Brain Stimulation Reward Thresholds Research Articles

Prefrontal cortex infusions of SCH 23390 cause immediate and delayed effects on ventral tegmental area stimulation reward

A reward-relevant relationship between dopamine projection regions of the ventral tegmental area (VTA) was investigated through the use of brain stimulation reward (BSR) thresholds. Using a rate-free method, changes in VTA BSR thresholds were determined after intracranial injections of the dopamine D1 antagonist, SCH 23390 into the prefrontal cortex (PFC), or the nucleus accumbens (NAcc). Reward thresholds assessed immediately after the infusion of SCH 23390 into the NAcc (0.5 μg/0.5 μl/side) were significantly higher than those assessed just after saline infusions, indicating a drug-induced attenuation of the rewarding effects of the brain stimulation. The effects of this dose subsided when tested 24 h later. Conversely, intra-PFC infusions of SCH 23390 at the same dose (0.5 μg/0.5 μl/side) resulted in lowered BSR thresholds when rats were tested immediately after infusion. In addition, animals tested 24 h after receiving the lowest dose (0.125 μg/0.5 μl/side) demonstrated a robust delayed threshold-lowering effect. These immediate and delayed effects of the intra-PFC dopamine antagonist demonstrate a facilitation of VTA BSR and are consistent with the view that PFC dopamine serves a modulatory role over important reward elements within the NAcc. The deferred effects of intra-prefrontal cortex DA receptor blockade on brain stimulation reward thresholds may reflect adaptive responses of subcortical structures to changes in PFC dopamine neurotransmission. It has been suggested that neural adjustments of this type may underlie long term changes in central nervous system functioning brought about by disease, drug use or behavioral conditioning.

Gamma-vinyl GABA attenuates cocaine-induced lowering of brain stimulation reward thresholds.

Gamma-vinyl GABA (GVG, also referred to as vigabatrin), an irreversible inhibitor of GABA transaminase (GABA-T), raises levels of GABA in nerve terminals, inhibits striatal dopamine release, and attenuates cocaine-induced increases in extracellular dopamine in the striatum and nucleus accumbens. In order to determine the action of GVG on dopamine-mediated reward, we examined its effects on the threshold for rewarding brain stimulation in male F-344 rats. GVG dose-dependently raised brain stimulation reward (BSR) thresholds at doses of 200, 300, and 400 mg/kg without significant effects on motor performance as measured by response latencies. In order to determine if GVG had similar modulatory effects on cocaine-induced lowering of BSR thresholds, the effective doses of GVG were co-administered with 2.5 and 5.0 mg/kg cocaine, doses that significantly lower BSR thresholds. The 400 mg/kg dose of GVG significantly blocked the lowering of thresholds seen at each dose of cocaine. Cocaine in combination with 200 or 300 mg/kg GVG, doses of GVG that significantly raise BSR thresholds, resulted in thresholds not significantly different from those obtained with cocaine alone. These data demonstrate that, at the doses tested, GVG is more effective at modulating basal reward thresholds that at modulating thresholds lowered by cocaine, implying that as dopaminergic activity increases, GABAergic activity must also increase in order to exert its inhibitory influence on dopaminergic activity.

DAMGO and DPDPE facilitation of brain stimulation reward thresholds is blocked by the dopamine antagonist cis-flupenthixol

The role of dopamine neurotransmission in opioid reward was investigated using a rate-independent measure for determining brain stimulation reward (BSR) thresholds. Intra-accumbens infusions of the mu- and delta-specific peptides, D-Ala2, N-Me-Phe4, Gly-ol5-Enkephalin and D-Pen2, D-Pen5-Enkephalin caused significant lowering of BSR thresholds. The dopamine D1/D2 antagonist, cis-flupenthixol, blocked these effects at a dose that did not significantly alter thresholds when given alone. These data suggest both mu- and delta-opioid potentiation of BSR is dopamine dependent.

Involvement of δ- and μ-opioid receptors in the potentiation of brain-stimulation reward

A rate-free method of determining brain-stimulation reward thresholds was used to identify the rewarding effects of the δ-opioid receptor and μ-opioid receptor agonist peptides, [ d-Pen 2, d-Pen 5]enkephalin (DPDPE) and [ d-Ala 2-MePhe 4-Gly(ol) 5]enkephalin (DAMGO). The nucleus accumbens-delivered opioid receptor agonists produced marked lowering of the threshold for ventral tegmental area brain-stimulation reward. No change in baseline thresholds was seen after peripheral administration of the nonpeptide δ-opioid receptor antagonist, naltrindole. However, an unexpected finding was that naltrindole blocked the threshold-lowering effects of both DPDPE and DAMGO. These data demonstrate nucleus accumbens activation of δ- and μ-opioid receptors and ventral tegmental area brain-stimulation reward share common brain substrates. In addition, the interference of both δ- and μ-opioid receptor mediated reward by naltrindole may have implications for therapeutic use.

