A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone.

RBP-7000 is a sustained-release (once-monthly injection for subcutaneous administration) formulation of risperidone using the ATRIGEL® Delivery System, developed for treatment of schizophrenia to address compliance issues associated with oral administration. The objective of this analysis was to report the results of a population pharmacokinetic analysis and to describe the relationship between risperidone and 9-hydroxyrisperidone levels with dopamine (DA) D2-receptor occupancy, prolactin levels, and adverse events using data collected in 45 clinically stable schizophrenic patients receiving RBP-7000 in single ascending doses (risperidone) of 60, 90, and 120 mg. The population PK model accounted for an initial peak, a delayed and slow delivery, the disposition of risperidone, and the conversion of risperidone to 9-hydroxyrisperidone. BMI was a covariate affecting absorption of risperidone and ultimately formation of 9-hydroxyrisperidone. A logistic analysis indicated a correlation between the increase in Active Moiety (risperidone + 9-OH-risperidone) exposure (Cmax ) and the probability of observing GI disorders. An Emax population PK/prolactin model best described the relationship between the circulating Active Moiety and the serum prolactin levels. Gender was a significant covariate associated with Emax . These data provided a comprehensive characterization of the relationship between circulating Active Moiety and the efficacy/safety profile of RBP-7000 in clinically stable schizophrenic patients.

Dopamine D2 receptor stimulation inhibits cold-initiated thermogenesis in brown adipose tissue in conscious rats.

Dopamine D(2)-like receptor agonists cause hypothermia. We investigated whether inhibiting heat production by interscapular brown adipose tissue (iBAT), a major thermogenic organ in rats, contributes to hypothermia caused by dopamine D(2)-like receptor agonists. Temperature of iBAT and tail artery blood flow were measured in conscious rats. Activity in postganglionic sympathetic nerves supplying iBAT was assessed in anesthetized rats. Conscious rats were housed in a warm cage maintained at 26-28 degrees C and then transferred to a cold cage at 5-10 degrees C to induce iBAT thermogenesis. Cold exposure increased iBAT temperature (+0.7+/-0.1 degrees C, 30 min after transferring to the cold cage, P<0.01, n=54). The mixed dopamine D(2)/D(3) receptor agonist, 7-hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT, 0.5 mg/kg s.c.) reversed the cold-induced increase in iBAT temperature (-2.8+/-0.2 degrees C at 30 min after 7-OH-DPAT treatment during cold exposure vs. +0.3+/-0.1 degrees C at 30 min after vehicle treatment during cold exposure, n=8). These temperature changes were blocked by pre-treatment with the D(2) receptor antagonists spiperone (20 microg/kg i.p.) and L-741,626 (2.5 mg/kg i.p.), but not by the selective D(3) receptor antagonist SB-277011A (10 mg/kg i.p.). Another mixed dopamine D(2)/D(3) receptor agonist, quinpirole (0.5 mg/kg s.c.) also reversed cold-induced iBAT thermogenesis, and this effect was also prevented by pre-treatment with spiperone, but not with a peripherally acting dopamine receptor antagonist, domperidone (2 mg/kg s.c.). Neither 7-OH-DPAT nor quinpirole reversed cutaneous vasoconstriction elicited by cold exposure. In anesthetized rats, quinpirole (0.5 mg/kg i.v.) abolished iBAT sympathetic nerve discharge elicited by cooling the trunk, and this change was reversed by spiperone (20 microg/kg i.v.). These results demonstrate that activation of CNS dopamine D(2) receptors inhibits sympathetically-mediated iBAT thermogenesis in response to cold exposure. Furthermore, they suggest that in rats hypothermia induced by dopamine D(2) receptor agonists in cold environments is mainly due to decreased heat production rather than to increased heat loss.

Isolation rearing induces recognition memory deficits accompanied by cytoskeletal alterations in rat hippocampus.

