A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats

Rationale and objective. It is well established that stress induces reinstatement of drug seeking in an animal model of relapse. Here we studied the role of the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) in foot-shock stress-induced reinstatement of cocaine seeking. Methods. Groups of rats were trained to self-administer cocaine (0.5 mg/kg per infusion, i.v., 3 h/day for 9 days) and after ten drug-free days were exposed to extinction and reinstatement test sessions. Each 60 min of extinction was separated by a 30-min time-out period after which the lever and stimulus lights were reintroduced. Rats were given four 1-h extinction sessions on day 1 and then on subsequent days were given two to three 1-h extinction sessions that were followed by a 3-h test for reinstatement. Tests were run every 48 h. In one set of experiments, the effects of inactivation of the prelimbic (PL), infralimbic (IL) or OFC by tetrodotoxin (TTX, 5 ng/0.5 μl per side) on reinstatement induced by foot shock (5 min, intermittent, 1 mA) or priming injections of cocaine (20 mg/kg, i.p.) were determined. In a second set, the effects of infusions of the D1-like and D2-like dopamine receptor antagonists (SCH 23390 and raclopride) were studied using the same methods. Results. TTX infusions into the PL cortex blocked both foot shock and cocaine-induced reinstatement. TTX into OFC attenuated foot-shock-induced, but not cocaine-induced reinstatement. Infusions into IL were ineffective. Infusions of SCH 22390 (0.25 μg/0.5 μl per side) into either PL or OFC blocked foot-shock-induced reinstatement, but infusions into PL had no effect on cocaine-induced reinstatement. Raclopride (5 μg/0.5 μl per side) had no effect on foot-shock-induced reinstatement in either PL or OFC or on cocaine-induced reinstatement when infused into PL. Neither TTX nor SCH23390 infusions into PL or OFC had any effect on lever pressing for sucrose. Conclusions. These results suggest that the PL and OFC regions form part of the circuitry mediating the effects of foot shock stress on reinstatement of drug seeking and that the PL region may be a common pathway for cue, drug and foot-shock stress-induced reinstatement of drug seeking.     

Effects and interactions of naloxone and amphetamine on self-stimulation of the prefrontal cortex and dorsal tegmentum

Naloxone (0.1 to 10 mg/kg) caused a dose-dependent depression of self-stimulation of the medial prefrontal cortex (PFC), lateral hypothalamus (LH) and a region in the dorsal tegmentum lateral to the central gray (DT). The DT contains many enkephalin fibers and is a site for stimulation-produced analgesia, while the PFC contains little enkephalin and does not support stimulation-produced analgesia. However, self-stimulation rates of the PFC, DT and LH were all equally depressed by naloxone. In order to study possible opiate-dopamine interactions, we examined the effects of naloxone on the facilitatory effects of D- and L-amphetamine (1.0 mg/kg) on self-stimulation of the DT and PFC. If amphetamine mildly facilitated self-stimulation (L-amphetamine on DT self-stimulation and D-amphetamine on PFC self-stimulation), then the addition of naloxone was without effect. If amphetamine greatly increased self-stimulation (D-amphetamine on DT self-stimulation), naloxone caused a depression of the amphetamine effect. It is argued that naloxone's effects in this and other reports reviewed is related to the level of self-stimulation performance, and not to the level of enkephalin at the self-stimulation site, nor to amphetamine's effects on dopamine activity.     

Effects of D2 dopamine receptor blockade with raclopride on intracranial self-stimulation and food-reinforced operant behaviour

To examine the involvement of D2 dopamine receptors in the neural mechanism of reinforcement, raclopride tartrate, a D2 specific dopamine antagonist with a relatively fast central action, was injected into 32 rats. The D2 antagonist reduced bar-pressing responses reinforced with electrical stimulation of the ventral tegmental area (ED₅₀=0.079 mol/kg) and those reinforced with food (ED₅₀=0.58 mol/kg) in 18–30 min after IP injection. The reduction in response rates could not be attributed to an interference with motor functions. An increase in the frequency of brain-stimulation pulses and a change in the schedule of food reinforcement, which respectively increased the baseline rate of responding, did not alter the effectiveness of raclopride. SCH 23390, a D1-specific dopamine antagonist, was sensitive to similar manipulation of reinforcement. These results seem to suggest that D1 and D2 antagonists may be acting at different locations in the neural mechanism underlying the reinforcement of operant behaviour.     