Low-dose apomorphine attenuates morphine-induced enhancement of brain stimulation reward

Thresholds for brain stimulation reward (BSR) delivered to the medial forebrain bundle-lateral hypothalamus were determined by means of a rate free psychophysical method. Lower doses of apomorphine (0.5 to 0.2 mg/kg) produced modest elevations in BSR thresholds. A 0.4 mg/kg dose of apomorphine resulted in emergence of Stereotypic behaviors and the loss of stimulus control. Morphine's BSR threshold lowering effects were significantly blocked by the concurrent administration of a 0.1 mg/kg dose of apomorphine. These results support the hypothesis that presynaptic dopamine neurons are involved in the mediation of morphine's reinforcing effects and that dopamine autoreceptor agonists may be of some use in the pharmacotherapy of opiate abuse.

Rewarding electrical brain stimulation: Similar thresholds for flinders sensitve line hypercholinergic and flinders resistant line hypocholinergic rats

Flinders Sensitive Line hypercholinergic rats, which exhibit augmented hypothermic responses to the cholinesterase inhibitor physostigmine and to the muscarinic agonist oxotremorine, have been proposed to represent a useful animal model for some aspects of human depression. With disturbance of reward processes considered to be a core feature of depression, the present studies were designed to investigate the neuropharmacology of brain stimulation-reward (BSR) in Flinders Sensitive Line (FSL) rats, Flinders Resistant Line (FRL) rats, and outbred control Sprague-Dawley rats. All animals were tested in a rate-free, current-threshold brain stimulation-reward paradigm, following acute challenges with the monoamine reuptake inhibitor cocaine, the dopamine D, receptor antagonist SCH-23390, the cholinergic muscarinic antagonist scopolamine, and the serotonin reuptake inhibitor fluoxetine. Baseline BSR thresholds did not differ across the three groups. For all groups, cocaine lowered thresholds, SCH-23390 and scopolamine-elevated thresholds, while fluoxetine had no significant effect. Thresholds for the three groups were not differentially affected by pharmacological challenge. Additionally, both Flinders Sensitive and Flinders Resistant Line rats exhibited diminished levels of locomotor activity relative to outbred Sprague-Dawley controls. These results suggest that both Flinders lines exhibit behavioral differences from outbred control rats, but not with regard to reward processes as assessed by rewarding electrical stimulation of the lateral hypothalamus.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Bromocriptine, a D 2 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 D 2 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.

The effects of systemic and intracerebral injections of D 1 and D 2 agonists on brain stimulation reward

That dopamine (DA) plays a role in reward-related learning is well documented but the mechanisms through which it acts are not well understood. The present set of experiments investigated the role of DA receptor subtypes within DA-innervated forebrain regions in brain stimulation reward (BSR). Thirty-two rats were implanted with electrodes in the ventral tegmental area (VTA) and cannulae aimed at the caudal nucleus accumbens (NAcc), the caudate-putamen (CP) or cortex. Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding (thresholds). After BSR thresholds stabilized rats received treatments with DA agonists and their effects on thresholds were analyzed. Systemic treatments consisted of injections of (+)-amphetamine (1.0 mg/kg, i.p., 10 min before testing), the D 2 agonist quinpirole (1.0 mg/kg, i.p., 10 min before testing), the novel D 1 agonist A-77636 (3.0 mg/kg, s.c., 90 min before testing) or their vehicle (distilled H 2O). Central treatments consisted of microinjections of quinpirole (0.3 – 10.0 μg/0.5 μl) directly into the caudal NAcc, CP or cortex or A-77636 (30 μg/0.5 μl) into the caudal NAcc or CP. Results showed that all three agonists, when injected systemically, significantly reduced the threshold frequency required for VTA BSR, indicating a potentiative effect on reward. Central injections of quinpirole in the caudal NAcc, CP or cortex produced significant increases in BSR thresholds indicative of reduced rewarding efficacy of stimulation. Central injections of A-77636 into the caudal NAcc, but not the CP, were associated with a reduction in VTA BSR thresholds, suggesting an increase in reward. These results suggest that stimulation of D 1 or D 2 receptors enhances the rewarding effect of brain stimulation. In the case of the systemic quinpirole enhancement of reward, the present results suggest that this may not occur in the caudal NAcc, CP or cortex. Finally, the present results suggest that D 1 receptor stimulation in the caudal NAcc can facilitate reward-related learning.