Social isolation from weaning affects hippocampal structure and function in the rat. The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal development and organization. Accordingly, the present paper investigated the effects of social isolation on hippocampal levels of alpha-tubulin isoforms associated with microtubule dynamics, the dendritic marker MAP-2 and alterations in locomotor activity and recognition memory. Male Lister Hooded rats (postnatal day 25-28) were housed either in groups or singly (isolated animals) for 30 days. Locomotor activity in a novel arena and novel object recognition were monitored in activity boxes. The hippocampus was dissected out 18 h after the novel object recognition task. Levels of alpha-tubulin isoforms and MAP-2 were analysed using Western blots. The experiments were conducted in duplicate, using two batches of rats obtained from different suppliers. Isolated animals were hyperactive and showed recognition memory deficits in the novel object recognition task. These behavioural alterations were accompanied by specific alterations in hippocampal alpha-tubulin isoforms and decreased MAP-2 expression. The results confirm that rearing rats in isolation produces hyperactivity and cognitive deficits. The behavioural alterations were accompanied by hippocampal cytoskeletal changes consistent with microtubule stabilization, and by decreased MAP-2 expression. These findings are indicative of an abnormal development of synaptic connections and/or reductions in neuronal cell number. The developmental structural abnormalities in the hippocampus may contribute to the cognitive impairments which result from isolation rearing in rats.

Selective down-regulation of [(125)I]Y0-alpha-conotoxin MII binding in rat mesostriatal dopamine pathway following continuous infusion of nicotine.

Prolonged exposure to nicotine, as occurs in smokers, results in up-regulation of all the neuronal nicotinic acetylcholine receptor subtypes studied so far, the only differences residing in the extent and time course of the up-regulation. alpha6beta2*-Nicotinic acetylcholine receptors are selectively enriched in the mesostriatal dopaminergic system and may play a crucial role in nicotine dependence. Here we show that chronic nicotine treatment (3mg/kg/day for two weeks, via s.c. osmotic minipumps) caused a significant decrease (36% on average) in the binding of [(125)I]Y(0)-alpha-conotoxin MII (a selective ligand for alpha6beta2*-nicotinic acetylcholine receptors in this system) to all the five regions of the rat dopaminergic pathway analyzed in this study. After one week of withdrawal, binding was still lower than control in striatal terminal regions (namely the caudate putamen and the accumbens shell and core). In somatodendritic regions (the ventral tegmental area and the substantia nigra) the decrease was significant at the end of the treatment and recovered within one day of withdrawal. This effect was not due to displacement of [(125)I]Y(0)-alpha-conotoxin MII binding by residual nicotine. In fact the binding was not changed by 565 ng/g nicotine (obtained with a single injection of nicotine), a concentration much higher than that found in the brain of rats chronically treated with nicotine (240 ng/g). In addition, consistent with previous studies reporting an up-regulation of other subtypes of nicotinic acetylcholine receptors, we found that nicotine exposure significantly increased (40% on average) the binding of [(125)I]epibatidine (a non-selective agonist at most neuronal heteromeric nicotinic acetylcholine receptors) in three up to five regions containing only alpha-conotoxin MII-insensitive [(125)I]epibatidine binding sites, namely the primary motor, somatosensory and auditory cortices. In conclusion, this work is the first to demonstrate that alpha6beta2*-nicotinic acetylcholine receptors, unique within the nicotinic acetylcholine receptor family, are down-regulated following chronic nicotine treatment in rat dopaminergic mesostriatal pathway, a finding that may shed new light in the complex mechanisms of nicotine dependence.

Neuronal plasticity, stress and depression: involvement of the cytoskeletal microtubular system?

In susceptible individuals, stressors can increase the risk of onset of depression and recent brain imaging studies have shown morphometric alterations in the limbic system of patients affected by depression. The volume loss observed in the hippocampus of depressed individuals suggests a possible involvement of structural neuronal plasticity in the pathogenesis of depression. Stressful conditions in animals can result in impaired structural neuronal plasticity in the hippocampus, characterised by retraction of apical dendrites and decreased neurogenesis. The intrinsic dynamic instability of the cytoskeletal microtubular system is essential for neuronal remodelling and plasticity. We have recently shown that both acute and chronic stress decrease microtubular dynamics in the rat hippocampus. Other authors have demonstrated that proteins functionally involved in the regulation of microtubule dynamics can be altered by stress in the rodent hippocampus. Furthermore, the existence of a link between stress-induced microtubular changes and depression is further strengthened by evidence showing that both acute and chronic treatment with antidepressant drugs can affect the expression of microtubular proteins. The present review will introduce a growing body of evidence suggesting that stress-induced alterations in neuronal plasticity might be considered the final result of activation and/or inhibition of molecular cascades regulating the dynamics of the microtubular system. In addition, the prospect of targeting microtubules as a pharmacotherapeutic approach to treat mood disorders will be discussed.

