Morphine: single-dose tolerance.

Rats show a significant degree of tolerance to a second dose of morphine, with the degree of tolerance increasing the longer the delay between the two doses of morphine. To measure the morphine effect a foot-shock attenuation procedure that allowed the animal to adjust the shock intensity was used in studying delays of up to 180 days.

Reticular stimulation and chlorpromazine: an animal model for schizophrenic overarousal.

It has been postulated that certain schizophrenic patients are in a state of continual central excitation and that improvement in these patients after treatment with chlorpromazine is a result of the action of the drug in reducing this excitation. A model was developed to test this postulated state of central excitation. Rats were electrically stimulated in the mesencephalic reticular formation while performing a simple attention task. Stimulation or treatment with chlorpromazine impaired the performance of the animals; however, the two treatments together resulted in performance indistinguishable from that seen after injections of saline alone.

Morphine lowering of self-stimulation thresholds: lack of tolerance with long-term administration.

Rats were given increasing amounts of morphine over a period of weeks in order to achieve tolerance. Doses of the drug which initially reduced the threshold for self-stimulation behavior continued to do so after long-term administration. These results demonstrate a persistent central effect of morphine which may be related to the opiate "high."

Hyporesponsivity of chronic schizophrenic patients to dextroamphetamine.

Among the evidence supporting the dopamine hypothesis of schizophrenia is the finding that both amphetamine and methylphenidate hydrochloride, potent releasers of dopamine, can cause exacerbation of symptoms in the acute schizophrenic patient. The present report describes three experiments in which the effects of amphetamine in chronic schizophrenic patients were studied. In one of the experiments, orally administered, daily doses of 20 mg of dextroamphetamine sulfate given at 8 PM had little or no effect on the sleep duration of the subjects. In the other two experiments, doses up to 40 mg given orally also had little or no effect on the performance of the subjects on a variety of behavioral tests. There was no evidence of an exacerbation of the disease process in any of the subjects. The most consistent amphetamine effect was a dose-related increase in blood pressure. These results indicate that the chronic schizophrenic patient may be hyporesponsive to amphetamine and suggest that if the dopamine hypothesis is correct, then it must be modified to take into account these findings in the chronic patient.

Intracranial self-stimulation thresholds: a model for the hedonic effects of drugs of abuse.

We present the thesis that many drugs of abuse are used for their hedonic effects and that a relevant animal model for the study of these effects is the action of these drugs on the pathways that support rewarding intracranial self-stimulation. A relationship between abuse potential of a drug and its ability to lower the threshold for rewarding brain stimulation in the rat was found. Of all the compounds we have studied, morphine and cocaine were the drugs that caused the maximum lowering of the rewarding threshold. Phencyclidine hydrochloride and the mixed agonist-antagonist pentazocine also lowered the threshold to a lesser degree, while the mixed agonist-antagonists cyclazocine and nalorphine hydrochloride had inconsistent effects. Naloxone hydrochloride, at the doses tested, had no effect on the threshold. Further, there is no evidence that tolerance develops to the threshold-lowering effect of morphine, suggesting that continued use of narcotics by the physically dependent individual is not simply due to an effort to avoid the pain of withdrawal.

Naloxone prevents and blocks the emergence of neuroleptic-mediated oral stereotypic behaviors.

A commonly used animal model for tardive dyskinesia is the oral stereotypy that is expressed by a challenge dose of a dopamine agonist after daily administration of dopamine antagonists (neuroleptics). In the first of two experiments the expression of this dopamine agonist-induced oral stereotypy was prevented by the concomitant administration of the opiate antagonist naloxone. In a second experiment, if the stereotypy was allowed to be expressed, it could be blocked by the administration of naloxone. To the extent that the effects of chronic neuroleptic treatment in rats is a model for tardive dyskinesia, the results suggest that administration of naloxone can both prevent and block the dyskinetic syndrome associated with neuroleptic use.

Dissociation of the attentional and motivational effects of pimozide on the threshold for rewarding brain stimulation.