Cocaine: acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle.

Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of rate-free psychophysical method. The acute administration of cocaine lowered the reinforcing thresholds independent of motor stimulatory effects. These results indicate that cocaine affects the sensitivity of the reward pathways in the brain, and further demonstrate the utility of rate-independent methods in the assessment of drug effects on self-stimulation behavior.     

6-Hydroxydopamine lesions of the medial prefrontal cortex fail to influence intravenous self-administration of cocaine

It has been suggested that the initiation and maintenance of cocaine self-administration (SA) is critically dependent on the dopaminergic (DA) projection to the medial prefrontal cortex (mPFC). Evidence for this hypothesis has been obtained from intracranial SA of cocaine, but a role of the mPFC in IV cocaine SA has not been established. The present experiment investigated the effect of destruction of DA-containing terminals in the mPFC on the rate and pattern of IV cocaine SA. Rats were trained to self-administer cocaine during daily 3-h sessions. After stable response patterns were obtained, the rats received either bilateral injections of 6-hydroxydopamine (6-OHDA) into the mPFC, or sham operations. The lesions did not affect either the rate or pattern of IV cocaine SA, despite producing substantial DA depletions in the mPFC. Thus, the mPFC does not appear to be a critical substrate for the maintenance of IV cocaine SA. The 6-OHDA lesions of the mPFC resulted in an apparent increase in DA turnover in both the striatum and the nucleus accumbens, suggesting that DA terminals in the mPFC may have an inhibitory influence on the activity of subcortical DA projections. Offprint requests to: C. Szostak     

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

 Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex. Received: 8 November 1996 / Final version: 30 July 1997     

Comparison of the effects of morphine on hypothalamic and medial frontal cortex self-stimulation in the rat

The effect of morphine (3.75, 7.5, and 15.0 mg/kg. s.c.) on medial frontal cortex (MF) and hypothalamic self-stimulation (SS) was determined 1, 3, 5, and 7 h after injection for 5 consecutive days. Morphine suppressed or enhanced SS responding as a function of dose, time after injection, and the site stimulated. The MF SS groups were less sensitive to the toxic effects of morphine, and evidenced elevated rates of responding earlier after injection than the hypothalamic animals. The dose-response relationship of the MF rats, thus, clearly differed from that of the hypothalamic rats. With repeated administration, tolerance was rapidly (3–4 days) developed to the suppressive effect while the excitatory effect appeared earlier and tended to be enhanced, peaking 1 and 3 h after injection in the MF and hypothalamic groups, respectively.These data provide additional evidence against the hypothesis that the effect of morphine on SS behavior is non-specific. It it were, the time course and degree of effects should be similar, regardless of the electrode site tested. Furthermore, an inhibitory effect was not observed in the groups receiving 3.75 mg/kg although both showed a significant increase in responding 1 and/or 3 h after injection. This observation indicates that the excitatory effect is not dependent on the depressant effect and, therefore, probably is not a rebound phenomenon. It also suggests that the toxic effects of morphine can either mask or delay the appearance of its facilitatory action on SS responding.     

The role of prefrontal cortex D1-like and D2-like receptors in cocaine-seeking behavior in rats

Rationale Evidence from preclinical and clinical studies indicates an important role for the mesocorticolimbic dopamine system in cocaine craving and relapse.Objectives To investigate the relative involvement of prefrontal cortex D1-like and D2-like dopamine receptors in cocaine-primed, drug-seeking behavior.Methods Rats were trained to press a lever to self-administer cocaine (i.v., 0.25 mg per infusion) in daily 2-h sessions. Responding was reinforced, contingent on a modified fixed-ratio 5 schedule. Reinstatement tests began after lever-pressing behavior was extinguished in the absence of cocaine and conditioned cues (light and tone). Before each reinstatement test, rats received bilateral microinfusions of different doses of selective D1-like and D2-like antagonists, SCH 23390, and eticlopride, respectively, followed by intraperitoneal administration of 10 mg/kg cocaine; 3 min later the session started. Responding in the reinstatement test was reinforced only by the conditioned cues contingent on a fixed-ratio 5 schedule.Results Both drugs dose dependently decreased cocaine-primed reinstatement without affecting operant behavior maintained by food. Eticlopride, but not SCH 23390, increased cocaine self-administration and decreased food-primed reinstatement at the dose found to decrease cocaine-primed reinstatement.Conclusions These data suggest that, although both D1-like and D2-like receptors in the prefrontal cortex are involved in cocaine-primed drug-seeking behavior, they may modulate different aspects of this process.     