Neural mechanisms of drug reinforcement.

The brain substrates involved in the effect of cocaine on brain stimulation reward, in the psychomotor activation associated with cocaine, and in cocaine self-administration appear to be focused on the medial forebrain bundle and its connections with the basal forebrain, notably the nucleus accumbens. Chronic access to cocaine produces a withdrawal state as reflected in increases in brain stimulation reward thresholds, and this change in reward threshold appears to be opposite to the actions of the drug administered acutely. These effects are thought to reflect a change in the activity of reward elements in the medial forebrain bundle and may be responsible for the negative reinforcing state associated with the anhedonia of cocaine withdrawal. Opiate receptors particularly sensitive to the reinforcing effects of heroin also appear to be located in the region of the nucleus accumbens and the ventral tegmental area. There is good evidence for both dopamine-dependent and dopamine-independent opioid interactions in the ventral tegmental-nucleus accumbens connection. In addition, the opiate receptors in the region of the nucleus accumbens may become sensitized during the course of opiate withdrawal and thus become responsible for the aversive stimulus effects of opiate dependence. Reliable measures of the acute reinforcing effects of ethanol have been established in rat models, and substantial evidence exists to show that non-deprived rats will orally self-administer pharmacologically relevant amounts of ethanol in lever-press choice situations. Neuropharmacological studies of ethanol reinforcement in non-dependent rats suggest important roles for serotonin, GABA and dopamine. A role for opioid peptides in ethanol reinforcement may reflect more general actions of opioid peptides in consummatory behavior. Studies of ethanol dependence have implicated brain GABAergic and CRF systems in the more motivational aspects of withdrawal. Future studies will need to focus on the common neurobiologic changes associated with all these drugs, particularly regarding their hedonic and motivational properties.

Dopamine, addiction and reward

The role of dopamine was inferred in reward processes from early studies showing that psychomotor stimulants such as cocaine and amphetamine could facilitate intracranial self-stimulation. Subsequent studies showed that dopamine-receptor antagonists could attenuate brain stimulation reward and completely block the reinforcing effects of cocaine and amphetamine as measured by direct intravenous self-administration of these drugs. A specific dopaminergic substrate for both the facilitation of brain stimulation reward and the self-administration of psychomotor stimulants appears to be the region of the nucleus accumbens in the forebrain. This structure receives significant limbic afferents and has significant projections to the extrapyramidal motor system. Chronic administration of cocaine and amphetamine seem to have the opposite effects to acute injections and during withdrawal lead to increases in brain stimulation reward thresholds and decreases in dopamine release in the nucleus accumbens. This same nucleus accumbens dopamine projection seems to be critical for the motor activation associated with the anticipation of both drug and non-drug rewards. These results suggest that drugs that activate the mesolimbic dopamine system have such powerful reinforcing effects because they facilitate the attentional-motor systems critical for approach behaviour and the behavioural activation associated with incentive-motivation.

Diazepam alters brain-stimulation reward thresholds in seizure-prone sites

Studies of the effect of diazepam and related compounds on the rewarding properties of brain stimulation as measured by response rates have not yielded clear results, with self-stimulation performance reported to be potentiated, diminished, or unchanged following drug administration. In this study, the effect of two doses of diazepam (2.5 and 5.0 mg/kg) and its vehicle on self-stimulation thresholds was examined in eight rats with electrode placements scattered along a 4 mm length of the medial forebrain bundle. Stimulation of the lateral preoptic area and the anterior and mid-lateral hypothalamus produced overt seizures. Rate-period curves were generated for a wide range of currents and the resulting period-current trade-off functions were compared across doses. In seizure-prone sites upward shifts in period threshold were observed after 2.5 mg/kg of diazepam with little additional increases incurred by the 5.0 mg/kg dose. The majority of non-seizure sites showed no effects of diazepam upon period threshold. The results suggest that diazepam alters brain-stimulation reward thresholds by suppressing competing seizure activity.

Chronic DMI reduces thresholds for brain stimulation reward in the rat

The authors sought a demonstration of the validity of brain stimulation reward (BSR) models of depression. It was predicted that chronic, but not acute antidepressant treatment would enhance BSR responding. Rats with medial forebrain bundle electrodes were separated into 4 groups that received either saline or desmethylimipramine at 5, 10, or 20 mg/kg daily. A rate-free, threshold measure that has not previously been employed in studies of BSR and antidepressants was used. BSR thresholds were monitored every 3rd day over a 9-day baseline period and an 18-day drug treatment period, and after 12 days of drug withdrawal. Groups did not differ from one another till the 15th and 18th day of drug treatment. The greatest effects were seen in the 10 and 20 mg groups. The 20 mg group returned to baseline after drug withdrawal, but the 10 mg group did not. The absolute size of the effect was considered to be small, leading the authors to speculate that antidepressants act on homeostatic mechanisms that stabilize BSR substrates, only indirectly enhancing transmission of the reward signal.

