Baclofen enhances extinction of opiate conditioned place preference.

Conditioned opiate reward (COR) is rapidly acquired and slowly extinguished. The slow rate of extinction of the salience of drug-related cues contributes to drug craving and relapse. The gamma-aminobutyric acid receptor type B (GABA(B)) agonist, baclofen, attenuates the unconditioned rewarding actions of several drugs of abuse and was investigated for effects on the extinction of COR. C57BL/6 mice were utilized in an unbiased conditioned place preference (CPP) protocol using morphine (10mg/kg, s.c.) and saline. CPP was measured by increases in time spent in the morphine-associated (CS+) vs. the saline-associated (CS-) chamber in a 15-min test after four morphine and four saline alternated conditioning sessions. CPP and locomotor sensitization were produced to the CS+ chamber. Subsequently, sixteen daily extinction sessions were conducted with either vehicle or baclofen (1 or 2.5mg/kg, s.c.) treatment given either before or after the sessions. This design was used to create the baclofen drug state before or after the activation of the CPP memory trace in the extinction protocol. After morphine CPP development, its extinction was significantly facilitated in a dose-dependent manner by post-session, but not by pre-session, baclofen treatments. No significant sedative effects of baclofen were detected during any extinction training or testing phase. Baclofen treatment facilitated the extinction of COR and reduced conditioned sensitization during extinction when given after, but not before, the activation of the CPP memory trace. Baclofen appears to have disrupted reconsolidation of conditioned reward memory during extinction training and might similarly facilitate extinction learning in human opiate addiction.

Role of medial prefrontal, entorhinal, and occipital 5-HT in cocaine-induced place preference and hyperlocomotion: evidence for multiple dissociations.

RATIONALE: Application of cocaine or exposure to cocaine-related stimuli induces widespread activation of the cortex in neuroimaging studies with human subjects. In accordance to these findings, it was reported in previous microdialysis experiments that cocaine increased serotonin (5-HT) and dopamine in various cortical brain areas. The present series of studies set out to investigate the functional role of the observed increases in 5-HT in the medial prefrontal cortex (mPFC), the entorhinal cortex (EC), and the occipital cortex (OccC) in the mediation of cocaine-induced conditioned place preference (CPP) and hyperactivity. MATERIALS AND METHODS: To reduce 5-HTergic neurotransmission in circumscribed brain areas, bilateral local infusions of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), were made into the mPFC, EC, or OccC. Two weeks following surgery, cocaine-induced (10 mg/kg; i.p.) CPP was measured in an unbiased design. RESULTS: The 90% depletion of 5-HT in the mPFC significantly attenuated the preference for the cocaine-associated environment and the hyperlocomotor response to cocaine. A 61% depletion of 5-HT in the EC reduced conditioned place preference without modulation of hyperactivity, while a 78% 5-HT depletion of the OccC cortex had no effect on cocaine-induced CPP and hyperactivity. No lesion affected general activity, habituation learning, or visual stimulation-induced behavioral activation. CONCLUSION: These results indicate an important role of cortical 5-HT in the mediation of cocaine-induced CPP and specify the region-dependent contribution of a neurochemical response to cocaine-mediated behavior.

Acute anxiolytic effects of cocaine: the role of test latency and activity phase.

The emotional effects of the initial consumption of cocaine can have a strong influence on the subsequent use of this drug. Several studies in rodents using long test latencies have reported anxiogenic effects of cocaine. Anxiogenesis, however, would seem to contradict cocaine's well known rewarding effects and its abuse liability. The present study was set up to shed light on conditions that influence cocaine's consequences, namely the time after administration and active vs. resting test phase. The aim of the first experiment was to investigate the effects of cocaine (0, 5, 10, 15 mg/kg, i.p.) on anxiety-related behavior in rats in their active phase with a short test latency of 10 min. In the open field test cocaine had an anxiolytic-like effect, which was confirmed in the elevated plus-maze test. A second experiment investigated the effects of cocaine after a latency of 30 min in animals in their active vs. resting phase. After 30 min significant anxiolytic-like effects were no longer observed in either of the paradigms, irrespective of the activity phase. This and other studies suggest that after first exposure cocaine has acute anxiolytic effects, which rapidly decline, and, may eventually reverse to a longer lasting anxiogenic state.