Opioid peptides and self-stimulation of the medial prefrontal cortex in the rat

The possible involvement of opioid peptides as part of the neurochemical substrates of self-stimulation (SS) in the medial prefrontal cortex (MPC) of the rat was investigated in two different groups of rats bilaterally implanted with monopolar electrodes in the MPC. In the first group, morphine (5, 10 and 20 g) and an enkephalin analogue (BW 180) (5, 10, 20 and 40 g) and an enkephalin analogue (BW 180) (5, 10, 20 and 40 g) were injected through cannulae implanted into the lateral ventricles (IV). In the second group, naloxone (0.04, 0.4, and 1.6 g) and morphine (5, 10 and 20 g) were injected through cannulae implanted into the MPC, 1.5 mm above the tip of the stimulating electrodes. In the first group, spontaneous motor activity (SMA) was measured as a control for non-specific effects (sedation or motor dysfunction). In the second group SS, contralateral to the microinjected side, served as control. SS and SMA were measured 1 and 2 h postinjection. One hour after IV injection of morphine SS was not affected, although SMA was decreased. Two hours postinjection, on the contrary, SS was increased while SMA remained decreased. Similar effects were found with IV microinjections of BW 180. Naloxone, intraperitoneally injected, reversed all these effects. Naloxone or morphine injected intracerebrally (MPC) produced no changes in SS either in the injected or in the contralateral side, which served as control. The present results suggest that the effects found with IV injections of opioids on SS of the MPC are indirect (through activation of other brain areas) and not mediated by a direct action on the neurochemical substrates underlying this behaviour in the MPC.Supported by the European Training Program in Brain and Behaviour Research Present address: University of Oxford, Department of Pharmacology, South Parks Road, Oxford OX1 3QT, Great Britain     

Effects of cocaine microinjections into the nucleus accumbens and medial prefrontal cortex on schedule-induced behaviour: comparison with systemic cocaine administration

The effects of cocaine HCl infusions into either the nucleus accumbens (NACC) or medial prefrontal cortex (PFC) were compared on the performance of schedule-induced polydipsia (SIP) and related behaviours. Food-deprived rats were exposed to a fixed-time 60-s schedule of food delivery in daily 30-min sessions until stable levels of behaviour were obtained (14 days). Rats were then bilaterally infused with cocaine into either the NACC or PFC via chronically indwelling guide cannulae. Each subject received a sequence of five cocaine infusions (0, 12.5, 25, 50, 100 µg) according to a Latin Square design. For comparison, following these intracranial infusions each rat received a sequence of five IP injections of cocaine (0, 2.5, 5, 10, 20 mg/kg) also in a counterbalanced order. NACC and PFC infusions of cocaine and IP cocaine dose-dependently reduced SIP. Cocaine infusions into the NACC, but not the PFC, increased locomotor activity but the characteristic temporal profile of locomotor activity during SIP was retained. IP cocaine also increased locomotor activity in a dose-dependent manner, but the temporal profile of activity was flattened following 20 mg/kg cocaine. NACC and PFC infusions of cocaine had little effect on the total number of panel presses to gain access to the food pellets, but did slightly decrease the high rates of responding immediately prior to the pellet delivery. IP cocaine increased the total number of panel presses at the higher doses, mainly by increasing the low rates of responding. The effects of cocaine infusions into the PFC were behaviourally the most selective, as they reduced SIP without having substantial effects either on locomotor activity or panel pressing. These data therefore implicate a role for the PFC in the performance of SIP.     

