Action of opioid drugs on the brain-reward system.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
C Kornetsky
Publications and source records attributed to C Kornetsky.
The local cerebral metabolic effects of morphine in rats exposed to escapable footshock.
The 2-deoxy-D-[1-14C]glucose (2-DG) method was used to examine the effects of morphine sulfate (MS) on local cerebral metabolic rates for glucose (LCMRglu) in male F-344 rats required to turn a wheel manipulandum in order to escape from nociceptive footshock. Four groups of rats were studied: control-saline, control-MS, footshock-saline and footshock-MS. All animals were administered MS (4 mg/kg, s.c.) or saline 7 days, 3 days and 10 min prior to the start of the 2-DG experiment. In agreement with its well-known effect on the emotional component of pain, MS administered to rats exposed to footshock caused a significant decrease in LCMRglu compared to footshock-saline rats in limbic structures such as the diagonal band of Broca, lateral septum, bed nucleus of the stria terminalis, horizontal limb of the diagonal band, habenular complex and medial amygdala. Additionally, two components of the midline thalamus with extensive connections with the limbic system, the paraventricular and paratenial thalamic nuclei, were similarly affected by morphine. Footshock caused an overall increase in cerebral metabolism as 52 of 73 measured structures demonstrated increases in activity compared to saline control; however, statistically significant effects in specific structures were limited. These results identify limbic and midline thalamic structures important in morphine-induced analgesia and indicate that footshock tends to have a generalized stimulatory effect on LCMRglu.
Animals↗
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.
Adult↗
Bromocriptine, a D2 receptor agonist, lowers the threshold for rewarding brain stimulation.
Drug-induced lowering of brain stimulation reward threshold can serve as a model for the pharmacological activation of reward pathways. Here, the effects of bromocriptine, a direct D2 dopamine receptor agonist, on reward thresholds were investigated. Bromocriptine administration resulted in the significant lowering of threshold levels in all test animals, suggesting that this agent can activate the same reward processes as do abused substances such as cocaine and morphine.
Animals↗
The use of a biopsy punch in surgical preparation of drug self-administering animals.
This report describes a simple surgical method of exiting an implanted intravenous catheter through the skin via a nonsutured site. The preparation, which makes use of a biopsy punch, avoids placing the catheter exiting point through the incision used for subcutaneously fixing the catheter platform on the back of the animal.
Animals↗
Dopamine, a common substrate for the rewarding effects of brain stimulation reward, cocaine, and morphine.
Explore the source record for details and available documents.
Animals↗
Nicotine and brain-stimulation reward: interactions with morphine, amphetamine and pimozide.
Using a rate-independent discrete trial method of determining thresholds for rewarding electrical intracranial stimulation in rats, we evaluated the pharmacological interaction of nicotine plus morphine, d-amphetamine, or the D2 receptor antagonist, pimozide. Both morphine and amphetamine shifted the dose-response curve for nicotine down and to the left, indicating increased efficacy and potency, respectively. Pimozide at doses that have no effect on performance and only minimal effect on brain-stimulation reward blocked the effect of nicotine. These data suggest that the same dopaminergic substrate that supports the positive reinforcing effects of other drugs of abuse also supports nicotine reward.
Amphetamine↗
Effects of nicotine on the threshold for rewarding brain stimulation in rats.
The rewarding effects of nicotine alone and nicotine challenged with mecamylamine, a nicotine receptor blocker, or naloxone were determined using a rate-independent discrete-trial threshold measure of brain-stimulation reward in rats. If nicotine acts as other drugs of abuse, it would be expected to lower the reward threshold, that is, increase an animal's sensitivity to rewarding brain stimulation, and naloxone would be expected to block this effect, as it does other stimulants in this paradigm. Nicotine was found to significantly lower the reward threshold and mecamylamine blocked this effect. However, although naloxone increased the variability of nicotine's effect on the reward threshold, it failed to dose dependently block nicotine's threshold-lowering effect.
Animals↗
Brain mechanisms of drug-induced reinforcement.
The results of the experiments described above suggest that although the abused psychomotor stimulants and opioids have independent actions that contribute to their reinforcing effects, there are common neuronal substrates for some of their rewarding effects. Additionally there is considerable evidence implicating dopamine systems in these rewarding effects. The neuronal systems involved in these pharmacological actions may be similar to those involved in the rewarding effects of electrical stimulation to the brain. Although both classes of compounds cause euphoria in humans and are reinforcing in animals, the opioids are also central nervous system depressant drugs. These depressant properties influence the subjective effects in humans and possibly the nature of the rewarding effect in animals. Experiments using the 2-deoxyglucose procedure indicate that BSR to either the ventral tegmental area or the medial forebrain bundle results in functional activation throughout the mesocorticolimbic system. The major effects are found in the nucleus accumbens, olfactory tubercle, and the medial prefrontal cortex. Cocaine produces increases in metabolic rates similar in distribution to BSR. Morphine, however, only causes significant increases in functional activity in the olfactory tubercle. Further, only in this brain site did the combination of BSR plus morphine or cocaine cause increases in functional activity over that of stimulation alone. These findings suggest that the olfactory tubercle plays a major role in the pharmacological actions of both the psychomotor stimulants and the opioids as well the rewarding effects of electrical stimulation of the brain.
Animals↗
Brain-stimulation reward: a model for the study of the rewarding effects of abused drugs.
