity, protein and mRNA, as well as DA metabolism were followed with time thereafter in the nigrostriatal neurons. We observed that chronic administration of D₁-like agonists had no effect on TH or AAAD activity, while D₂-like agonists decreased AAAD, but not TH activity. Additionally, chronic blockade of DA D₂-like receptors resulted in prolonged induction of TH and AAAD, while chronic blockade of DA D₁-like receptors induced changes of AAAD only. Compared to TH the induction of AAAD was longer lasting. DA metabolism was altered by chronic administration of drugs acting on DA D₂-like, but not DA D₁-like receptors, and in general the patterns of change did not follow those for TH or AAAD. When studied 48 h after the last dose of the chronic haloperidol schedule TH displayed tolerance to acute drug challenge. At the same time interval, there was tolerance to the enhancing effects of haloperidol and SCH 23390 on DA metabolism. The induction of AAAD by haloperidol or SCH 23990 did not appear to develop tolerance after chronic administration. These observations complement existing knowledge, and provide novel information about AAAD that may have practical importance for Parkinson's patients on -DOPA therapy.     

Genotype-dependent effects of chronic stress on apomorphine-induced alterations of striatal and mesolimbic dopamine metabolism

After 10 daily consecutive restraint experiences, DBA/2 (DBA) mice showed an increase of climbing behavior after injection of 0.25 mg/kg of the dopamine (DA) agonist apomorphine (APO), while no changes were observed following vehicle or 1 mg/kg of APO. By contrast, chronically stressed C57BL/6 (C57) mice showed a clear-cut decrease of climbing behavior at the dose of 0.25 mg/kg of APO and a similar, although less pronounced, effect of stress on the behavior of mice injected either with vehicle or with 1 mg/kg APO. The DA agonist at these same doses decreased 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) concentrations in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of both strains. Higher DOPAC, HVA and 3-MT concentrations were evident in stressed DBA mice receiving 0.25 mg/kg but not 1 mg/kg of APO, in both CP and NAS. Concerning C57 mice, lower concentrations of the 3 metabolites were present at both doses of APO in the NAS of stressed mice in comparison with non-stressed animals, while no significant stress-related effects were evident in the CP. Non-significant differences between control and stressed mice of both strains were evident as regards DA concentrations in CP and NAS. These results suggest that repeated stressful experiences lead to a hyposensitivity of DA presynaptic receptors in DBA mice while they produce a sensitization of mesolimbic DA presynaptic receptors possibly accompanied by down-regulation of postsynaptic DA receptors in the C57 strain.     

神经节苷脂对帕金森病鼠旋转行为、纹状体多巴胺浓度及黑质病理的影响

目的观察神经节苷脂对帕金森病（Ｐａｒｋｉｎｓｏｎｄｉｓｅａｓｅ，ＰＤ）鼠模型的旋转行为、纹状体多巴胺浓度及黑质病理的影响。方法将６－羟基多巴胺用立体定向法注入大鼠一侧中脑被盖腹侧区制作ＰＤ大鼠模型，并于同侧侧脑室注射混合型神经节苷脂（ａｍｉｘｅｄｇａｎｇｌｉｏｓｉｄｅｐｒｅｐａｒａｔｉｏｎ，ＧＭ），观察ＧＭ对由阿朴吗啡所诱发的旋转行为、受损侧纹状体多巴胺浓度及黑质病理的影响。结果ＧＭ能减轻ＰＤ大鼠模型的旋转行为、使受损侧纹状体多巴胺浓度下降和黑质神经细胞减少。结论ＧＭ可减轻６－羟基多巴胺对黑质多巴胺能神经元的损伤。     

NMDA glutamate receptor stimulation is required for the expression of D2 dopamine mediated responses in apomorphine primed 6-hydroxydopamine lesioned rats

Three priming injections with the D1/D2 dopamine agonist apomorphine permits a challenge with the D2 agonist quinpirole to elicit robust contralateral rotation and ipsilateral striatal Fos expression in 6-hydroxydopamine lesioned rats. Pretreatment with NMDA glutamate antagonists MK-801 or CPP dose-dependently attenuates these quinpirole-mediated responses. These findings suggest that concomitant NMDA receptor stimulation is required for the expression of D2-mediated responses in apomorphine primed dopamine-depleted rats.     