The decreased sensitivity of animals to rewarding brain stimulation caused by pimozide has been interpreted as a selective pharmacologic blockade of central reward pathways rather than a nonspecific disruption of performance. In an attempt to confirm this hypothesis, the effects of pimozide on both reward and detection thresholds for intracranial stimulation delivered to the medial forebrain bundle-lateral hypothalamic area (MFB-LH) were determined in four animals. The drug caused a systematic increase in the reward threshold of each subject but had no such effect on the detection threshold. We conclude that pimozide selectively inhibits the rewarding effects of brain stimulation, and that therefore, the D2 dopamine receptor has a major role in activating central reward pathways subserving pharmacologic and electrical reinforcement. The dual anhedonic/antipsychotic effects of neuroleptic medication are discussed as a possible paradox of central importance to the psychopathology of schizophrenia.

Effects of clonidine and yohimbine, alone and in combination with morphine, on supraspinal analgesia.

Morphine raised the threshold for escape from aversive electrical stimulation, delivered to the mesencephalic reticular formation. Clonidine, given alone, had no effect; however, when administered with morphine it blocked the analgesic effect of morphine. Conversely, clonidine, but not morphine, increased the latency to respond to the aversive stimulation, suggesting that clonidine may not have analgesic properties but may merely impair the ability of the animal to respond to the nociceptive stimulation. Yohimbine produced hyperalgesia and also blocked the effect of morphine. These findings are similar to those seen with dopamine agonists and may be related to the effects of yohimbine on the release of dopamine.

DAMGO and DPDPE facilitation of brain stimulation reward thresholds is blocked by the dopamine antagonist cis-flupenthixol.

The role of dopamine neurotransmission in opioid reward was investigated using a rate-independent measure for determining brain stimulation reward (BSR) thresholds. Intra-accumbens infusions of the mu- and delta-specific peptides, D-Ala2, N-Me-Phe4, Gly-ol5-Enkephalin and D-Pen2, D-Pen5-Enkephalin caused significant lowering of BSR thresholds. The dopamine D1/D2 antagonist, cis-flupenthixol, blocked these effects at a dose that did not significantly alter thresholds when given alone. These data suggest both mu- and delta-opioid potentiation of BSR is dopamine dependent.

Skin-testing with neurotransmitters in schizophrenic patients.

Pilot data are presented on a methodology to study a profile of simultaneous reactivity to intradermally injected norepinephrine, dopamine, serotonin, and histamine. The subject groups were young and old schizophrenics on medication and young control volunteers. Skin reactivity in terms of vasoconstriction, vasodilation, and whealing was measured over the course of 3 hours after the injections. Although interpretation of the results is limited by several sources of confounding error and the small number of subjects, the data suggest that skin-test profiles are sensitive enough to yield significant differences between the groups, particularly in the area of vasoconstriction. Further, abnormal skin reactivity may mirror the hypothesized alterations in CNS neurotransmitter physiology in schizophrenic patients.

Effects of chronic d-amphetamine on social behavior of the rat: implications for an animal model of paranoid schizophrenia.

Hooded rats in a social colony were given increasing daily doses of d-amphetamine up to 8 mg/kg. Time-lapse 16 mm cinematographically recorded behavior was analyzed for the following: grooming, feeding, sex, sleeping, resting, sterotypy, agonistic behavior, muricidal activity, and the location and movement of each rat. Subordiant rats receiving d-amphetamine actively withdrew from social interactions by retreating to strategically defensible locations in the environment. They remained hypervigilant of other rats and overreacted to their approaches by either fleeing or by defensively rearing and "boxing". On the other hand, when the dominant rat received the maximum dose, it seemed totally oblivious to the other rats. The responses to drug treatment in subordinant rats may provide a model for the social behavior of frightened paranoid schizophrenics.

Fluoxetine blocks expression but not development of sensitization to morphine-induced oral stereotypy in rats.

RATIONALE: Repeated high doses of morphine in the rat cause stereotypic gnawing behavior that can be re-expressed by a low dose of morphine weeks and even months after the initial treatment. The determination of the role of serotonin in this sensitized morphine-induced behavior has both empirical and theoretical relevance. OBJECTIVES: To determine whether the serotonin-reuptake blocker fluoxetine will block the development and/or the expression of this opiate-induced stereotypy. METHODS: Rats were given four 10-mg/kg injections of morphine alone or with 5.0 mg/kg fluoxetine over a 36-h period. At weekly intervals for 6 weeks after the last of the sensitizing morphine doses, all rats were challenged with 4.0 mg/kg morphine. At week 2 and week 4, however, the morphine was co-administered with fluoxetine. RESULTS: Fluoxetine completely blocked the expression of the morphine-induced stereotypy; however, when the morphine/fluoxetine-treated rats were challenged with morphine alone, they expressed similar degrees of stereotypy as the rats that initially only received morphine. CONCLUSIONS: The results indicate that increasing synaptic serotonin will block the expression but not the development of sensitization to the oral stereotypic effects of repeated high doses of morphine. Also, despite the complete blocking of the morphine effect by fluoxetine during the sensitization phase, the presence of significant biting by these rats during the challenge with morphine alone argues that conditioning factors are not a necessary component for the morphine sensitization to develop.

