Social interaction plays a critical role in neurogenesis and recovery after stroke.

Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20-25 g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72 h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain-derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2'-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury.

ß-Blockers associated with no class-specific survival benefit in acute intracerebral hemorrhage.

OBJECTIVES: Despite the high mortality, there is currently no specific treatment for intracerebral hemorrhage (ICH). Research investigating optimum degree of blood pressure control in patients presenting with ICH and hypertension is ongoing. However, there is limited understanding of the potential benefits of specific classes of antihypertensive therapy. ß-Adrenergic antagonists may provide neuroprotection from inflammation-induced injury by inhibiting sympathetic nervous system mediated immune activation. We examined mortality in ICH patients receiving ß-adrenergic antagonists to determine whether this class of antihypertensive therapy was associated with improved survival. METHODS: A retrospective analysis of a large, prospectively collected database of patients presenting with acute ICH was performed. Patients were grouped by inpatient ß-blocker treatment to determine an effect on mortality during the inpatient stay and at 3 months of follow-up. Additional analysis was conducted comparing ß-blocker therapy to any other antihypertensive treatment to determine a class-specific association of ß-blocker treatment with mortality. RESULTS: The study population included 426 patients with acute, spontaneous ICH. Inpatient ß-blocker use was independently associated with decreased rates of inpatient death and mortality at 3 months of follow-up. However, univariate and multivariable analyses comparing ß-blocker use to other antihypertensives failed to show any class-specific reduction in mortality at either time point. DISCUSSION: Our study demonstrates that the improvement seen in patients treated with ß-adrenergic antagonists is not an effect unique to this class. This supports ongoing trials to determine optimum levels of blood pressure control using multiple classes of antihypertensives.

NAD+ and nicotinamide: sex differences in cerebral ischemia.

BACKGROUND: Previous literature suggests that cell death pathways activated after cerebral ischemia differ between the sexes. While caspase-dependent mechanisms predominate in the female brain, caspase-independent cell death induced by the activation of poly(ADP-ribose) polymerase (PARP) predominates in the male brain. PARP-1 gene deletion decreases infarction volume in the male brain, but paradoxically increases damage in PARP-1 knockout females. PURPOSE: This study examined stroke-induced changes in NAD+, a key energy molecule involved in PARP-1 activation in both sexes. METHODS: Mice were subjected to middle cerebral artery occlusion and NAD+ levels were assessed. Caspase-3 activity and nuclear translocation were assessed 6h after ischemia. In additional cohorts, Nicotinamide (500 mg/kg i.p.) a precursor of NAD+ or vehicle was administered and infarction volume was measured 24h after ischemia. RESULTS: Males have higher baseline NAD+ levels than females. Significant stroke-induced NAD+ depletion occurred in males and ovariectomized females but not in intact females. PARP-1 deletion prevented the stroke-induced loss in NAD+ in males, but worsened NAD+ loss in PARP-1 deficient females. Preventing NAD+ loss with nicotinamide reduced infarct in wild-type males and PARP-1 knockout mice of both sexes, with no effect in WT females. Caspase-3 activity was significantly increased in PARP-1 knockout females compared to males and wild-type females, this was reversed with nicotinamide. CONCLUSIONS: Sex differences exist in baseline and stroke-induced NAD+ levels. Nicotinamide protected males and PARP knockout mice, but had minimal effects in the wild-type female brain. This may be secondary to differences in energy metabolism between the sexes.

Interventional stroke therapies in the elderly: are we helping?

BACKGROUND AND PURPOSE: It is unclear whether endovascular therapies for the treatment of AIS are being offered or are safe in older adults. The use and safety of endovascular interventions in patients older than 75 years of age were assessed. MATERIALS AND METHODS: A retrospective review of patients with AIS 75 years or older (n = 37/1064) was compared with a younger cohort (n = 70/1190) by using an established data base. Admission and discharge NIHSS scores, rates of endovascular treatment, SICH, in-hospital mortality, and the mBI were assessed. RESULTS: Rates of endovascular treatments were significantly lower in older patients (5.9% in the younger-than-75-year versus 3.5% in the older-than-75-year cohort, P = .007). Stroke severity as measured by the NIHSS score was equivalent in the 2 age groups. The mBI at 12 months was worse in the older patients (mild or no disability in 52% of the younger-than-75-year and 22% in the 75-year-or-older cohort, P = .006). Older patients had higher rates of SICH (9% in younger-than-75-year versus 24% in the 75-year-or-older group, P = .04) and in-hospital mortality (26% in younger-than-75-year versus 46% in the 75-year-or-older group, P = .05). CONCLUSIONS: Patients older than 75 years of age were less likely to receive endovascular treatments. Older patients had higher rates of SICH, disability, and mortality. Prospective randomized trials are needed to determine the criteria for selecting patients most likely to benefit from acute endovascular therapies.