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.

Acute morphine lowers brain stimulation reward thresholds in rats with depressed or elevated response rates

The positively-reinforcing effect of acute morphine sulfate (MS) administration was assessed by concurrent rate-dependent and rate-independent measures of brain stimulation reward in male rats. An acute 4 mg/kg MS injection produced a rapid, statistically-significant decrease in reward threshold of 28.5%, when compared with saline control values, 45 min after injection. Response rates for brain stimulation delivery decreased by 60.6%, when compared with saline values during the period of maximum threshold change. Other animals, injected with an acute 1 mg/kg MS dose, exhibited significant threshold decreases (21.5%), relative to changes in saline values that occurred in a prior session, and response-rate increases of 23.1%, relative to saline-session changes, when the data were recorded 40 min after injection. The findings reported here demonstrate that the decreases in reward threshold produced by acute morphine administration are independent of the response-rate changes that occur and also support the idea that morphine's rewarding effect may be independent of the behavioral inhibition or activation that can result from the effects of different morphine doses.

Threshold procedures for assessing the impact of agents on brain reward systems

Chemical effects on the reinforcing quality of electrical stimulation of the rat brain can be assessed using a variety of methods, most commonly by observing changes in response rates maintained under specific schedules of reinforcement. We present results demonstrating the utility of procedures for assessing the minimum amount of electrical stimulation required to support rat leverpress responding, that is, the brain-stimulation reward (BSR) threshold. In these threshold procedures, each leverpress produced by the rat decreases the duration of the electrical stimulus delivered to the posterior lateral hypothalamus until the rat fails to respond. The stimulus duration is then reset to its initial value and the procedure begins again. The last stimulus duration in a series supporting a response is defined as the stimulus duration (SD) threshold, and the mean SD threshold is determined daily. Stable SD thresholds are achieved within 2 weeks, and this measure is sensitive to agent-induced changes in rats' response to BSR. To illustrate the utility of this approach, data are presented showing that rats' BSR thresholds changed significantly following exposure to triethyltin or carbon monoxide. The results support the view that threshold methods can be used to dissociate agent-induced effects on brain reward systems and BSR quality from changes in performance or effects on other behavioral processes.

Effects of a single inescapable swim on long-term brain stimulation reward thresholds

Rats were subjected to a 15-min inescapable swim in a procedure which induces “behavioral despair” (immobility) 24 hr later. Their thresholds for brain stimulation reward were measured six times over the subsequent two weeks. Under one condition thresholds were first determined 3 hr postswim and, under a second condition, 24 hr postswim. Rats tested in the 3-hr condition showed elevated thresholds compared to preswim baselines. Elevations remained significant for six days. Thresholds for rats in the 24-hr condition did not change. Results are discussed in terms of a) the lack of correspondence between behavioral despair and brain stimulation reward models of depression, b) possible mechanisms for the 3-hr condition effect, and c) the significance of long-term changes in brain reward substrates.

Neurobehavioral studies of ethanol reward and activation

Although generally considered to be a depressant drug, ethanol has both stimulant and depressant effects on behavior. This biphasic action of ethanol may be related to its reinforcing effects and to the neurobehavioral events that occur with changes in blood alcohol concentration (BAC). Ethanol was found to reduce the threshold and increase response rates for brain stimulation reward (BSR) at lateral hypothalamic, but not ventral noradrenergic bundle brain sites. These effects were also found to only occur when testing occurred on the ascending limb of the BAC. Studies of the effects of ethanol on open-field activity showed that the stimulant effects of low doses of ethanol were also seen only during the ascending limb of the BAC; depression was usually found during the descending limb. Neurochemical data from other investigators suggest that the facilitation of BSR and stimulation of activity may be mediated by mesolimbie dopamine systems.

Chronic imipramine does not block cocaine-induced increases in brain stimulation reward

Self-stimulating rats implanted with ventral tegmental area electrodes were tested with 15 mg/kg cocaine HCl before and after chronic impramine treatment. Chronic imipramine had no influence on cocaine's ability to lower brain stimulation reward thresholds, suggesting that tricyclic antidepressant treatment does not block cocaine-induced euphoria.