Dissociating effects of cocaine and d-amphetamine on dopamine and serotonin in the perirhinal, entorhinal, and prefrontal cortex of freely moving rats.

RATIONALE: Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However, the neurochemical nature of these brain activities is not characterized. OBJECTIVE: The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal cortex (PFC). MATERIALS AND METHODS: We conducted in vivo microdialysis experiments in behaving rats measuring DA and 5-HT in the perirhinal cortex (PRC), entorhinal cortex (EC), and PFC, after application of cocaine (0, 5, 10, 20 mg/kg; i.p.) or d-amphetamine (0, 0.5, 1.0, 2.5 mg/kg; i.p.). RESULTS: Cocaine and d-amphetamine dose-dependently increased DA and 5-HT levels in the PRC, EC, and PFC. A predominant DA response to d-amphetamine was only found in the PFC, but not in the PRC and EC. Cocaine increased DA and 5-HT to an equal extent in the PFC and PRC but induced a predominant 5-HT response in the EC. When comparing the neurochemical responses between the drugs at an equal level of behavioral activation, cocaine was more potent than d-amphetamine in increasing 5-HT in the PFC, while no differences were found in the PRC or EC or in the DA responses in all three cortical areas. CONCLUSIONS: We conclude that cocaine and d-amphetamine increase DA and 5-HT levels in PRC and EC largely to the same extent as in the PFC.

Cocaine-induced 'active immobility' and its modulation by the serotonin1A receptor.

'Active immobility' (AI) is an independent behaviour that can be characterized by behavioural immobility, an increased muscular rigidity and the sustaining of an unusual posture. In previous studies with cocaine we observed, concomitant with hyperlocomotion and increased rearing activity, an increase in AI in well-habituated animals, which may constitute another 'positive' acute effect of cocaine on behaviour. The contribution of the serotonergic (5-HT) system to AI is well established. However, little information exists about the contribution of particular 5-HT-receptor subtypes. In order to examine a possible role of the 5-HT1A receptor on this effect of cocaine, we systematically re-analysed four previous experiments in well-habituated animals and one in little-habituated animals, focusing on the acute behavioural effects of cocaine on AI. We found that, in well-habituated animals, cocaine at a medium dose (10 mg/kg, i.p.) induces AI behaviour, which, however, does not correlate with cocaine effects on locomotion, rearing or grooming behaviour. However, there was no effect of cocaine (1, 5 or 15 mg/kg, i.p.) on AI in little-habituated animals. The 5-HT1A-receptor antagonist, WAY 100635 [N-[2-(4-2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride] (0.4 mg/kg, i.p.), potentiated cocaine-induced AI in well-habituated animals, while the 5-HT1A-receptor agonist, 8-OH-DPAT (0.2 mg/kg, i.p.), attenuated it. The local application of 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] into the nucleus accumbens (0, 1, 10 micromol/l) or hippocampus (0, 0.1, 1, 10 micromol/l) modulated cocaine-induced AI in a complex way. These results showed that cocaine induces AI at a medium dose in well-habituated but not in little-habituated animals. The cocaine-induced AI in well-habituated animals can be potentiated by systemic 5-HT1A-receptor antagonism and attenuated by 5-HT1A-receptor agonism. Two experiments with local activation of postsynaptic 5-HT1A receptors revealed that both nucleus accumbens and hippocampal 5-HT1A-receptor populations are involved in the expression of cocaine-induced AI.

Nucleus accumbens serotonin1A receptors control cocaine-induced hyperactivity but not local serotonin increase: an in vivo microdialysis study.