Effects of d-amphetamine and naloxone on brain stimulation reward.

Self-stimulation thresholds were determined in rats by means of a modification of the psychophysical method of limits. Reinforcement values were determined after the administration of d-amphetamine alone, naloxone alone, and naloxone administered concurrently with d-amphetamine. d-Amphetamine yielded dose-related decreases in the threshold (0.25--2.00 mg/kg IP), while naloxone alone (2.0--16 mg/kg IP) caused no consistent changes. For each animal, a dose of d-amphetamine that substantially lowered the threshold was then selected to be administered with varying doses of naloxone. The threshold-lowering effect of d-amphetamine was blocked by naloxone at doses as low as 2.0 or 4.0 mg/kg. This finding suggests the possible involvement of an opiate receptor in the mediation of the enhancement by d-amphetamine of brain stimulation reward.

Gamma-vinyl GABA attenuates cocaine-induced lowering of brain stimulation reward thresholds.

Gamma-vinyl GABA (GVG, also referred to as vigabatrin), an irreversible inhibitor of GABA transaminase (GABA-T), raises levels of GABA in nerve terminals, inhibits striatal dopamine release, and attenuates cocaine-induced increases in extracellular dopamine in the striatum and nucleus accumbens. In order to determine the action of GVG on dopamine-mediated reward, we examined its effects on the threshold for rewarding brain stimulation in male F-344 rats. GVG dose-dependently raised brain stimulation reward (BSR) thresholds at doses of 200, 300, and 400 mg/kg without significant effects on motor performance as measured by response latencies. In order to determine if GVG had similar modulatory effects on cocaine-induced lowering of BSR thresholds, the effective doses of GVG were co-administered with 2.5 and 5.0 mg/kg cocaine, doses that significantly lower BSR thresholds. The 400 mg/kg dose of GVG significantly blocked the lowering of thresholds seen at each dose of cocaine. Cocaine in combination with 200 or 300 mg/kg GVG, doses of GVG that significantly raise BSR thresholds, resulted in thresholds not significantly different from those obtained with cocaine alone. These data demonstrate that, at the doses tested, GVG is more effective at modulating basal reward thresholds that at modulating thresholds lowered by cocaine, implying that as dopaminergic activity increases, GABAergic activity must also increase in order to exert its inhibitory influence on dopaminergic activity.

Potentiation of morphine analgesia by d-amphetamine.

Rats were trained to escape from aversive electrical brain stimulation delivered to the mesencephalic reticular formation (MRF). The threshold for this escape behavior was determined by a modification of the classic psychophysical method of limits. Escape thresholds were determined after the administration of morphine alone, d-amphetamine alone, and the combination of d-amphetamine and an ineffective dose of morphine. Morphine alone caused a dose-dependent raising of the escape threshold (1.0-16.0 mg/kg IP) while d-amphetamine alone (0.06-2.0 mg/kg IP) had no effect or caused a slight lowering of threshold. For each animal, a dose of morphine that produced no change in escape threshold was then selected to be administered concomitantly with various doses of d-amphetamine. The co-administration of morphine and d-amphetamine resulted in a significant, dose-dependent increase in the escape threshold, which was not seen with d-amphetamine alone and was as great or greater in magnitude than the increase seen with the highest dose of morphine tested. The results of this study clearly demonstrate that opiate analgesia is potentiated by concomitant d-amphetamine administration. The mechanisms involved in this potentiation warrant further investigation for the clinical management of pain.

The threshold lowering effects of MDMA (ecstasy) on brain-stimulation reward.

