George T. Bain

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.

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.

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.

The effects of chlorpromazine and pentobarbital on sustained attention in the rat.

SummaryThe effects of chlorpromazine and pentobarbital were studied in rats trained on a conditioning schedule designed to measure sustained attention. This schedule is a modification of the continuous performance test used in studies with human subjects. Two independent measures of performance are obtained in this schedule: 1. errors resulting from a failure of the animal to respond to a relatively brief and infrequently appearing visual signal and 2. errors resulting from a response by the animal to an inappropriate but more frequently appearing visual signal. The former type of error is believed to be a measure of sustained attention, while the latter is believed to be a measure of discriminative-associative functioning.The results indicated that the attentive measure was particularly sensitive to low doses of chlorpromazine (0.25 mg/kg) while pentobarbital did not affect this measure except at relatively high doses (12 mg/kg and above). The reverse results were obtained on the discriminative-associative measure. Chlorpromazine did not affect this measure but it was significantly altered by pentobarbital. These results support the findings in man that chlorpromazine effects are more pronounced on a task requiring a high degree of sustained attention while the effects of subhypnotic doses of the barbiturates are more pronounced on a task requiring a relatively high degree of cognitive ability.

Ethanol oral self-administration and rewarding brain stimulation ☆

The effects of orally self-administered ethanol (ETOH) on responding for rewarding brain stimulation were studied. Bipolar electrodes were implanted in either the lateral hypothalamic region of the medial forebrain bundle (MFB-LH) or the ventral tegmental area (VTA) of 6 male F-344 rats. After surgery subjects were trained in a continuous reinforcement procedure (CRF) for constant current rewarding brain stimulation. On alternate days subjects were allowed to drink an ethanol and sucrose solution (12% and 5%, respectively) for 30 min and subsequently tested on the brain stimulation procedure. All subjects showed facilitation of responding (increase in rate) after ingesting low to moderate doses of ETOH (0.4-1.7 g/kg). Depression of responding (decrease in rate) or return to baseline levels (control solution rate) was observed only in those subjects which ingested 2 g/kg or greater during the drinking period. These results indicate that low to moderate doses of self-administered ethanol will increase responding for rewarding brain stimulation. Further, the results suggest that this facilitation of responding is, at least in part, a function of the method of administration and/or the contingent nature of the ethanol delivery (self-administration).

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.

Hypertensice response to saline microinjection in the area of the nucleus tractus solitarii of the rat

We investigated the blood pressure response elicited by microinjection of various hypertonic solutions into the area of the nucleus tractus solitarii (NTS) of the brainstem, an area rich in catecholaminergic neurons. Equiosmolar solutions of NaCl, dextrose, LiCl and KCl were employed. NaCl produced a prolonged blood pressure rise; LiCl and normal saline produced a similar rise of short duration; and KCl produced epileptic-type seizures with postictal hypertension. Dextrose had no effect and neither had NaCl microinjection in areas relatively distant from the NTS. The rise in blood pressure was not reversed by a vasopressin antagonist injected systemically, but was totally abolished by systemic alpha-adrenergic blockade with phentolamine. These findings suggest that sodium can cause hypertension by direct stimulation of the central sympathetic nervous system without participation of peripheral mechanisms such as fluid volume expansion or alteration of the vascular wall.

Attenuated effect of chlorpromazine on conditioned avoidance as a function of rapid acquisition.

SummaryFour groups of rats were trained to avoid electric shock by responding to an initially neutral stimulus in four different test situations: 1) by turning a wheel in presence of a buzzer stimulus, 2) by turning a wheel in presence of a small light, 3) by crossing a hurdle in presence of a buzzer stimulus, and 4) by depressing a lever in presence of a tone stimulus. The facility with which the four groups acquired the conditioned avoidance response (CAR) corresponded to the order of their description above. It is postulated that what retards CAR acquisition is a competitive, conditioned crouching-freezing response. After training, all animals were tested under 1 and 2 mg/kg of chlorpromazine hydrochloride (CPZ). The degree of CAR inhibition under CPZ was a function of the acquisition history, the fastest learners being least affected. It is suggested that the additive effects of depressed arousal and disinhibition of crouching-freezing account for the differential effects of CPZ on the CAR.

BIOBEHAVIORAL BASES OF THE REINFORCING PROPERTIES OF OPIATE DRUGS

One thing that is certainly not in short supply in the field of drug abuse is theories. A recent NIDA monograph edited by Lettieri et a1.l gives 43 theories presented by 43 different researchers and commentators. Each of the theories is classified into one of four types of theories: self, others, society, and nature. The editors of the monograph point out that many theories could be classified into more than one category. What the monograph clearly indicates is that there are multiple contributions to initiation, continuation, cessation, and relapse to substance abuse. Despite these multiple factors, the focus of the present essay is that there exists a commonality of central nervous system action of many substances of abuse that for the user is translated into some pleasurable feelings that have been described as the “high.” At the level of the CNS it is translated into an activation of those areas of the brain for which electrical stimulation is rewarding. At a behavioral level in an animal it is translated into abuse substances causing a lowering of the threshold for rewarding brain stimulation. Of interest for the main focus of this meeting, opioids in mental illness, is that the experiments described implicate an important interaction between the catecholaminergic and the endorphinergic systems.

Ethanol and Rewarding Brain Stimulation

When a substance is repeatedly used it is reasonable to assume that in some way its use is reinforcing. It may be that it is necessary for life, it has a taste or smell worth seeking, or its use may lead to acceptance by peers. During periods of depression or anxiety, self-administration of an abused substance may relieve anxiety or depression.