The nucleus accumbens (Nac) is an important structure for cocaine-induced hyperactivity and receives a dense serotonergic (5-HT) innervation. Previous studies showed that a systemic activation of 5-HT(1A) receptors potentiates cocaine-induced hyperlocomotion, but attenuates the cocaine-induced 5-HT increase in the Nac. In order to address the role of Nac 5-HT(1A) receptors in the control of cocaine-induced and spontaneous behavioural activity and local 5-HT release, we used in vivo microdialysis in freely moving rats. The 5-HT(1A)-receptor agonist, 8-OH-DPAT (0, 1 and 10 microM), was applied locally into the Nac by reverse dialysis followed by a cocaine (10 mg/kg) or saline i.p. injection. The Nac 5-HT(1A)-receptor activation potentiated cocaine-induced hyperlocomotion, but attenuated rearing behaviour dose-dependently. Parallel to that, the cocaine-induced increase in Nac 5-HT dialysate level was unaffected, as were the decreases in 5-HIAA and DOPAC dialysate levels after cocaine. In saline treated rats, the local application of 8-OH-DPAT into the Nac affected neither spontaneous behavioural activity nor 5-HT, 5-HIAA or DOPAC dialysate levels in the Nac. These data suggest that Nac 5-HT(1A) receptors exert a bi-directional control of cocaine-induced hyperactivity, while not affecting spontaneous behaviour. Furthermore, accumbal 5-HT(1A) receptors do not appear to be directly involved in the acute effects of cocaine on 5-HT, 5-HIAA or DOPAC levels in the Nac.

Systemic mechanisms of individual reproductive life history in female Medflies.

This paper is the second one in a series of two papers hypothesizing and testing systemic grounds of reproductive life history in the female fruit fly. In the first paper, we analyzed mechanisms of individual fecundity scheduling and have drawn the following conclusions. Individual fecundity in female flies is endowed as a flat pattern with a steady-state period of a constant rate of egg-laying. An individual female reveals three stages in her adult life history: maturation, maturity, and senescence. The first stage is a transient period of achieving a steady state at maturity, which can be maintained until the senescence stage. Thus, an individual fecundity pattern has no maximum. The maximums observed experimentally are averaging-caused artifacts. Two natural causes of deaths exist in flies, senescence-caused ones and premature deaths, probably due to a reproductive overload. In this paper, to confirm these findings, we use individual daily scores of egg-laying in four populations of Mediterranean fruit flies. Based on fecundity scores, we divide each Medfly population into four classes, namely zero-egg, short-, medium- and long-lived egg-layers. We demonstrate that, indeed, the three above findings definitely exist in Medflies. Our procedure allows the efficient storage of individual fecundity in parametric form, with only five numbers for each fly. Finally, this protocol will allow a more precise analysis of fecundity-energy trade-offs in flies carrying appropriate longevity mutations.

Serotonin1A-receptor agonism attenuates the cocaine-induced increase in serotonin levels in the hippocampus and nucleus accumbens but potentiates hyperlocomotion: an in vivo microdialysis study.

The hippocampus and the nucleus accumbens (Nac) are important structures for the modulation of spontaneous locomotor activity. Both structures receive a serotonergic (5-HT) innervation. We have previously reported that the 5-HT(1A)-receptor antagonist WAY 100635 blocked cocaine-induced hyperactivity, while potentiating cocaine-induced 5-HT increases in the hippocampus and the Nac. In order to further investigate the relationship between extracellular 5-HT concentration and cocaine-induced behaviour, we used in vivo microdialysis to measure the effects of the 5-HT(1A)-receptor agonist 8-OH-DPAT on cocaine-induced changes in the extracellular 5-HT concentration in the hippocampus and the Nac and on behavioural activity. Following a pilot pretest in which we determined the lowest effective dose of 8-OH-DPAT for potentiating cocaine-induced hyperlocomotion, four groups of rats were given one of the following drug treatments: 8-OH-DPAT (0.2 mg/kg) and cocaine (10 mg/kg), saline and cocaine (10 mg/kg), 8-OH-DPAT (0.2 mg/kg) and saline, or saline and saline. The injections were administered i.p. and spaced 30 min apart. We found that the 5-HT(1A)-receptor agonist 8-OH-DPAT attenuated the cocaine-induced increases in 5-HT in the hippocampus and the Nac, but potentiated cocaine-induced hyperlocomotion. 5-HT metabolite measurements revealed a complex role for the 5-HT(1A)-receptor in the broad spectrum of cocaine's neurochemical effects. Altogether, these observations support an important role of the 5-HT(1A)-receptor in the hippocampus and Nac in the modulation of cocaine stimulant effects.

