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.

Conditioning and the delayed onset of a haloperidol-induced behavioral effect.

In a series of experiments, rats were given daily injections of 0.3 mg/kg haloperidol or vehicle 1 hr prior to behavioral testing. In these experiments, when rats were placed in an illuminated compartment and given the opportunity to enter a darkened compartment, haloperidol- and vehicle-treated rats initially entered the dark compartment with similar latencies. With repeated treatments, however, the haloperidol group gradually took increasingly longer times to enter the dark compartment. Furthermore, when the drug treatments of the groups were reversed, behavioral performance was dissociated from the drug state of the animal. Vehicle rats switched to haloperidol entered the dark compartment much more rapidly than haloperidol rats switched to vehicle. As additional control procedures, rats were given haloperidol 1 hr posttrial or were given haloperidol and only placed in the dark compartment. These haloperidol treatments did not differ from vehicle treatments. The gradual development of long latencies to initiate behavior and the persistence of this behavior during withdrawal from the haloperidol are consistent with the establishment of a conditioned drug response. This observation suggests that conditioning may contribute to the delayed onset of response in the clinical use of neuroleptic drugs.

Differential liabilities of haloperidol and thioridazine for inducing apomorphine hypersensitivity.

In an animal model of tardive dyskinesia, sensitivity to apomorphine-induced stereotyped behavior reflects increased dopamine receptor activity induced by chronic neuroleptic treatment. Four groups of Sprague-Dawley rats received haloperidol (H) 0.5 mg/kg, haloperidol 0.5 mg/kg + benztropine 2.0 mg/kg (H + B), thioridazine (T) 25 mg/kg, or saline (S) ip daily for 18 days, were withdrawn for 21 days, and then received another 10 days of drug. Drug-induced catalepsy was measured daily during the second phase of drug treatment. Sensitivity to apomorphine 0.125 mg/kg and 0.250 mg/kg was assessed during the first and second weeks of withdrawal from each phase of drug treatment. Catalepsy scores for H, H + B, and T groups showed an unexpected progressive increase over treatment days. Following withdrawal from the first drug phase, only H and H + B rats showed enhanced apomorphine stereotypy. H rats were hypersensitive for both weeks of testing while H + B rats were only hypersensitive for the first week. All rats showed changes in apomorphine sensitivity after withdrawal from the second drug phase. H and H + B rats showed significant enhancement of stereotypy at both apomorphine dose levels and at both weeks of testing. T rats showed a significant enhancement but only at the higher apomorphine dose level and only during the first withdrawal week. S rats had a significant enhancement of apomorphine-induced stereotypy during the second withdrawal week. We conclude that H, H + B, and T have differential liability for inducing dopamine receptor hypersensitivity, with haloperidol being most effective and thioridazine being least effective.

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.

Concomitant obsessive-compulsive disorder and schizotypal personality disorder.

Despite advances in the management of patients with obsessive-compulsive disorder, some remain refractory to treatment. The authors retrospectively examined characteristics of 43 treatment-resistant obsessive-compulsive patients and found that those with concomitant schizotypal personality disorder had an extremely high rate of treatment failure. Of the 29 treated nonschizotypal patients, 26 (90%) improved at least moderately; only one of 14 (7%) schizotypal patients improved. In addition, the number of schizotypal features in each patient was strongly negatively correlated with treatment outcome.

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.

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.

MMPI correlates of obsessive-compulsive disorder.

The MMPI was administered to 32 patients with pure obsessive-compulsive disorder. Twelve of the patients had been previously misdiagnosed as having schizophrenia, 10 had been treated with neuroleptics, and 1 developed severe tardive dyskinesia. An MMPI profile for obsessive-compulsive disorder is described.

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.

A conditioned anti-parkinsonian drug effect in the hemi-parkinsonian rat.

In two separate experiments contralateral rotation was classically conditioned in hemi-Parkinsonian rats. In the first experiment, ten rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, which produced ipsiversive circling, were given five daily injections of the dopamine receptor agonist apomorphine (0.5 mg/kg) to induce circling contralateral to the lesion hemisphere. One half of the rats (the conditioning group) were placed in a novel environment for 15 min during each apomorphine treatment. Subsequently, when placed into this environment 3, 10, 17, and 24 days after the final apomorphine injection, the conditioning group spontaneously rotated contralateral to the lesion hemisphere, whereas a similarly drug-treated non-conditioned group spontaneously rotated ipsilateral to the lesion hemisphere. On day 26, all rats were given a 2.0 mg/kg injection of d-amphetamine, which generated ipsilateral rotation in all rats in their home environment, but when placed in the conditioning environment, the conditioned group rotated contralateral whereas the non-conditioned group rotated ipsilateral. In the second experiment, eight rats with unilateral destruction of dopamine neurons were given differential conditioning in two novel environments. In every case, environments associated with 0.5 mg/kg apomorphine treatment induced contralateral rotation when the rats were tested without drug but ipsilateral rotation in environments not associated with apomorphine. These findings suggest a role for respondent or Pavlovian conditioning in the pharmacological management of Parkinsonism.

Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine.

Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.

Facilitation of responding for rewarding brain stimulation by a high dose of amphetamine when hyperthermia is prevented.

Rats given a 5 mg/kg injection of d-amphetamine did not respond for brain stimulation reward when tested under normal laboratory temperatures. In addition to the usual manifestations of stereotypy the rats were markedly hyperthermic. If the hyperthermia was prevented, however, by initially placing the rats in a cold room (10 degrees C) and subsequently testing for brain stimulation under a cool chamber temperature (14--16 degrees C), the rats responding for brain stimulation was facilitated. Thus, the occurrence of hyperthermia appears to be a critical factor responsible for this behavioral dysfunction produced by a high dose of amphetamine.

Pavlovian conditioning of L-dopa induced movement.

Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drug L-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence of L-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as the L-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior and L-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlike L-dopa-induced contralateral rotation, is not affected by D1/D2 receptor blockade. Thus, the conditioned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D1/D2 antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects of L-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.

A comparison of the food intake suppression produced by giving amphetamine as an aversion treatment versus as an anorexic treatment.

Separate groups of rats were given either 1 or 2 mg/kg injections of amphetamine 30 min before or after eating a preferred high-fat food. When given before eating as an anorexic treatment, amphetamine initially suppressed intake almost completely, but with repeated injections tolerance developed. In contrast amphetamine given after eating as an aversion treatment initially had little effect on intake, but with repeated injections it suppressed intake almost completely in rats receiving the higher dose.

Treatment schedule as a determinant of the development of tolerance to haloperidol.

Three groups of rats received haloperidol 0.5 mg/kg IP twice daily for 20 days, twice daily for 10 days, or every other day for 40 days. The rats in control groups received saline injections according to the same schedules as the experimental groups. During the chronic treatments, spontaneous motor activity was measured as an indicator of behavioral tolerance, and at the completion of treatments, limbic and striatal homovanillic acid (HVA) levels were determined in order to provide a biochemical indication of tolerance. Both of the haloperidol groups on twice-daily injection schedules exhibited a trend towards recovery of spontaneous motor activity during treatment, indicative of behavioral tolerance, as well as reduced HVA levels indicative of near complete biochemical tolerance. The group receiving haloperidol every other day exhibited a trend toward behavioral intolerance to haloperidol, along with elevated HVA levels that indicated a complete absence of tolerance. The suggested importance of treatment schedule rather than cumulative drug dosage in the development of tolerance to haloperidol may have significance to long-term side effects of chronic neuroleptic treatment such as tardive dyskinesia and clinical issues such as drug holidays.

Chronic low-dose haloperidol effects on self-stimulation rate-intensity functions.

Animals responding for biphasic square wave stimulation to the VTA were treated for 26 days with a low dose (0.07 mg/kg) of the neuroleptic haloperidol and tested at 1 h post-injection. Initially the drug induced a pronounced lateral displacement of the baseline rate-intensity function, concomitant with a depression in slope. Over the course of chronic treatment, partial tolerance was observed to the drug-induced increases in threshold concomitant with the onset of a significant suppression in peak response rate. Biochemical tolerance to stimulated dopamine metabolism (as per cent non-drug control) was significant only for mesolimbic (versus neostriatal) regions, in animals receiving haloperidol according to pre- and post-test administration schedules. The observation of sensitization to peak rate reductions parallels previous reports for spontaneous locomotor activity measures and is compatible with depolarization inactivation mechanisms proposed to account for delayed-onset clinical effects. Further, selective biochemical tolerance in mesolimbic regions supports suggestions that mesolimbic dopamine is important as a substrate for subtle low dose neuroleptic effects which may be relevant for studying pharmacotherapeutic treatment issues.

Environmental stimulation promotes recovery from haloperidol-induced extinction of open field behavior in rats.

Rats receiving 0.1 mg/kg haloperidol showed a progressive decline in their rate of spontaneous motor activity in an open field environment, suggesting that incentive motivational properties of stimuli in the experimental situation may be blunted by neuroleptic treatment. After removal for a short time-out in the home cage they were re-tested in this, or a novel stimulus environment, for a second observation session. Under novel (but not familiar) stimulus conditions haloperidol-treated rats showed an enhancement of spontaneous activity, similar to that observed in vehicle-treated animals, and exceeded their previous low rates of crossing and rearing responses. As drug conditions were similar for the two haloperidol groups, it is likely that neuroleptic-induced effects on spontaneous motor behavior are sensitive to the stimulus complexity of the environmental situation.