Acute effects of lithium on dopaminergic responses: iontophoretic studies in the rat visual cortex

The interactions between lithium and cortical dopaminergic receptors were investigated using the iontophoretic technique to record and apply dopaminergic compounds, GABA, acetylcholine and LiCl on neurons in the primary visual cortex of the rat. The main responses to dopamine (DA) or to the D1 agonist (+/- )SKF38393 on spontaneously-active (SA) or visually-driven (VD) units was a prolonged decrease in firing and a reduction in the responsiveness to pulses of acetylcholine. The D1 antagonist SCH23390, applied iontophoretically or intravenously, blocked or attenuated the inhibitory responses to both DA and (+/- )SKF38393. The D2 agonist quinpirole (LY171555) either produced only slight excitations or had no effects on both VD and SA units. The concomitant application of lithium blocked the inhibitory responses to DA and to (+/- )SKF38393 but did not modify the responsiveness to LY171555. In addition, the DA- and (+/- )SKF38393-induced decreases in responsiveness to acetylcholine were also suppressed by lithium. These effects were on dopaminergic mechanisms, since the excitatory responses to acetylcholine alone as well as the inhibitions caused by GABA were unchanged by the application of lithium. These results imply that the modifications in sensitivity to dopaminergic agents induced by lithium are mediated by dopamine D1 receptors and are discussed in relation to adenylate-cyclase.     

Potent, hydroxyl radical-scavenging effect of apomorphine with iron and dopamine perfusion in rat striatum

In dopaminergic neurons, free radicals are likely produced via dopamine metabolism by monoamine oxidase or via its auto-oxidation, a process facilitated by transition metals. In this study we examined the effect and possible mechanisms of apomorphine to reduce iron- and dopamine-induced 2,3-dihydroxybenzoic acid (2,3-DHBA) formation by microdialysis. We have shown that (1) FeSO(4).7H(2)O reduced both the release of dopamine and the output of dihydroxyphenylacetic acid (DOPAC); (2) apomorphine may reduce FeSO(4).7H(2)O-induced increases of 2,3-DHBA formation; (3) apomorphine has substantially reduced DOPAC output in early phase and blocked dopamine-induced increase of 2,3-DHBA levels. It is concluded that apomorphine is a potent hydroxyl radical scavenger in vivo, especially for the dopamine formation.     

Modulation of apomorphine-induced stereotypy by estrogen: Time course and dose response

Previous data have indicated that estrogen may either suppress or enhance the potency of dopamine and/or dopamine agonists. The effects of estrogen (estradiol benzoate; EB) in ovariectomized rats were indicative of a dose related suppression of apomorphine-induced stereotypy at 24 hours after the last dose of EB. However, at 48 hours after the last dose of EB, the apomorphine-induced stereotypy was enhanced in those animals that received EB at 100 μg/kg × 3 days. Ninety-six hours after the last injection of EB, all animals that received either the 100 or 50 μg/kg dose of EB displayed an enhanced behavioral response to apomorphine. Animals pretreated with a low dose of EB (10 μg/kg × 3 days) displayed a suppressed apomorphine stereotypy score at 24 hours, after the last dose, but were indistinguishable from Oil injected ovariectomized controls in all subsequent behavioral tests. These data indicate that estrogen can suppress dopamine and/or dopamine agonist potency 24 hours after the last dose of estrogen. However, an enhanced behavioral response to dopamine agonists can be seen at 48 hours (or more) after the last dose of estrogen. The time delay and the dose dependence of the enhanced response to dopamine agonists are indicative of a “withdrawal” phenomenon, suggesting the possibility that the role of endogenous estrogen is to suppress dopaminergic function.     