Cocaine and serotonin: a role for the 5-HT(1A) receptor site in the mediation of cocaine stimulant effects.

Cocaine induced locomotor stimulant effects are generally attributed to cocaine effects on brain dopamine. In this report, we present evidence that the 5-hydroxytryptamine(1A) (5-HT(1A)) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) and the 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cycylhexanecarboxaminde maleate (WAY 100635) can enhance or block, respectively, the locomotor stimulant effects induced by cocaine. In two separate experiments, rats administered cocaine (10 mg/kg) exhibited a locomotor stimulant effect and decreased grooming behavior compared to saline treated rats. Pretreatment with the 5-HT(1A) agonist, 8-OHDPAT (0.2 mg/kg) enhanced and pretreatment with the 5-HT(1A) antagonist, WAY 100635 (0.4 mg/kg) eliminated the locomotor stimulant effect of cocaine. Neither the 8-OHDPAT nor WAY 100635 effects were attributable to effects on the behavioral baseline. The 8-OHDPAT and WAY 100635 had opposite effects on grooming behavior. 8-OHDPAT decreased and WAY 100635 increased grooming. Neither treatment, however, affected the grooming suppression induced by cocaine. Ex vivo biochemical measurements indicated that neither 8-OHDPAT or WAY 100635 affected brain dopamine metabolism or cocaine availability in brain. Both treatments affected 5-HT metabolism and altered the effect of cocaine on 5-HT metabolism. 8-OHDPAT increased and WAY 100635 decreased cocaine effects on 5-HT metabolism. Cocaine and 8-OHDPAT but not WAY 100635 increased corticosterone. Altogether, these findings indicate that the 5-HT(1A) receptor site may be an important target for the development of pharmacotherapies for the treatment of cocaine abuse.

Effects of dizocilpine (MK-801) on motor activity and memory.

The effects of MK-801 upon motor activity and memory were assessed in a novel use of open-field behavior testing. In this study, rats were treated with different doses of MK-801 (0.025, 0.05, 0.1 and 0.2 mg/kg) and given a brief 10-min exposure to an open-field in which locomotor activity and within-session habituation were measured. Doses of MK-801 < or =0.1 mg/kg had no effect upon locomotor activity or within-session habituation. MK-801 0.2 mg/kg produced a marked hyperlocomotion and completely prevented within-session habituation. One day later, the animals were tested for their retention of habituation to evaluate the effects of MK-801 on memory processes. In that animals treated with 0.2 mg/kg MK-801 failed to habituate to the novel environment under the influence of 0.2 mg/kg MK-801, it was not surprising that these animals were impaired on the retention test for the novel environment. Importantly, however, the 0.1 mg/kg MK-801 treatment, which did not affect locomotor activity or within-session habitation to the novel environment, severely interfered with retention of the novel environment. Additional experiments indicated that this result could not be accounted for by drug conditioning or drug state-dependent effects. Thus, the results indicated that MK-801 can produce profound effects upon motor activity and memory and that these two effects can be disassociated.

Cocaine conditioning and cocaine sensitization: what is the relationship?

With repeated cocaine use, cocaine conditioned behavior develops to associated stimuli, and in addition, sensitization can occur to the unconditioned stimulant effects of cocaine. To investigate the relationship between the conditioned and unconditioned behavioral effects of repeated cocaine use, two groups of rats (n = 7) were given five daily paired cocaine treatments (10 mg/kg i.p.) immediately before a 20-min placement in an open-field environment. Other groups received either saline before testing or cocaine unpaired which was administered 30 min after testing in the homecage. When tested in the open-field with saline for conditioned effects, the two cocaine paired groups selectively exhibited substantial and equivalent cocaine conditioned responses. One of these groups was subjected to an extinction procedure which was effective in eliminating the cocaine conditioned responses. Subsequently, all the rats which had received cocaine in the first phase of the experiment, paired and unpaired, along with a subset of saline animals were given a cocaine (10 mg/kg i.p.) challenge test. The paired cocaine animals exhibited an earlier onset of the cocaine induced behavioral response (sensitization) as compared with the saline and the unpaired cocaine animals. Critically, the sensitization effects were unaffected by extinction, and in addition, the conditioned response did not contribute to the sensitization effect. It is suggested that the cocaine drug response occludes the cocaine conditioned response. Subsequent to this sensitization test, the animals were retested for conditioning. In this test, the paired cocaine animals which had not been subjected to the extinction procedure still exhibited a conditioned cocaine response, whereas, the paired cocaine group subjected to extinction was indistinguishable from saline controls. Although the present results show that Pavlovian conditioned responses to exteroceptive contextual cues do not directly contribute to cocaine induced behavioral sensitization effects, the sensitization effects were context-specific, and therefore, were tied to associative processes. It is suggested that context specificity is mediated by a compound stimulus complex comprised of exteroceptive stimuli and interoceptive cocaine drug cues. Furthermore, these exteroceptive and interoceptive cues associated with cocaine effectively expedite the onset of cocaine effects, and thereby, facilitate the addictive potency of cocaine.