Facilitation of self-stimulation of the prefrontal cortex in rats following chronic administration of spiroperidol or amphetamine

The effect of chronic administration of spiroperidol, a dopaminergic antagonist, on self-stimulation of the prefrontal cortex was investigated. When spiroperidol was administered either before or after daily self-stimulation tests for 9 days, self-stimulation rates were significantly elevated for several weeks following withdrawal of the drug. Self-stimulation of the nucleus accumbens, supracallosal bundle, and other forebrain sites was not altered, suggesting that the increased self-stimulation of the prefrontal cortex was not due to increased motor activity. Self-stimulation of the prefrontal cortex was also facilitated by chronic administration of d-amphetamine whereas self-stimulation of the supracallosal bundle was suppressed and self-stimulation of the nucleus accumbens was unchanged. The results suggest that dopamine modulates self-stimulation of the prefrontal cortex. Additionally, the effects of chronic spiroperidol on self-stimulation of this structure may model the therapeutic effects of neuroleptics in humans.     

The influence of amphetamine on preference for lateral hypothalamic versus prefrontal cortex or ventral tegmental area self-stimulation

Rats were trained to bar-press for intermittent reinforcement on a concurrent schedule offering self-stimulation (SS) at the animal's choice of one of two different brain loci. On the concurrent schedule, the relative reward value of the two reinforcers is evaluated by the way the subject divides its session time responding for these reinforces, thus yielding a rate-free measure of reward in addition to response rate data. In animals with electrodes in the lateral hypothalamus (LH) and prefrontal cortex (PFC), amphetamine dose-dependently increased response rates as well as the proportion of time allotted to LH stimulation, demonstrating that the reward value of LH stimulation was increased relative to PFC stimulation. This finding supports the hypothesis that DA systems modulate the rewarding value of LH but not PFC SS, and it suggests that differing neural mechanisms underlie these two behaviors. In animals with LH/ventral tegmental area (VTA) implants, amphetamine had no effect on preference, although it produced an overall increase in rate. This suggests that the drug elevates the rewarding value of LH and VTA stimulation to a similar degree, and that the two regions may have a common DA-related reward substrate. Finally, it was found that when the two reinforcers were equally preferred (50% session time allotted towards each reinforcer), response rates for the two rewards were not necessarily equal. This confirms that SS response rate is not a simple function of reward magnitude.     

Self-administered and passive cocaine infusions produce different effects on corticosterone concentrations in the medial prefrontal cortex (MPC) of rats

Although our lab, as well as several others, has demonstrated a role for corticosterone in cocaine self-administration, there are no studies of the central dynamics of this hormone over the course of a behavioral session when rats are self-administering cocaine or receiving passive injections. The assay of corticosterone in microdialysates collected during such sessions allows for determinations of changes in brain corticosterone during drug-taking behavior. By using the combination of microdialysis in terminal fields for the mesocorticolimbic dopaminergic system and the yoked-triad model, one can distinguish between the direct cocaine-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis from the activation of the HPA axis related to drug-taking. In these experiments, we measured corticosterone in microdialysis samples collected from probes aimed at the medial prefrontal cortex, nucleus accumbens and basolateral amygdala in rats self-administering cocaine and receiving identical, passive infusions of cocaine or saline. While corticosterone was increased in all three brain regions in rats receiving cocaine, medial prefrontal cortex corticosterone was increased significantly more in rats receiving non-contingent infusions of the drug compared to rats self-administering cocaine. The results of these experiments demonstrate that control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the central nervous system. These results also provide evidence of the role steroid hormones play in shaping the functional activity of the brain.     

Medial prefrontal cortex is involved in the discriminative stimulus effects of nicotine in rats

Rationale: Central nicotinic receptors have been reported to be involved in the discriminative stimulus (DS) effects of nicotine. Objectives: The purpose of the present study was to investigate the role of the medial prefrontal cortex (mPFC) and the medial habenular nucleus (mHb) in the DS effects of nicotine. Methods: Substitution tests with nicotine administered into mPFC and mHb were conducted in rats trained to discriminate nicotine (0.5 mg/kg, SC) from saline in a two-lever, food reinforced, operant task. Results: Nicotine (40 μg) administered into mPFC substituted for nicotine (0.5 mg/kg, SC), whereas nicotine administered into mHb did not. Conclusions: Together with our previous study indicating that the nucleus accumbens and the ventral tegmental area are partially involved in the DS effects of nicotine, the present study suggests that mPFC is primarily involved in the DS effects of nicotine. Received: 18 January 1999 / Final version: 24 March 1999     

Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis

Abstract Rationale. Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of "impulsive choice" in animals. Objective. A quantitative method was used to analyse inter-temporal choice in rats with lesions of the OPFC and sham-lesioned control rats. Methods. Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 μl; two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 μl of the sucrose solution after a delay d _A ; a press on B resulted in delivery of 100 μl of the same solution after a delay d _B . d _B was increased progressively across successive blocks of six trials in each session, while d _A was manipulated systematically across phases of the experiment. The indifference delay, d _B(50) (value of d _B corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d _B(50) versus d _A were derived, and the parameters of the function compared between the groups. The locations of the lesions were verified histologically at the end of the experiment. Results. In both groups, d _B(50) increased linearly with d _A (r ²>0.98 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. The brains of the lesioned rats showed extensive atrophy/gliosis of the OPFC, with sparing of the dorsolateral prefrontal cortex. Conclusions. The results indicate that lesions of the OPFC can alter inter-temporal choice, either promoting or suppressing "impulsive choice", depending upon the relative sizes and delays of the two choice alternatives. Theoretical analysis based on a quantitative model of inter-temporal choice indicates that the pattern of effect of the OPFC lesion is likely to reflect two actions: (i) an increase in the rate of time discounting; (ii) an increase in sensitivity to the ratio of the sizes of two reinforcers. Electronic Publication     

Effects of acute olanzapine after sustained fluoxetine on extracellular monoamine levels in the rat medial prefrontal cortex

The combination of selective serotonin reuptake inhibitors with atypical antipsychotic drugs exhibits beneficial effects in treatment-resistant depression. We investigated the effects of a 2-week treatment with a low fluoxetine dose (3 mg/kg per day) plus a single injection of olanzapine (3 mg/kg) on the dialysate concentration of noradrenaline, dopamine and serotonin (5-HT) in the medial prefrontal cortex of the rat. Chronic fluoxetine increased only 5-HT levels whereas single olanzapine administration increased the concentration of catecholamines and decreased that of 5-HT to a comparable extent in vehicle- and fluoxetine-treated rats. Therefore, it is possible that the therapeutic benefit of this pharmacological combination may not be associated to changes in the cortical concentration of monoamines, but to postsynaptic blockade of monoaminergic receptors.     

Clozapine-induced dopamine release in the medial prefrontal cortex is augmented by a moderate concentration of locally administered tyrosine but attenuated by high tyrosine concentrations or by tyrosine depletion

Rationale Tyrosine availability can affect indices of dopamine (DA) release in activated central DA systems. There are, however, inconsistencies between studies. One possibility is that the relationship between tyrosine availability and DA release is non-linear.Objectives This study aimed to determine how tyrosine depletion as well as a range of administered tyrosine concentrations affect antipsychotic drug-induced extracellular DA levels in the MPFC or striatum.Methods A guide cannula was implanted over the medial prefrontal cortex or striatum of adult male rats. After a 24-h recovery period, a microdialysis probe was inserted. Microdialysate collection began on the following day. Some rats received vehicle or a tyrosine- and phenylalanine-free neutral amino acid solution NAA(–) (IP) prior to clozapine (CLZ 10 mg/kg IP). Others received vehicle, CLZ (10 mg/kg IP) or haloperidol (HAL) (1 mg/kg IP) while the probe was perfused with artificial cerebrospinal fluid containing tyrosine 0–200 g/ml.Results NAA(–) reduced tyrosine levels in MPFC dialysate by 35%. This reduction did not affect basal MPFC DA levels but attenuated the peak of CLZ-induced MPFC DA levels. The NAA(–) effect could be reversed by administration of tyrosine. Infused tyrosine 12.5–200 g/ml did not affect basal DA levels either in MPFC or striatum. Within the MPFC, tyrosine 50.0 g/ml significantly increased CLZ-induced DA levels. Within the striatum, tyrosine 25.0 g/ml significantly increased while 150.0 g/ml significantly decreased HAL-induced DA levels.Conclusions Basal extracellular levels of DA in the MPFC and striatum are not affected by wide changes in tyrosine availability. However, modestly increased brain tyrosine levels can augment CLZ-induced MPFC and HAL-induced DA levels. Very high tyrosine concentrations attenuate HAL-induced striatal DA levels. These data may explain inconsistencies in the literature and suggest that tyrosine availability could be exploited to modulate psychotropic drug-induced DA levels in the brain.Presented in preliminary format at the annual meeting of the Society for Neuroscience, 2001     