Concurrent pharmacological MRI and in situ microdialysis of cocaine reveal a complex relationship between the central hemodynamic response and local dopamine concentration.

The mechanisms underlying the signal changes observed with pharmacological magnetic resonance imaging (phMRI) remain to be fully elucidated. In this study, we obtained microdialysis samples in situ at 5-min intervals during phMRI experiments using a blood pool contrast agent to correlate relative cerebral blood volume (rCBV) changes with changes in dopamine and cocaine concentrations following acute cocaine challenge (0.5 mg/kg iv) in the rat over a duration of 30 min. Three brain areas were investigated: the dorsal striatum (n = 8), the medial prefrontal cortex (mPFC; n = 5), and the primary motor cortex (n = 8). In the striatum and mPFC groups, cocaine and dopamine temporal profiles were tightly correlated, peaking during the first 5-min period postinjection, then rapidly decreasing. However, the local rCBV changes were uncorrelated and exhibited broader temporal profiles than those of cocaine and dopamine, attaining maximal response 5-10 min later. This demonstrates that direct vasoactivity of dopamine is not the dominant component of the hemodynamic response in these regions. In the motor cortex group, microdialysis revealed no local change in dopamine in any of the animals, despite large local cocaine increase and strong rCBV response, indicating that the central hemodynamic response following acute iv cocaine challenge is not driven directly by local dopamine changes in the motor cortex. The combination of phMRI and in situ microdialysis promises to be of great value in elucidating the relationship between the phMRI response to psychoactive drugs and underlying neurochemical changes.

Rapid high-throughput assay for the measurement of amino acids from microdialysates and brain tissue using monolithic C18-bonded reversed-phase columns.

A rapid precolumn high-performance liquid chromatography method based on fluorescence detection has been developed for the measurement of multiple amino acids from both ex vivo and in vivo biological samples using monolithic C18 columns. A mixture of 18 primary amino acids were derivatised with napthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide. The resulting isoindole derivatives were resolved within 10 min using a linear binary gradient elution profile with Rs values in the range 1.2-9.0. The limit of detection (LOD) was found to be between 6.0 and 60 fmol for 5 microl injection with a signal to noise ratio of 3:1. The NDA derivatives were found to be stable for 9 h at 4 degrees C. This assay has been employed for the rapid analysis of amino acids from brain tissue and microdialysis samples. Examples of application of the method are given.

LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease.

Several psychiatric diseases, including schizophrenia, are thought to have a developmental aetiology, but to date no clear link has been made between psychiatric disease and a specific developmental process. LPA(1) is a G(i)-coupled seven transmembrane receptor with high affinity for lysophosphatidic acid. Although LPA(1) is expressed in several peripheral tissues, in the nervous system it shows relatively restricted temporal expression to neuroepithelia during CNS development and to myelinating glia in the adult. We report the detailed neurological and behavioural analysis of mice homozygous for a targeted deletion at the lpa(1) locus. Our observations reveal a marked deficit in prepulse inhibition, widespread changes in the levels and turnover of the neurotransmitter 5-HT, a brain region-specific alteration in levels of amino acids, and a craniofacial dysmorphism in these mice. We suggest that the loss of LPA(1) receptor generates defects resembling those found in psychiatric disease.

Selective responding of nucleus accumbens core and shell dopamine to aversively conditioned contextual and discrete stimuli.

Dopamine transmission within the nucleus accumbens has been implicated as a neurochemical substrate of associative learning processes. It has been suggested that the acquisition of classically conditioned fear to a specific environment, or context, differs fundamentally from the development of conditioned fear to a discrete stimulus, such as a light or a tone. In this study, we assessed extracellular dopamine in the rat nucleus accumbens shell and core during the expression of a conditioned fear response. Animals were aversively conditioned to either a context or a tone and extracellular dopamine was measured in the nucleus accumbens shell and core by in vivo microdialysis over the next 2 days as animals were returned first to the conditioning chamber (day 1: context test), and subsequently as animals were again returned to the chamber and presented with the conditioned tone stimulus (day 2: tone test). Dopamine levels in the core were significantly higher in the Context-Shock group compared to the Tone-Shock group during the 30-min exposure to context while dopamine levels in the nucleus accumbens shell did not differ significantly during the context test between groups. In contrast, extracellular dopamine in the shell but not the core of Tone-Shock animals increased significantly during presentation of the tone. Dopamine in both the shell and core remained unchanged during the tone test in the Context-Shock groups.These data suggest distinct roles for shell and core dopamine transmission in the expression of a conditioned emotional response. While dopamine increased in the shell primarily during the presentation of a discrete tone conditioned stimulus, core dopamine responded more to a contextual conditioned stimulus. These results may reflect differences in either the type of information acquired or the salience of the learned associations which are formed to a context vs. a discrete tone cue.