The robustness of the findings of the BSR effects of abused substances indicates that almost any technique used to measure these effects will be useful. The simplest procedure, however, of selecting a single intensity of stimulation and determining the effects of drugs on the rate of response for that selected intensity is fraught with difficulty in interpretation. More than 25 years ago the interpretation of changes in response rate as a reflection of changes in the reward value of the stimulation was challenged (Hodos and Valenstein 1962). Today it is rare to see a single stimulation intensity used in a published manuscript. However, most studies still use procedures of which rate of response is an integral part. Because animals will press a lever more than 80 times per minute and--on a continuous reinforcement schedule--receive as many as 80 stimulations a minute, conclusions about the specificity of the effects of drugs are difficult. The results of BSR experiments on mechanisms of action of abused substances clearly indicate that the reinforcing effect of most, if not all, such substances is probably the result of activation of a reward system that originates in the cell bodies of the ventral tegmental area and courses rostrally to the limbic and frontal projection sites of the mesocortical system. Thus, we believe, the technique has clearly fulfilled its promise as a "window on the brain" (Olds 1977).
Animals↗
Heroin, 6-acetylmorphine and morphine effects on threshold for rewarding and aversive brain stimulation.
Studies investigating the reinforcing and analgesic activity of heroin and morphine have found that heroin is a more potent compound. The rapid deacetylation of heroin to 6-acetylmorphine and morphine raises questions concerning the underlying mechanism responsible for this difference in potency. The present series of experiments addressed this issue by examining, in the rat, the relative potency of heroin and its active metabolites, 6-acetylmorphine and morphine, to lower the threshold for rewarding stimulation of the medial forebrain bundle and raise the threshold for aversive stimulation of the mesencephalic reticular formation. Reward and escape thresholds were determined by using a modification of the psychophysical method of limits. Heroin was found to be approximately 40 times more potent than morphine in lowering the reward threshold and approximately 6.5 times more potent in raising the escape threshold. 6-Acetylmorphine and heroin were approximately equipotent in producing significant effects on the threshold for both rewarding and aversive brain stimulation. These findings suggest that heroin's increased potency when compared to morphine may be due, in part, to the activity of 6-acetylmorphine.
Animals↗
The role of the olfactory tubercle in the effects of cocaine, morphine and brain-stimulation reward.
Using the quantitative 2-[14C]deoxyglucose autoradiographic method, local rates of glucose utilization were measured in rats after the administration of morphine or cocaine in the presence or absence of rewarding brain stimulation to the medial forebrain bundle. In animals that did not receive brain stimulation, cocaine significantly increased glucose utilization in the olfactory tubercle, medial prefrontal cortex and substantia nigra pars reticulata, whereas morphine significantly increased glucose metabolism in the olfactory tubercle only. Stimulation itself increased metabolic rates in a number of sites, such as the olfactory tubercle, nucleus accumbens, medial prefrontal cortex, ventral tegmental area and others. However, in self-stimulating animals both morphine and cocaine caused further increases in activity in the olfactory tubercle. Since the olfactory tubercle was the only structure to cause a significant increase in metabolic rate following each treatment, the results implicate this limbic structure in the rewarding effects of morphine, cocaine and brain-stimulation reward.
Animals↗
L-histidine attenuates the effects of pentazocine on rewarding brain-stimulation.
Previous research has indicated that the antihistamine tripelennamine potentiates the threshold lowering effects of pentazocine on brain stimulation reward, a model of drug-induced euphoria. To determine the importance of histamine in this interaction, we studied the effects of co-administration of L-histidine and pentazocine on the threshold for brain stimulation reward. Pentazocine (2.5-10.0 mg/kg) lowered the threshold for rewarding stimulation to the medial forebrain bundle-lateral hypothalamus in male F344 rats. L-histidine (500 and 750 mg/kg) by itself had no significant effects, yet antagonized the threshold lowering effects of pentazocine. These doses of L-histidine are known to significantly raise brain histamine concentrations. Our results suggest that histamine may play a tonic inhibitory role, at least in part, on the neural systems responsible for the reinforcing properties of pentazocine.
Animals↗
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.
Animals↗
The distribution of changes in local cerebral energy metabolism associated with brain stimulation reward to the medial forebrain bundle of the rat.
Using the quantitative 2-[14C]deoxyglucose autoradiographic method, local rates of glucose utilization were measured in rats during brain stimulation reward to the medial forebrain bundle. Metabolic activation was observed both rostral and caudal to the site of stimulation. These sites included the nucleus accumbens, olfactory tubercle, lateral septum, and ventral tegmental area. In many cases, increases in glucose utilization occurred bilaterally. These data suggest the involvement of both ascending and descending systems in brain stimulation reward. Furthermore, despite the unilateral nature of the electrical stimulation, increases in glucose utilization were observed both ipsilateral and contralateral to the site of stimulation.
Animals↗
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.
Analgesics↗
Pharmacologic evidence for nociception resulting from noncontingent "rewarding" brain stimulation.
Prolonged noncontingent electrical stimulation to rewarding brain sites will elicit escape behavior in rats. This study was designed to determine if this escape behavior is reinforced by the termination of a nociceptive stimulus or reinforced by the rewarding effects of the onset of the next stimulus. In the present experiment we determined the effects of the hyperalgesic naloxone (NX) and the analgesic ethylketocyclazocine (EKC) on the threshold for escape from electrical brain stimulation to the medial forebrain bundle-lateral hypothalamic area (MFB). Results indicate that EKC (0.5-1.0 mg/kg) raises the escape threshold, whereas NX (8.0-16.0 mg/kg) lowers the escape threshold, suggesting that escape from electrical brain stimulation to the MFB is the result of the nociceptive quality of stimulation and not the result of the rewarding effects of the onset of stimulation.
Analgesics, Opioid↗
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.
Animals↗