Induction of tolerance to ischemia: Alterations in second-messenger systems in the gerbil hippocampus

Preconditioning the brain with sublethal ischemia protects against neuronal damage following subsequent ischemic insult. Using [3H]inositol 1,4,5-triphosphate (IP3), [3H]phorbol 12,13-dibutyrate (PDBu), [3H]cyclic adenosine monophosphate (cAMP) and [3H]rolipram, we performed quantitative autoradiography to determine postischemic alterations in second-messenger systems in the gerbil hippocampus following preconditioning the brain with sublethal ischemia. At 7 days of reperfusion, no alterations were observed in brains subjected to 2 min of forebrain ischemia which produced no neuronal damage. However, 3-min ischemia caused a 75% reduction in [3H]IP3 binding (p < 0.01 vs. control) and 15-25% reductions in [3H]forskolin (p < 0.01 vs. control), [3H]cAMP (p < 0.05 vs. control), and [3H]rolipram (p < 0.01 vs. control) binding in the CA1 subfield coincident with histopathological CA1 pyramidal cell destruction, but no significant alterations in [3H]PDBu binding. Preconditioning the brain with 2 min of ischemia followed by 4 days of reperfusion prevented both histopathological cell death and the reductions in binding following subsequent 3 min of ischemia. Interestingly, [3H]IP3 and [3H]rolipram binding in CA1 showed a transient reduction, by 30% and 20% (both p < 0.01 vs. control), respectively, in the early reperfusion period. This downregulation of the IP3 system may play a role in the protection against cell death.     

Dopamine depletion in the medial prefrontal cortex induces sensitized-like behavioral and neurochemical responses to cocaine

It has been postulated that behavioral sensitization to cocaine is associated with an attenuation of cocaine-induced dopamine (DA) transmission in the medial prefrontal cortex (mPFC). Hence, experiments were designed to examine the effects of chemically-induced cortical DA depletion on the acute behavioral and neurochemical responses to cocaine. One week following two bilateral 6-hydroxydopamine (6-OHDA) injections into the mPFC, animals received injections of cocaine (7.5, 15 or 30 mg/kg, i.p.) or saline (1 ml/kg, i.p.) in a randomized fashion with a minimum 3 day intertrial interval. Cocaine produced a dose-dependent increase in motor activity which was significantly enhanced in animals depleted (mean of 76%) of dopamine in the mPFC. Likewise, 6-OHDA lesions of the mPFC produced a significant enhancement of cocaine-induced DA transmission in the nucleus accumbens (NAC) as estimated by in vivo microdialysis. These data indicate a permissive involvement of cortical DA in mediating behavioral and neurochemical responses to cocaine, as well as confirm the ability of the mPFC to influence subcortical structures in response to an acute injection of cocaine. Collectively, the present findings suggest that alterations in cortical DA transmission may be a neural substrate mediating the development of sensitization to cocaine, and thus, may contribute to the addictive properties of cocaine.     

Medial preoptic area dopaminergic responses to female pheromones develop during puberty in the male Syrian hamster

Chemosensory cues from receptive females do not elicit similar reactions before and after puberty in male hamsters. While pheromones facilitate a complex display of reproductive behavior in adults, prepubertal males do not engage in these same behaviors. Dopamine (DA) released from the medial preoptic area (MPOA) in response to a receptive female or her odors is an important component of the neural events underlying adult male rat sexual behavior. The current experiment investigated whether increased dopaminergic activity occurs in the adult male hamster MPOA in response to female pheromones, and if so, whether this response is absent in prepubertal males, which do not mate. Sexually nai;ve prepubertal and adult male hamsters were exposed to cotton swabs with or without pheromone from an estrous female for 0, 5, 15, or 25 min, after which brains were collected and frozen on dry ice. The MPOA was micropunched from frozen coronal sections (500 microm), and concentrations of DA and its primary metabolite DOPAC were determined by high-performance liquid chromatography-electrochemical detection. DOPAC was used as an index of dopaminergic activity. DOPAC levels significantly increased in adults after 15 min exposure to pheromone. In contrast, MPOA DOPAC concentrations did not increase in prepubertal males exposed to pheromone. These data demonstrate that the neural processing of sexually relevant chemosensory stimuli matures during puberty. The absence of a DA response to female pheromones prior to puberty may contribute to the inability of prepubertal males to display reproductive behavior.     

Amphetamine sensitization of stress-induced turning in animals given unilateral dopamine transplants in infancy

Infant rats given bilateral dopamine-depleting brain lesions and unilateral transplants of embryonic nigral tissue develop turning in response to both amphetamine and stress. However, stress-induced turning did not develop unless animals were previously exposed to amphetamine, and was greatest in animals exposed early to the drug. These findings suggest that amphetamine alters certain properties of the transplanted cells so as to enhance their functional capacity.     