A new methodological approach to the study of habituation: the use of positive and negative behavioral indices of habituation.

This report details a new method to measure habituation in an open-field. In addition to the measurement of spontaneous locomotor activity, time spent per visit to the center zone (CZ) is also measured. Critically, a small object is placed in the CZ to modulate an animal's investigatory response. When an animal is first exposed to the open-field, the presence of the object does not affect the duration of its visits to the CZ but, if the animal is given one additional 10-min exposure to the open-field, then the presence of the object substantially increases the duration of its visits to the CZ. The presence of the object, however, has no effect on the rat's locomotor activity. Thus, habituation could be observed by two different measures: a decrease in locomotor activity and an increase in an animal's investigatory response to a stimulus object. A basic problem with a reliance solely upon a decrease in locomotor activity to measure habituation is that it represents a negative change in behavior. The present method circumvents this shortcoming by incorporating a positive behavioral measure of habituation in conjunction with the measurement of locomotor activity. This modification of the open-field test offers substantial utility for studies of neurotoxicology and memory because one can assess concurrently treatment effects on motor activity, attention to an object and memory.

L-DOPA and psychosis: evidence for L-DOPA-induced increases in prefrontal cortex dopamine and in serum corticosterone.

L-DOPA can often induce psychotic reactions during treatment for Parkinson's disease. This study was undertaken to assess, in an animal model of Parkinson's disease, the impact of L-DOPA treatment on two potential biological risk factors for psychosis, namely, an increase in prefrontal cortex dopamine and an increase in the stress-related hormone corticosterone. Hemiparkinsonian rats with unilateral 6-hydroxydopamine (6-OHDA) lesions which resulted in severe unilateral denervation of dopamine neurons were treated with either saline or 25 mg/kg L-DOPA methyl ester (with 2 mg/kg carbidopa). Serum L-DOPA concentrations were found to be positively and highly correlated with serum corticosterone, with medial prefrontal cortex dopamine and with the dopamine metabolite homovanillic acid. Serum L-DOPA, however, was found not to be correlated with serum or brain concentrations of serotonin, 5-hydroxyindoleacetic acid, or norepinephrine. These findings support the possibility that chronic L-DOPA treatment can expose parkinsonian patients to two significant risk factors for psychosis: 1) increased levels of prefrontal cortex dopamine, and 2) increased levels of serum corticosterone.

The NMDA receptor and cocaine: evidence that MK-801 can induce behavioral sensitization effects.

Antagonism of the NMDA receptor with MK-801 is considered to be an effective pharmacologic manipulation to prevent the development of sensitization effects to drugs such as cocaine. The present study investigated this issue by comparing the behavioral response of separate groups of rats to three treatment cycles of either saline, 0.1 mg/kg MK-801, 10 mg/kg cocaine, or combined MK-801-cocaine (0.1/10 mg/kg). The treatments were spaced 1 week apart and were preceded by two nondrug baseline tests. In the first test cycle, the four groups had equivalent activity levels in the two nondrug tests. In the first drug test only the MK-801-cocaine group exhibited hyperactivity. By the third drug test, the MK-801-cocaine group exhibited an enhanced hyperactivity and the MK-801 group became hyperactive. Thus, behavioral drug sensitization developed but only with groups treated with MK-801. Antagonism of the NMDA receptor under some circumstances can be a highly effective treatment for the induction of behavioral sensitization effects.