3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive phenylisopropylamine which is structurally similar to both amphetamine-related sympathomimetics and the hallucinogen, mescaline. MDMA produces pleasurable effects which include euphoria, and recent reports continue to demonstrate its widespread recreational use. The aim of the present study was to assess the effects of racemic MDMA on the threshold for rewarding intracranial self-stimulation, an animal model used to assess a drug's abuse liability in man. Rewarding electrical stimulation was delivered via electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic area of the rat brain. Thresholds were determined by means of a rate-independent psychophysical method. MDMA produced a dose-related lowering of the reward threshold in all four animals tested. Given that increased sensitivity for rewarding brain stimulation, measured as a lowering of the reward threshold, is an animal model of drug-induced euphoria these results suggest a similar mode of action for its reinforcing effects as other abused substances.

Lack of hepatotoxicity with naltrexone treatment.

Naltrexone, a specific opiate receptor antagonist, is used clinically in the treatment of heroin addiction and more recently, for the treatment of dyskinesia associated with Huntington's disease (HD). Naltrexone may act as a potential hepatotoxin, as reflected in the elevation of transaminase levels. However, one study concluded that, for a brief treatment period of 12 weeks, there is no contraindication to naltrexone treatment based solely on increased hepatic enzyme values. This study monitored liver transaminase levels, in ten HD patients receiving daily doses, between 50 mg/day and 300 mg/day, of naltrexone for periods of 10 to 36 months. Serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were obtained before treatment and at intervals of 1 to 4 months during treatment. Only one of the ten patients treated with naltrexone had increased levels of both SGOT and SGPT, whereas one other patient showed elevated levels of SGPT. These elevations, which initially appeared dose related decreased to normal limits with continued treatment. Because many of the patients were receiving other medications, a combination of drugs with naltrexone may contribute to the increased transaminase levels seen in two of the patients. In summary, chronic administration of naltrexone in doses up to 300 mg/day for periods up to 36 months does not significantly change hepatic function, as measured by SGOT and SGPT levels.

Detection thresholds for electrical stimulation of forebrain and midbrain loci in the rat.

Current intensity thresholds for the detection of electrical brain stimulation were determined from a variety of forebrain and midbrain sites in rats. In a discrete trial, instrumental paradigm, the detection stimulus delivered via one electrode acted as a cue for the availability of response contingent rewarding brain stimulation delivered via a second electrode in the posterolateral hypothalamus. The current intensity of the detection stimulus (20 Hz) was varied according to a modification of the psychophysical method of constant stimuli, while the intensity of contingent rewarding stimulation (160 Hz) was fixed at a highly reinforcing level. Detection thresholds measured from forebrain sites were significantly lower than thresholds from midbrain sites. This difference in detection thresholds was not related to any variability between subjects in site or parameters of the rewarding stimulus used to maintain behavior. Lower detection thresholds from forebrain loci may be due to greater sensitivity to electrical stimuli at the detection site or of the pathways from those sites to areas mediating perception or conditioning.

Cue-induced changes in basal local cerebral glucose utilization 13 days after morphine sensitization in the Fischer 344 rat: relevance for drug craving.

The present experiment tested the hypothesis that some persistent neural adaptation develops during the course of repeated sensitizing doses of morphine administered to rats. A sub-hypothesis was that this imprint would be of greater magnitude in the presence of morphine-conditioned cues. In order to test these hypotheses basal local cerebral metabolic rates for glucose (LCMR(glu)) were determined 13 days after the last of four 10-mg/kg doses of morphine administered in 36 h to Fischer 344 male rats. LCMR(glu) was determined using the 2-deoxy-D-[1-(14)C]glucose method (2-DG). Half of the rats, the conditioned group, were placed in the 2-DG chamber after each injection and half, the nonconditioned group, were placed in a neutral environment. A control group received only saline in lieu of morphine. All metabolic rates were determined in a nondrugged state. The major finding was large increases in metabolic rate throughout the forebrain in the sensitized rats. This was especially so in the conditioned group, 46 out of 93 areas examined had significant increases while in the nonconditioned group it was 25 out of 93. Both the core and shell of the nucleus accumbens showed significant elevations in metabolic rates in the presence of morphine cues but only the shell in the absence of the cues. There were no significant decreases in basal metabolic activity in any of the brain regions evaluated in either experimental group. The present finding suggests that changes in the brains of these morphine-sensitized rats may model the altered brain states responsible for drug craving in human drug addicts.