Olanzapine and clozapine but not haloperidol reverse subchronic phencyclidine-induced functional hyperactivity of N-methyl-D-aspartate receptors in pyramidal cells of the rat medial prefrontal cortex

In the present study, we have investigated and compared the ability of olanzapine, clozapine and haloperidol to modulate phencyclidine (PCP)-induced effect in pyramidal cells of the medial prefrontal cortex (mPFC) of rats using the techniques of intracellular recording and voltage-clamp. Subchronic treatment of rats with PCP (2 mg/kg, b.i.d., 7 days, 48-60 h withdrawal) produced: (1) a depolarized resting membrane potential, a decrease of slow after hyperpolarization (sAHP) and spike frequency adaptation, (2) a shift of the concentration response curve of N-methyl-D-aspartate (NMDA), but not (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), to the left, (3) a decrease of the paired pulse facilitation (PPF) with an increase of excitatory postsynaptic current variance (EPSC variance), and (4) a reduction of the blockade of NMDA response by in vitro application of PCP. Repeated treatment with either olanzapine or clozapine, but not haloperidol, completely prevented the aforementioned subchronic PCP-induced effects. The present results indicate that the atypical antipsychotic drugs (APDs) clozapine and olanzapine share a common property in preventing subchronic PCP-induced functional hyperactivity of NMDA receptors.     

Shuttlebox self-stimulation in the rat: An anatomical analysis and the effect of morphine with two current levels

A shuttlebox paradigm was used to train rats to turn electrical stimulation ON and OFF by crossing back and forth in a stabilimeter cage. Two experiments are presented. In the first experiment a threshold current level was used in testing four electrode sites: the lateral hypothalamic area (LHA), lateral septal nucleus (LSN), periaqueductal grey (PAG), and the mesencephalic reticular formation (MRF). In the second experiment, a suprathreshold current level was used to explore two electrode sites: the PAG and the MRF. Stimulation with electrodes in the MRF produced an aversive behavioral response; animals shuttled mainly to turn electrical stimulation OFF. At the other electrode sites, both rewarding and aversive properties were apparent: animals shuttled to turn the stimulation ON as well as OFF. Systemic morphine (10 mg/kg) injections nonselectively increased both average ON and OFF times for the three rewarding sites (minimum p<0.05) at the threshold current level. Systemic morphine injections (10 mg/kg) in animals stimulated at a suprathreshold current level in the PAG selectively increased time spent with stimulation ON (p<0.05) as opposed to time spent with stimulation OFF. No significant behavioral change due to morphine was seen in the aversive MRF at either current level. Animal behavior also was found to vary as a function of site of stimulation (p<0.05). The use of suprathreshold currents appears necessary to produce selective reward facilitation effects of morphine such as those found in the PAG or LHA.     

Haloperidol increases the disruptive effect of alcohol on spatial working memory in rats: a dopaminergic modulation in the medial prefrontal cortex

Rationale The prefrontal cortex (PFC) has been considered the anatomic site for working memory. The medial portion of the PFC (mPFC) is also part of a "brain reward circuit" as constituted by the mesocorticolimbic dopaminergic system. Objective This study examined the effects of acute administration of alcohol (ETOH) in the mPFC or systemically on the performance of 5-s or 1-h delayed tasks in an eight-arm radial maze. Effects of haloperidol (HAL), a dopamine antagonist, combined with ETOH, were also examined in a 1-h delayed task. Methods Male Wistar rats trained in the radial maze and with bilateral cannulae implanted in the mPFC received intraperitoneal (IP) or intracortical (IC) drug administration. Results As compared to saline (SAL) IC, ETOH IC in doses of 100 μg and 180 μg (5 min before session) increased significantly the number of errors in the 1-h and 5-s post-delay performance, respectively. HAL in doses with little or no effect alone IC (10 or 32 μg, 10 min before session) or IP (3.2 mg/kg, 35 min before session) increased the disruptive effect of ETOH IC (100 μg) on 1-h delayed task. Conclusions These results showed that ETOH administered directly in the mPFC disrupts short- and long-term spatial working memory. The increase of the disruptive effect of ETOH produced by a dopaminergic blockage, particularly in the mPFC, suggests that the dopaminergic neurotransmission in this cortical area might modulate ETOH effects on spatial working memory.