Effects of repeated nicotine pre-treatment on mesoprefrontal dopaminergic and behavioral responses to acute footshock stress

The effects of acute and repeated nicotine administration on the stress response of rat mesoprefrontal dopaminergic pathways were examined. Rats were given daily injections of nicotine (0.15 or 0.60 mg/kg, s.c., freebase) or saline for 4 days, then challenged with either nicotine or saline. A regimen of inescapable electrical footshocks or no footshocks was then administered. Thirty minutes after final injection, rats were sacrificed, brains removed and dopamine (DA) and its metabolite dihydroxy-O-phenylacetic acid (DOPAC) were extracted from medial prefrontal cortex (mPFC), nucleus accumbens septi (NAS) and dorsolateral striatum and quantified by high performance liquid chromatography with electrochemical detection. Acute administration of low dose nicotine (0.15 mg/kg) produced an increase in DA utilization (increased DOPAC/DA ratio) in mPFC and NAS, but not striatum. High dose nicotine (0.60 mg/kg) produced activation in NAS, but not mPFC or striatum. Repeated low dose nicotine pre-treatment produced tolerance to the effects of nicotine challenge in the mPFC, and reduced its effects in NAS. Footshock stress preferentially increased DA utilization in mPFC and associated footshock stress-induced immobility responses, and these were reduced by low, but not high, dose repeated nicotine pre-treatment. Further, a single dose of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MCA) 30 min prior to nicotine challenge dose-dependently blocked the reduction of mesoprefrontal DA stress responsivity and immobility responses produced by repeated nicotine pre-treatment. These results indicate that: (1) there are dose-dependent differential effects of acute and repeated nicotine pre-exposure on regional DA utilization; (2) low, but not high, dose repeated nicotine reduces both the mesoprefrontal DA and behavioral effects of acute footshock stress; and (3) these effects of repeated nicotine may depend on mecamylamine-sensitive nAChR stimulation. These results may have relevance to acute stress and nicotine dependence, particularly in schizophrenic disorders, which have high prevalence rates of co-morbid nicotine dependence, stress-induced symptom exacerbation and prefrontal cortical dysfunction.     

Nigral dopaminergic mechanisms in drug-induced circling

Unilateral injections of dopamine into the substantia nigra pars reticulata of pargyline-pretreated rats caused a prolonged, contralateral circling, similar in magnitude to that elicited by the injection of the same amount of dopamine intrastriatally. Contralateral circling was also elicited by the unilateral intranigral injection of amphetamine (after pargyline pretreatment), or by the dopamine agonists ergometrine and SKF 38393. In contrast, bilateral intranigral injection of the dopamine antagonist haloperidol greatly reduced the amphetamine-induced circling of rats with unilateral 6-hydroxydopamine-induced nigrostriatal lesions. These results support the hypothesis that dopaminergic mechanisms in the substantia nigra are involved in motor behavior.     

Effects of cocaine and footshock stress on extracellular dopamine levels in the ventral striatum

Behavioral and neurochemical cross-sensitization between cocaine and stress was examined. The effects of stress and cocaine on extracellular levels of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis in the rostral ventral striatum, including the nucleus accumbens. Pretreatment with a daily 20 min footshock stress (0.45 mA/200 ms/s) for 5 days enhanced the cocaine-induced increase in extracellular dopamine levels in shock compared to sham shock-pretreated rats. The motor stimulant response to acute cocaine was also augmented in shock-pretreated rats. There was a slight but significant decrease in the levels of DOPAC and HVA in both groups following cocaine but no differences between shock and sham shock animals. In contrast, in the converse experiment, pretreatment with daily cocaine (15 mg/kg, i.p.) for 5 days did not significantly alter the stress-induced levels of extracellular dopamine compared to controls. The levels of DOPAC and HVA were not different between cocaine- and saline-pretreated groups although there was a trend towards enhanced metabolite levels in cocaine-pretreated animals. These data in part support a role for enhanced dopamine neutrotransmission in mediating behavioral cross-sensitization between psychostimulants and stress.