Early social isolation, but not maternal separation, affects behavioral sensitization to amphetamine in male and female adult rats.

Early life stressful manipulations, such as maternal separation (MS) or social isolation (SI), can influence the neurobiological development of rats and alter the response of adult animals to drugs of abuse. The present study examined the acute and sensitized behavioral responses (locomotor activity (LMA) and stereotypy) induced by amphetamine after MS or SI in male and female rats. In addition, the hypothesis that the combination of SI and MS could lead to additional effects on the behavioral response to amphetamine was tested. After the repetitive, intermittent administration of 1.5 mg/kg D-amphetamine over five consecutive days, the behavioral expression of sensitization to a challenge injection was assessed following a 2-day withdrawal period. In both sexes, MS and SI did not alter the acute locomotor activating effects of amphetamine as measured in the open-field environment after the first administration of the drug. Whereas SI altered the expression of sensitization to amphetamine in both sexes, MS did not affect it. Finally, in none of the behavioral variables measured did MS and SI interact to further modify the behavioral profile of the animals. The present results suggest that a postweaning manipulation of the environment (SI) is more effective than a preweaning manipulation (MS) in modifying the expression of sensitization to amphetamine.

Development and application of a sensitive high performance ion-exchange chromatography method for the simultaneous measurement of dopamine, 5-hydroxytryptamine and norepinephrine in microdialysates from the rat brain.

A high performance liquid chromatography (HPLC) method based on cation exchange separation has been developed for the measurement of dopamine (DA), 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in microdialysates. The separation conditions have been optimised for using electrochemical detection. All three bioamines were resolved in less than 22 min using isocratic conditions. The optimum oxidation potential for the three bioamines was found to be +0.4 V vs. in situ Ag/AgCl reference electrode. Linear regression analysis of HPLC-peak area as a function of concentrations in the range 1-50 ng x ml(-1) gave coefficients of correlation between 0.998 and 0.999. The limit of detection for DA, 5-HT and NE was found to be between 50 and 100 pg x ml(-1) with a signal to noise ratio of 3:1. The method has been applied to the simultaneous measurement of the three monoamines in microdialysates from the medial prefrontal cortex under basal conditions and following the administration of the antipsychotic drug clozapine (10 mg x kg(-1) s.c.).

Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation.

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has been associated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypical antipsychotics such as olanzapine. In rodents, early life exposure to stressful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg s.c.), olanzapine (5 mg/kg s.c.), and haloperidol (0.5 mg/kg s.c.) on dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of the mPFC in group- and isolation-reared rats. Rats reared in isolation showed significant and robust deficits in prepulse inhibition of the acoustic startle. In group-reared animals, both clozapine and olanzapine produced a significant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics compared with group-reared animals. In contrast, the administration of haloperidol failed to modify dialysate DA levels in mPFC in either group- or isolation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D2 or D3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate, GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA responsiveness to the atypical antipsychotic drugs clozapine and olanzapine may explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, namely hyperactivity and attention deficit.

An automated analysis of rat behavior in the forced swim test.

The Porsolt forced swim test (FST) is a commonly used paradigm to evaluate antidepressant activity of drugs. This test is based on visual measurement of the rat's floating time (FT) in a tank filled with water. Here, we present an automated, accurate and faster method for estimating FT by the distance moved (DM) by the animal via the use of the Ethovision software in three separate experiments. Experiment 1 investigated the effect of varying delays (24-h and 7-day) between pretest and test on FT and DM. Experiment 2 aimed at examining the effects of a 2-day withdrawal period in rats sensitized to amphetamine and cocaine, on FT and DM. Finally, Experiment 3 looked at the effects of desipramine and fluoxetine on FT and DM. The results of these experiments show that increasing the delay between pretest and test reduced FT during subsequent exposure (test). In addition, rats sensitized to and then withdrawn from either amphetamine or cocaine did not differ in FT or DM compared with control rats. Finally, both desipramine and fluoxetine reduced FT and increased DM. Furthermore, DM was consistently significantly negatively correlated with FT. These results support the use of an automated method for the evaluation of rat behavior in FST.

