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Biomedical subjects

C Kornetsky

Publications and source records attributed to C Kornetsky.

At least 55 records · Page 3Linked to original sources
PubMed1989

Opiate dependence alters central reward of nalbuphine or pentazocine plus tripelennamine.

The threshold lowering effects of the coadministration of tripelennamine plus nalbuphine or tripelennamine plus pentazocine on the threshold for rewarding electrical intracranial stimulation, a model of drug-induced euphoria, was determined in rats physically dependent to morphine. Although tripelennamine plus nalbuphine had threshold-lowering effects similar to tripelennamine plus pentazocine in non-opiate-dependent subjects, tripelennamine plus nalbuphine failed to lower the threshold for rewarding stimulation in morphine-dependent animals. To the extent that these data may be applied to human addicts, it suggests that opiate-dependent addicts are unlikely to use the combination of tripelennamine plus nalbuphine but are likely to use tripelennamine plus pentazocine.

Animals↗
PubMed1989

Evidence for the role of dopamine D1 receptors in morphine induced stereotypic behavior.

In the course of studying the effects of morphine on the escape from electrical stimulation to the rat medial forebrain bundle, we observed that a combination of low doses of morphine and stimulation, neither of which caused stereotypy in the rat, resulted in marked stereotypic behavior that was similar to that seen with high doses of morphine alone. This behavior could be blocked by either naloxone or by the D1 antagonist SCH 23390, but not by the D2 antagonist raclopride. Furthermore, the stereotypy caused by chronically administered high doses of morphine was blocked by naloxone and the D1 antagonist. These results strongly implicate the role of dopamine D1 activation in morphine-induced stereotypies.

Animals↗
PubMed1989

The effects of amfonelic acid alone and in combination with naloxone on brain-stimulation reward.

Thresholds for rewarding brain stimulation delivered to the medial forebrain bundle-lateral hypothalamus were determined by means of a rate-free psychophysical method. Amfonelic acid (AFA), an indirect dopamine agonist, alone caused a significant dose-dependent lowering of the rewarding threshold. Although naloxone treatment by itself did not significantly alter the reward threshold, it blocked AFA's threshold lowering effect in every animal at one or more of the dose combinations of the two drugs tested. Naloxone was found to be more effective in blocking the threshold lowering actions of a higher (1 mg/kg) dose as opposed to a lower (0.25 mg/kg) dose of AFA. Since a lowering of threshold for rewarding intracranial stimulation is a model for drug-induced euphoria, the findings presented here indicate that AFA may have abuse potential. Furthermore, these results suggest that endogenous opioid systems may begin to modulate the effects of AFA on the reward system only when a certain level of activation of dopaminergic systems is reached.

Animals↗
PubMed1989

The effect of amfonelic acid or nisoxetine in combination with morphine on brain-stimulation reward.

Many drugs of abuse, including stimulants such as cocaine and amphetamine, and opioids like morphine and heroin, will lower threshold at which rats will work to receive electrical stimulation to the medial forebrain bundle-lateral hypothalamic region (MFB-LH). This effect is even greater when the two classes of drugs are coadministered. The underlying mechanisms by which this occurs are not completely understood, however there is considerable evidence suggesting that the catecholamines play a major role in mediating the reinforcing effects of these drugs. The present study was conducted to investigate the effects of amfonelic acid, an indirect dopamine agonist, and nisoxetine, a highly selective norepinephrine uptake blocker, alone and in combination with morphine, on the reward threshold for rewarding electrical intracranial stimulation. As in previous studies, morphine, as well as amfonelic acid, lowered the reward threshold with the amfonelic acid causing greater threshold lowerings than that of morphine. When a low (ineffective) dose of amfonelic acid was administered concomitantly with morphine, the threshold lowerings observed were larger than those seen with either drug alone and were often more than additive. Nisoxetine alone had no effect on the reward threshold and produced inconsistent results when combined with morphine. These findings support the thesis that amfonelic acid has abuse potential, and that its reinforcing effects may, in fact, be even greater than that of the opioids. Further, these results support the hypothesis that dopamine plays a more critical role in mediating brain-stimulation reward than dose norepinephrine.

Animals↗
PubMed1988

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.

3,4-Methylenedioxyamphetamine↗
PubMed1988

The reinforcing properties of the mixed agonist-antagonist buprenorphine as assessed by brain-stimulation reward.

The effect of buprenorphine on the threshold for rewarding brain stimulation to the medial forebrain bundle-lateral hypothalamus was determined in rats using a rate-independent psychophysical method. Increased sensitivity to rewarding brain stimulation (i.e., lowering of the reward threshold) was used as the measure of a drug's reinforcing action. Buprenorphine (SC) produced a significant dose-dependent lowering of the reward threshold, with effective doses varying from 0.004-0.06 mg/kg. These results are consistent with buprenorphine's euphoria producing effects in humans and its ability to sustain self-administration in animals and suggest that buprenorphine may have abuse potential.

Animals↗
PubMed1988

Brain stimulation reward: effects of ethanol.