Evidence for N-methyl-D-aspartate receptor mediation of cocaine induced corticosterone release and cocaine conditioned stimulant effects.

The role of the N-methyl-D-aspartate (NMDA) receptors in cocaine conditioning and sensitization of locomotor activity was studied in four groups of Sprague-Dawley rats. A sub-motoric dose of the NMDA antagonist MK-801 (0.1 mg/kg, i.p.) was employed using a novel dual-compartment Pavlovian drug conditioning paradigm. The animals were placed sequentially in two different test environments in which locomotor activity was monitored. In the first compartment, the animals always received a non-drug test for 20 min. Upon completion of this test, the animals received either saline, cocaine (10 mg/kg i.p.), MK-801 or MK-801 plus cocaine depending on group assignment and were then placed immediately into the second compartment and again tested for 20 min. A total of six non-drug and six drug tests were conducted every other day over a 12-day period. Across all drug/saline treatment and post-treatment tests for conditioning, there were no statistical differences in locomotor activity among the saline and drug treatment groups in the non-drug test environment. In the drug/saline associated environment, however, cocaine had a reliable stimulant effect on locomotion when administered alone or in combination with MK-801. Following a 1-day and again after 21-days of withdrawal, all animals were administered a non-drug test for conditioning in which no injections were administered. On both tests, all groups had equivalent activity levels in the non-drug environment. In the drug/saline environment, only the cocaine group of the three drug treatment groups exhibited conditioned hyperlocomotion. Importantly, MK-801 blocked conditioned hyperlocomotion in the combined cocaine+MK-801 group. MK-801 did not alter serum or brain cocaine concentration or the cocaine effects on dopamine metabolism in limbic brain tissue. The co-administration of MK-801 with cocaine, however, blocked the corticosterone release effect of cocaine. Thus, the NMDA receptor site appears critical for cocaine induced conditioning and for corticosterone release.

Stimulation of D1- or D2-receptors in drug-naive rats with different degrees of unilateral nigro-striatal dopamine lesions.

We had previously found that in animals with moderate nigro-striatal dopamine (DA) lesions (i.e. 45-65% residual neostriatal DA) the mixed D1/D2-agonist apomorphine induced ipsiversive rather than the usual contraversive turning found after more radical DA lesions. Since this result promised to provide a behavioral animal model for pre-clinical Parkinson's disease, we hoped to delineate the responsible receptor by challenging with selective D1- and D2-agonists. Thus, in the present study, the behavioral effects of the D1-agonist SKF38393 (5.0 mg/kg) and the D2-agonist LY171555 (0.5 mg/kg) were tested in drug-naive rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal DA system. This analysis was performed dependent on the degree of the lesion, classified post-mortem with respect to the level of residual DA in the neostriatum: < 20%, 20-45%, 45-65%, and > 65% (as percentage of the intact hemisphere). The measures of turning, thigmotactic scanning and locomotion did not yield differences between animals treated with the D1-agonist and vehicle-treated rats. For example, animals with severe lesions (residual DA < 20%) showed ipsiversive asymmetries in turning and scanning, which were similar after vehicle or the D1-agonist, both with respect to degree and time-course. However, the analysis of grooming behavior, which was performed in a subset of animals with moderate lesions yielded differences between vehicle and the D1-agonist, since the duration of grooming was increased after SKF38393. In contrast to the D1-agonist, behavioral effects after the D2-agonist LY17155 were evident in all behavioral measures. The general response to this agonist could be characterized by a rapid decrease of behavioral activity including turning, scanning, locomotion and grooming. Although we failed to find significant behavioral asymmetries with either agonist, a micro-analysis showed evidence for selective effects after the D2-agonist, since a contraversive asymmetry in turning (and scanning) became apparent between 45 and 60 min after injection in animals with severe lesions (residual DA of about 10% or less), and since there was a weak ipsiversive turning asymmetry in animals with residual DA levels of 45-65%. Such asymmetries were not observed after vehicle or the D1-agonist. The possible physiological mechanisms of these effects, i.e. DA receptor mechanisms and DA availability, are discussed in the context of results from previous experiments using lesioned or intact animals.