In vivo characterization of basal amino acid levels in subregions of the rat nucleus accumbens: effect of a dopamine D(3)/D(2) agonist.

Recent evidence demonstrates that two subdivisions of the nucleus accumbens, the dorsolateral core and the ventromedial shell can be distinguished by morphological, immunohistochemical and chemoarchitectural differences. In the present study, we measured basal levels of amino acids in microdialysates from both the shell and core subterritories of the nucleus accumbens in freely moving rats using HPLC with fluorescence detection. The effect of the dopamine D(3)/D(2) receptor agonist quinelorane (30 microg/kg s.c.) was then investigated in both subregions. With the exception of glutamate, histidine, and serine, which showed similar levels in both subterritories, alanine, arginine, aspartate, gamma-aminobutyric acid, glutamine, and tyrosine were significantly higher in the shell compared with the core. In contrast, taurine levels were significantly lower in the shell than in the core. A particularly striking difference across subregions of the nucleus accumbens was observed for basal GABA levels with a shell/core ratio of 18.5. Among all the amino acids investigated in the present study, quinelorane selectively decreased dialysate GABA levels in the core subregion of the nucleus accumbens. The results of the present study point to specific profiles of both shell and core in terms of: (1) basal chemical neuroanatomical markers for amino acids; and (2) GABAergic response to the DA D(3)/D(2) agonist quinelorane.

Modulation of the behavioral and neurochemical effects of psychostimulants by kappa-opioid receptor systems.

The repeated, intermittent use of cocaine and other drugs of abuse produces profound and often long-lasting alterations in behavior and brain chemistry. It has been suggested that these consequences of drug use play a critical role in drug craving and relapse to addiction. This article reviews the effects of psychostimulant administration on dopaminergic and excitatory amino acid neurotransmission in brain regions comprising the brain's motive circuit and provides evidence that the activation of endogenous kappa-opioid receptor systems in these regions opposes the behavioral and neurochemical consequences of repeated drug use. The role of this opioid system in mediating alterations in mood and affect that occur during abstinence from repeated psychostimulant use are also discussed.

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

Hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus and the effects of pretreatment with haloperidol and clozapine.

This study re-examined the hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the rat ventral hippocampus and compared how both effects were affected by pretreatment with either haloperidol or clozapine. While the hyperactivity is thought to depend on dopamine receptor activation in the nucleus accumbens, the dopamine D2-class receptor blocker haloperidol failed to antagonize the disruption of prepulse inhibition in previous studies. However, an ameliorative effect of the atypical neuroleptic clozapine on disruption of prepulse inhibition was suggested by our previous experiments [Zhang et al. (1999) NeuroReport 10, 1-6]. In the present study, bilateral infusion of N-methyl-D-aspartate (0.5microg/side) into the ventral hippocampus of Wistar rats increased open field locomotor activity and disrupted prepulse inhibition. Both effects were observed immediately after infusion but disappeared 24h later. Injection of haloperidol (0.2mg/kg) or clozapine (5mg/kg), 45min prior to N-methyl-D-aspartate infusion, totally antagonized the hyperactivity but did not affect the disruption of prepulse inhibition. We conclude that dopaminergic mechanisms are differentially involved in the hyperactivity and disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus. Activation of accumbal dopamine receptors, which is blocked by clozapine and haloperidol to a comparable extent, seems to be crucial for the hyperactivity but not the disruption of prepulse inhibition. The present finding that both clozapine and haloperidol failed to antagonize the disruption of prepulse inhibition induced by N-methyl-D-aspartate stimulation of the ventral hippocampus is discussed with respect to our previous contrary finding concerning the ameliorative effect of clozapine and with respect to the disruption of prepulse inhibition in rats being considered as a model of sensorimotor gating deficits in schizophrenia.

Expression of sensitization to amphetamine and dynamics of dopamine neurotransmission in different laminae of the rat medial prefrontal cortex.