This paper briefly describes and compares the effects of ethanol with those of other abuse substances on brain stimulation reward. The most frequently observed effects of abuse substances on this phenomenon is an increase in sensitivity of the animal to the stimulation. This increased sensitivity to rewarding brain stimulation has been studied as a model of drug-induced euphoria. Although many studies have reported that ethanol does increase the sensitivity of animals to this stimulation, there is much less consistency in results between laboratories than observed with the abused opiates or psychomotor stimulants. Data is presented that suggests that associative factors, e.g., self- versus experimenter-administered ethanol, as well as route of administration and time of brain stimulation testing may all contribute to the variability in results obtained between laboratories. Further, the effects of ethanol on brain stimulation reward are more like those of other sedative-hypnotics than the opiates or psychomotor stimulants.

Alcohol Drinking↗
PubMed1987

Naloxone attenuation of the effect of cocaine on rewarding brain stimulation.

Antagonism of the threshold lowering effect of cocaine for brain stimulation reward by naloxone was investigated. Rats with bipolar electrodes implanted in either the median forebrain bundle (MFB) or the ventral tegmental area (VTA) were trained on a rate-independent threshold procedure. Effective threshold lowering doses of cocaine (10-15 mg/kg i.p.) were determined for each subject. A moderate dose of naloxone (4 mg/kg i.p.) effectively blocked the threshold lowering action of the cocaine. Lower (2 mg/kg) and higher (8 mg/kg) doses of naloxone attenuated but did not completely block the cocaine effect. These results provide further evidence for a catecholamine/endogenous opioid interaction in central reward.

Animals↗
PubMed1987

Evaluation of the supraspinal analgesic activity and abuse liability of ethylketocyclazocine.

Rats were trained to escape from aversive electrical brain stimulation delivered to the midbrain reticular formation (MRF) or to obtain rewarding intracranial stimulation delivered to the medial forebrain bundle (MFB). The threshold for escape behavior was determined by a modification of the psychophysical method of limits. Likewise, reward thresholds were determined by a rate-free psychophysical method. Acute administration of ethylketocyclazocine (EKC) (0.06-1.0 mg/kg s.c.) raised escape threshold in a dose-dependent manner while having no effect on non-specific measures of sedation or motor impairment. This suggests that opioids with kappa receptor activity specifically modulate pain at a supraspinal level. Administration of EKC had no effect on the threshold for rewarding intracranial stimulation to the MFB suggesting that EKC has low potential for abuse.

Analgesics↗
PubMed1987

The combined effects of morphine and d-amphetamine on the threshold for brain stimulation reward.

The effect of morphine and d-amphetamine co-administration on the threshold for rewarding intracranial electrical stimulation was studied in rats with electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic or ventral tegmental area of the brain. Thresholds were determined by means of a rate-independent psychophysical method. Individually, morphine and d-amphetamine both caused a dose-related lowering of the reward threshold. Low doses of morphine or d-amphetamine which were ineffective or minimally effective in lowering the reward threshold were then tested with various doses of either d-amphetamine or morphine, respectively. In both cases, the combined administration of morphine and d-amphetamine resulted in a lowering of the reward threshold that was greater than for the corresponding doses of morphine and d-amphetamine when given alone. Given that increased sensitivity for rewarding brain stimulation has been suggested to be an animal model of drug-induced euphoria, this effect is congruent with the reported increase in the degree of euphoria produced when amphetamine is used in conjunction with opiate drugs.

Animals↗
PubMed1986

Evidence for a supraspinal analgesic effect with cyclazocine and pentazocine.

The antinociceptive effect of the benzomorphan class of opioid analgesics have been difficult to measure utilizing some of the standard animal pain models. This may be due, in part, to the sedative and/or motor effects associated with these drugs. In addition, it has been proposed that the major site of action for drugs with agonist activity at the kappa opiate receptor is exclusively at the spinal level opposed to both spinal and supraspinal as with the mu receptor agonists such as morphine. The present study examines the antinociceptive effect of the mixed agonist-antagonists cyclazocine and pentazocine utilizing electrical stimulation of the midbrain reticular formation (MRF) as the aversive stimulus in the rat. Animals were trained to escape MRF stimulation by turning a cylindrical manipulandum. An escape threshold was determined by varying the current intensity according to a modification of the psychophysical method of limits. In addition to the determination of the escape threshold the response latency and strength of response was also measured. Both cyclazocine (0.25-1.0 mg/kg) and pentazocine (2.5-12.5 mg/kg) raised the escape threshold in a dose-dependent manner without any concomitant change in the response latency or strength of response. These data suggest that the observed threshold elevation is due to a specific antinociceptive effect. Since the aversive stimulation was delivered supraspinally, the data also suggest that there are supraspinal mechanisms mediated by kappa receptors responsible for this analgesic effect.

Analgesia↗
PubMed1986

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.

Analgesics↗
PubMed1986

Effects of nalbuphine alone and in combination with tripelennamine on rewarding brain stimulation thresholds in the rat.

Reinforcing thresholds for rewarding brain stimulation to the medial forebrain bundle-lateral hypothalamus were determined in rats by means of a rate-free psychophysical method. Nalbuphine, a mixed agonist-antagonist opioid, alone caused a significant, but modest, dose-dependent lowering of the threshold for reinforcing stimulation. Concomitant administration of an ineffective dose of tripelennamine, an antihistamine, with nalbuphine potentiated the threshold lowering effect of nalbuphine. These results are similar to previous results obtained with tripelennamine and pentazocine suggesting that nalbuphine may have abuse potential if combined with tripelennamine.

Animals↗