Conan Kornetsky

Opioids and rewarding brain stimulation

Abstract Studies are reviewed which demonstrate opioid-induced facilitative effects on self-stimulation to a number of different neuroanatomical sites in the rat brain. Tolerance has not been demonstrated to this facilitation. Evidence is presented to support the contention that these behavioral effects reflect an increase in sensitivity of the neuronal pathways subserving brain stimulation reward. It is proposed that these actions are directly related to the hedonic subjective effects and addiction liability associated with human use of this class of compounds.

Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking in Rats

Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 μA. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.

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.

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.

On certain psychopharmacological and physiological differences between schizophrenic and normal persons.

SummaryThe schizophrenic patient is generally regarded to be less responsive than the normal person to many drugs as well as to certain nonpharmacological conditions. Evidence is presented that there is not an attenuated response in the schizophrenic with all centrally acting drugs. The schizophrenic may in fact be more responsive than the normal person to some nonpharmacological conditions. These studies are reviewed and a neuropsychological hypothesis proffered which may account for some of the differences between the normal and the schizophrenic.The hypothesis states that the schizophrenic patients are in a state of chronic hyperarousal. This results from dysfunction in those areas of the brain concerned with the maintainence of arousal, and attention, i. e. the brain stem reticular activating system.

Negative and positive intracranial reinforcement tresholds: Effects of morphine

Negative (aversive) and positive (self-stimulation) intracranial reinforcement thresholds were determined in rats using a “double staircase” psychophysical procedure. Morphine raised aversive thresholds at all doses tested, while the drug lowered positive reinforcement thresholds at low or moderate doses. The results suggest the possible involvement of central motivational systems in the mediation of morphine-induced analgesia, the narcotic “high”, and narcotic addiction.

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 animals 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 nicotines effect on the reward threshold, it failed to dose dependently block nicotines threshold-lowering effect.

Deep brain stimulation of the nucleus accumbens reduces ethanol consumption in rats.

Recent studies have shown that deep brain stimulation (DBS) of the nucleus accumbens (NAcc) has an inhibitory effect on drug-seeking behaviors including reinstatement responding for cocaine. The objective of the present study was to expand on these findings by assessing the effects of DBS on behaviors related to alcohol consumption. The specific aim of this study was to determine whether DBS delivered to either the shell or core of the NAcc would reduce ETOH intake in rats using a two-bottle choice limited access procedure. Long Evans rats were induced to drink a 10% ethanol solution using a saccharin fading procedure. Bipolar electrodes were implanted bilaterally into either the core or shell of the NAcc. During testing animals received DBS 5 min prior to and during a 30-minute test session in which both ETOH and water bottles were accessible. Current was delivered at amplitudes ranging from 0 to 150 microA. ETOH consumption was significantly reduced from baseline levels at the 150 microA current for both shell and core electrode placements. A significant current effect was not found for water consumption for either site. These results provide evidence that DBS delivered either to the nucleus accumbens core or shell subregions can significantly reduce ethanol intake in the rat.

Psychoactive drugs in the immature organism.

SummaryThe findings reported in this review present a number of avenues of approach to the study of the effects of drugs on children. Many investigators have begun to classify the behavior of disturbed children on a number of sophisticated, but operationally simple procedures which allow some dissection of the behavior deficits. This type of approach can lead to a better understanding not only of the pathological condition but also to a better understanding of the way in which a drug works.An understanding of the manner in which amphetamines produce their therapeutic effect in the hyperkinetic child cannot be forthcoming from studies that only elaborate the pathological behavior. More attention must be paid to the function of the central and autonomic nervous systems and how these systems relate to the behavior of the child. Since many of the drugs that are useful in treating behavior problems in children have marked effects upon catecholamine levels in the brain, studies comparing urine catecholamine levels in various types of behavior disordered children after the administration of sympathomimetic amines might give specific direction to further research.Finally, I think that some attention should be directed toward animal models for understanding some of the behavior disorders. Studies such as those of Young (1963, 1964 and 1966), with some modification, could be directed toward giving us a more complete grasp of the aberrant behavior seen in the human child. Animal models can complement studies in humans and they have the further advantage of allowing a more complete biochemical and neuropharmacological study of behavior.

On the dissimilar effects of drugs on the digit symbol substitution and continuous performance tests

A tentative hypothesis is presented to account for the dissociation of the effects of various centrally-acting drugs and other agents on performance of the Continuous Performance Test (C.P.T.) and the Digit Symbol Substitution Test (D.S.S.T.): L.S.D., secobarbital, pentobarbital meprobamate and phenobarbital produced significantly greater impairment of the D.S.S.T. than of the C.P.T., while chlorpromazine, sleep deprivation and centrencephalic epilepsy had the reverse effect. Psychological, neurophysiological, electroencephalographic and neuropharmacological data were cited which suggested that the tests were affected differently because they are dependent upon the functioning of somewhat different neural organizations which are, in turn, differentially sensitive to the action of various centrally-active agents.SummaryA tentative hypothesis is presented to account for the dissociation of the effects of various centrally-acting drugs and other agents on performance of the Continuous Performance Test (C.P.T.) and the Digit Symbol Substitution Test (D.S.S.T.): L.S.D., secobarbital, pentobarbital meprobamate and phenobarbital produced significantly greater impairment of the D.S.S.T. than of the C.P.T., while chlorpromazine, sleep deprivation and centrencephalic epilepsy had the reverse effect. Psychological, neurophysiological, electroencephalographic and neuropharmacological data were cited which suggested that the tests were affected differently because they are dependent upon the functioning of somewhat different neural organizations which are, in turn, differentially sensitive to the action of various centrally-active agents.