Metabolic mapping of the brain during rewarding self-stimulation.

Local rates of cerebral glucose utilization were measured in rats by the quantitative 2-deoxy-D-[14C]glucose autoradiographic method during electrical stimulation of the ventral tegmental area. Rats trained in intracranial self-stimulation showed a pattern of changes in forebrain metabolic activity distinctly different from the pattern seen in rats stimulated by the experimenter. These findings provide information about the distribution of local cerebral activity specific to reinforced instrumental behavior.

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.

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.

Reward and detection thresholds for brain stimulation: dissociative effects of cocaine.

The effects of cocaine on both rewarding and detection thresholds for intracranial stimulation to the same brain sites in the same animals were determined. The drug caused a dissociation in effects on the two types of brain stimulation. Detection threshold was elevated at doses of cocaine that lowered the reward threshold.

Specific modulation of brain stimulation reward by haloperidol.

Low doses of haloperidol (3--18 micrograms/kg) caused dose related increases in reinforcing thresholds for self-stimulation to the medial forebrain bundle in rats. These effects, which were demonstrated completely independent of performance variables, indicate a direct modulation of central reinforcement processes by this drug, at doses which have highly selective action on dopaminergic neurotransmission.

Effects of chronic naloxone treatment on brain-stimulation reward.

Rats were tested on a rate-free psychophysical procedure in order to determine the absolute reinforcement thresholds for self-stimulation behavior. The administration of naloxone (16 mg/kg) for five days failed to alter the reinforcement thresholds on this procedure. To the extent that naloxone is an effective antagonist of endogenous opioids, we conclude that central endorphin systems are not necessary to support self-stimulation behavior.

Cocaine: acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle.

Reinforcing thresholds for self-stimulation behavior to the medial forebrain bundle were determined in rats by means of rate-free psychophysical method. The acute administration of cocaine lowered the reinforcing thresholds independent of motor stimulatory effects. These results indicate that cocaine affects the sensitivity of the reward pathways in the brain, and further demonstrate the utility of rate-independent methods in the assessment of drug effects on self-stimulation behavior.

Euphorigenic drugs: effects on the reward pathways of the brain.

This report summarizes a number of experiments designed to examine the changes in the threshold for intracranial self-stimulation (ICSS) in the rat after the administration of morphine and a number of narcotic agonist-antagonists, as well as three nonnarcotic drugs that have extensive nonmedical use (cocaine, d-amphetamine, and phencyclidine). The results of these experiments clearly indicate that morphine lowers the threshold for ICSS and, furthermore, there appears to be little or no tolerance to this effect. The only mixed agonist-antagonist that consistently lowered the ICSS threshold was pentazocine. Cocaine, d-amphetamine, and to a lesser degree, phencyclidine also lowered the ICSS threshold. These results suggest that the abuse liability of these agents may be directly related to their ability to sensitize the neural substrate involved with natural reward.

Enkephalinergic-dopaminergic "reward" pathways: a critical substrate for the stimulatory, euphoric and memory-enhancing actions of alcohol--a hypothesis.

Recent evidence indicates that alcohol (ethanol) exerts specific effects on dopaminergic-enkephalinergic neuronal pathways which are involved with natural drive-induction and have also been implicated in reward and memory consolidation. It is proposed herein that the euphorigenic and "paradoxical" memory-enhancing effects of low doses of alcohol are related to its direct actions on this specific brain substrate.

Changes in local cerebral glucose utilization during rewarding brain stimulation.

The quantitative 2-deoxy[14C]glucose method was used to determine local cerebral glucose utilization in unrestrained rats responding (lever-press) for rewarding electrical stimulation to area A10 (ventral tegmental area) and in similarly implanted inactive controls. Self-stimulation was associated with significant increases in metabolic activity, highly circumscribed in the ventral tegmental area, that continued rostrally within a rather compact zone of activity through the medial forebrain bundle, extending via the diagonal band of Broca to the level of the preoptic area. In the forebrain terminal areas bilateral increases in local cerebral glucose utilization were noted in the nucleus accumbens, lateral septum, hippocampus, and the mediodorsal nucleus of the thalamus. Ipsilateral (i.e., side of stimulation) increases in glucose utilization were noted in the bed nucleus of the stria terminalis, the basolateral and central amygdaloid nuclei, and the medial prefrontal cortex. Caudal to the stimulation site, increases in glucose utilization were found in the midline dorsal raphe, the ipsilateral pontine gray, medial parabrachial nucleus, and the locus coeruleus. Significant bilateral increases were noted in various sensory and motor areas. These results indicate that rather than a diffuse pattern of activity, rewarding brain stimulation is associated with discrete activation of specific neuronal projection fibers and selective terminal sites.