The present study investigated the effect of acute and repeated administrations of amphetamine (AMPH) on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the two main cytoarchitectonic subterritories of the medial prefrontal cortex (mPFC) (anterior cingulate and dorsocaudal prelimbic cortices vs ventral prelimbic and rostral infralimbic cortices). Both the acute locomotor effects of AMPH and the expression of behavioral sensitization following its repeated administration were also simultaneously assessed. The repeated, intermittent administration of AMPH over five consecutive days led to a significant sensitized locomotor response to a subsequent challenge that occurred following a 48-h withdrawal period. Basal dialysate DA levels were higher in the ventral mPFC compared with its dorsal counterpart in naive animals, that is prior to the acute administration of AMPH. However, the inverse relationship was observed in animals that had developed sensitization: basal dialysate DA levels were significantly lower in the ventral mPFC compared with the dorsal mPFC. In naïve animals, AMPH produced a significant decrease in DA levels in both the ventral and dorsal subregions of the mPFC. However, the inverse relationship was observed in animals that had developed sensitization: dialysate DA levels in response to AMPH remained significantly decreased in the dorsal mPFC, whereas DA went back to baseline levels in the ventral mPFC. Given that a critical concentration of DA is required for normal function of the mPFC, our results suggest that AMPH-induced changes in DA levels in different subregions of the mPFC are critical for both the acute effects of the drug and the expression of behavioral sensitization to its repeated administration by producing either less or more selectivity or sharpening of stimuli to cortico-cortical dendrites and subcortical synaptic afferents to the pyramidal cells located in the dorso-ventral axis of the mPFC.

Autoregulation of dopamine synthesis in subregions of the rat nucleus accumbens.

The discovery of a core-shell dichotomy within the nucleus accumbens has opened new lines of investigation into the neuronal basis of psychiatric disorders and drug dependence. In the present study, the autoregulation of dopamine synthesis in subdivisions of the rat nucleus accumbens was examined. We measured the accumulation of L-3,4-dihydroxyphenylalanine (DOPA) after the inhibition of aromatic L-amino acid decarboxylase with 3-hydroxylbenzylhydrazine (NSD-1015, 100 mg kg(-1)) as an in vivo index of dopamine synthesis. The effect of the dopamine D(1)/D(2) receptor agonist apomorphine (0, 20, 100, 500 microgram kg(-1)) and the dopamine D(2)/D(3) receptor agonist quinpirole (0, 20, 100, 500 microgram kg(-1)) on dopamine synthesis was determined in the dorsolateral core, ventromedial shell, and rostral pole of the nucleus accumbens. DOPA accumulation was also measured in the frontal cortex, olfactory tubercle, and caudate nucleus of the same rats for comparative purposes. The results show that the three sectors of the nucleus accumbens had similar basal levels of DOPA. Both apomorphine and quinpirole produced a decrease in the dopamine synthesis rate in all brain regions examined. In general, the dopamine D(2)/D(3) receptor agonist quinpirole produced a significantly greater decrease in DOPA accumulation than the dopamine D(1)/D(2) receptor agonist apomorphine. Within the nucleus accumbens, we found no core-shell differences in the agonist-induced suppression of dopamine synthesis, but the rostral pole was less sensitive to the highest dose of both dopamine agonists. These results suggest that differences in dopamine function between the core and shell might not involve region-specific differences in the receptor-mediated autoregulation of dopamine neurotransmission. Moreover, the blunted effect of dopamine agonists in the rostral pole illustrates that this region of the accumbens is functionally distinct, possibly due to a lower dopamine receptor reserve when compared to the core and shell.

Effects of administering cocaine at the same versus varying times of day on circadian activity patterns and sensitization in rats.

The effects of different schedules of cocaine administration on circadian activity patterns and locomotor sensitization were studied. Rats received intraperitoneal injections of either saline or 20 mg/kg cocaine at either 24- or 33-hr intervals for 8 cycles (development). After a 2-day withdrawal, they were given a cocaine challenge in a novel environment. Rats given cocaine at 24-hr intervals were hypoactive 4 to 9 hr postinjection during development and, during cocaine challenge, showed sensitization of locomotor activity. Rats given cocaine at 33-hr intervals did not show these effects. On the 33-hr-period schedule, activity was enhanced beginning 24 hr after drug receipt. Different intermittent schedules of cocaine receipt may alter the vulnerability to cocaine, and altered vulnerability may be more likely when a subsequent cocaine injection interacts with a distal state of sensitivity produced by a prior injection.