A simple, rapid HPLC method for the concurrent measurement of cocaine and catecholamines in brain tissue samples.

We describe a simplified HPLC method for the measurement of cocaine and catecholamines in the same brain tissue sample. Using this method to measure cocaine in the brain of rats which received either 10 or 20 mg/kg cocaine injections, we found substantial cocaine concentration differences between medial prefrontal cortex, striatum and limbic brain areas. Specifically, for each cocaine dose level there was a nearly 2-fold differential between cocaine concentration in the cortex as compared to limbic tissue. A shortcoming of many neurobehavioral studies of cocaine effects is the absence of brain cocaine measurements. The simplicity of the present method makes the measurement of cocaine and catecholamines from the same tissue sample a procedure which can readily be incorporated in the studies designed to evaluate the neurochemical effects of cocaine treatments.

NMDA antagonist effects on the development of L-dopa behavioral sensitization in rats.

This study, which used an animal model of Parkinsonism, evaluated whether the NMDA antagonist MK-801 can prevent the development of L-3-4-dihydroxyphenylalanine (L-DOPA) sensitization. In separate groups, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were treated with saline, 25 mg/kg L-DOPA methyl ester, 0.1 mg/kg MK-801, or MK-801 plus L-DOPA once per day for 13 days beginning 18 to 20 hr postoperatively, well before the onset of denervation supersensitivity. Following 14 days of withdrawal, all treatment groups were given a saline test and on the next day, an L-DOPA challenge test. Contralateral rotation, the behavioral index of denervation supersensitivity, emerged on Day 7 in both L-DOPA groups. However, on the L-DOPA challenge test, only the L-DOPA group showed enhanced contralateral rotations compared with a drug-naive group. In contrast, the MK-801 and MK-801/L-DOPA groups were indistinguishable from the drug-naive L-DOPA-treated rats. These findings indicate that although MK-801 treatment did not prevent the development of behavioral sensitization to the L-DOPA treatment, it did prevent its persistence following drug withdrawal.

L-DOPA metabolism in cortical and striatal tissues in an animal model of parkinsonism.

Rats with unilateral 6-hydroxydopamine lesions of the midbrain tegmentum were treated with 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa. The effects of the L-DOPA treatment upon serum, neocortical, and striatal L-DOPA and 3-O-methyl dopa (3-OMD) concentrations were measured. The highest L-DOPA and 3-OMD concentrations were obtained in the serum and in a ratio of approximately 2:1. In the brain, there was a uniform distribution of 3-OMD but L-DOPA concentrations were highly nonhomogeneous. Regression line equations for the statistically significant correlation coefficients between L-DOPA and tissue dopamine concentrations suggested that L-DOPA generated 50-60 times as much dopamine in the intact striatum as in cortex. The regional variation of L-DOPA concentration appears related to the capability of the brain tissue to generate and store dopamine from L-DOPA. In addition, the findings suggest that the behavioral ineffectiveness of L-DOPA in intact animals is related to its capacity to transform L-DOPA to tissue bound dopamine.

Time course effects of MK-801: the relationship between brain neurochemistry and behavior.

Separate groups of rats were given saline or MK-801 treatments (0.3 mg/kg) and tested for locomotion activity levels for 10 min at 30, 60, and 120 min postinjection. At each postinjection time interval the MK-801 rats exhibited a marked hyperactivity that was unchanged across the three postinjection intervals. Ex vivo biochemical assays were performed to assess the neurochemical effects of MK-801 at each injection interval. In the striatum, a marked increase in dopamine metabolism was observed in the 120 injection group, but, otherwise, no other changes in striatum were detected. In contrast, a significant increase in dopamine metabolism was observed after 30 min in the medial prefrontal cortex, and this effect persisted across all postinjection intervals. At 120 min, however, the biochemical impact of the MK-801 treatment on medial prefrontal cortex broadened to include a decrease in purine metabolism and norepinephrine. Serotonin metabolism was unaffected in striatum or medial prefrontal cortex across all injection intervals, and there was no effect of MK-801 on plasma corticosterone levels.