Effects of chronic and acute oestrogen replacement therapy in aged animals after experimental stroke.

The effect of oestrogen replacement therapy (ERT) on stroke incidence and severity has been extensively debated. Clinical trials of ERT have demonstrated an increased risk of stroke in treated women, although the study participants were well past menopause when therapy was initiated. It has been suggested that detrimental effects of ERT may be unmasked after prolonged periods of hypoestrogenicity. To date, very few studies have examined the effect of ERT in aged animals, although the timing of replacement may be critical to the neuroprotective effects of ERT. We hypothesised that chronic ERT initiated in late middle age would decrease infarct size in the brain after an induced stroke, whereas acute ERT would have no beneficial effects in aged females. To test this hypothesis, two paradigms of ERT were administered to aged mice of both sexes aiming to determine the effects on stroke outcome and to explore the possible mechanisms by which ERT interacts with age. Female mice that received chronic ERT from 17-20 months of age showed improved stroke outcomes after experimental stroke, whereas females that had acute ERT initiated at 20 months of age did not. Chronic ERT females exhibited diminished levels of nuclear factor kappa B (NF-κB) translocation compared to acute ERT females after stroke. Acute ERT females demonstrated both an increase in nuclear NF-κB and enhanced expression of pro-inflammatory cytokines. In addition, a sexual dimorphic effect of ERT was seen because males benefited from ERT, regardless of the timing of initiation. Aged males had significantly reduced expression of pro-inflammatory markers after stroke compared to age-matched females, suggesting a pro-inflammatory milieu emerges with age in females. These results are consistent with the emerging clinical literature suggesting that ERT should be initiated at the time of menopause to achieve beneficial effects. The present study demonstrates the importance of using appropriate animal models in preclinical studies.

Preconditioning induces sustained neuroprotection by downregulation of adenosine 5'-monophosphate-activated protein kinase.

Ischemic preconditioning (IPC) induces endogenous neuroprotection from a subsequent ischemic injury. IPC involves downregulation of metabolic pathways. As adenosine 5'-monophosphate-activated protein kinase (AMPK) is a critical sensor of energy balance and plays a major role in cellular metabolism, its role in IPC was investigated. A brief 3-min middle cerebral artery occlusion (MCAO) was employed to induce IPC in male mice 72 h before 90-min MCAO. Levels of AMPK and phosphorylated AMPK (pAMPK), the active form of the kinase, were assessed after IPC. A pharmacological activator or inhibitor of AMPK was used to determine the dependence of IPC on AMPK signaling. Additionally, AMPK-α2 null mice were subjected to IPC, and subsequent infarct damage was assessed. IPC induced neuroprotection, enhanced heat shock protein-70 (HSP-70), and improved behavioral outcomes. These beneficial effects occurred in parallel with a significant inhibition of pAMPK protein expression. Although both pharmacological inhibition of AMPK or IPC led to neuroprotection, IPC offered no additional protective effects when co-administered with an AMPK inhibitor. Moreover, pharmacological activation of AMPK with metformin abolished the neuroprotective effects of IPC. AMPK-α2 null mice that lack the catalytic isoform of AMPK failed to demonstrate a preconditioning response. Regulation of AMPK plays an important role in IPC-mediated neuroprotection. AMPK may be a potential therapeutic target for the treatment of cerebral ischemia.

Inhibition of X-linked inhibitor of apoptosis with embelin differentially affects male versus female behavioral outcome following neonatal hypoxia-ischemia in rats.

Hypoxia-ischemia (HI; concurrent oxygen/blood deficiency) and associated encephalopathy represent a common cause of neurological injury in premature/low-birth-weight infants and term infants with birth complications. Resulting behavioral impairments include cognitive and/or sensory processing deficits, as well as language disabilities, and clinical evidence shows that male infants with HI exhibit more severe cognitive deficits compared to females with equivalent injury. Evidence also demonstrates activation of sex-dependent apoptotic pathways following HI events, with males preferentially activating a caspase-independent cascade of cell death and females preferentially activating a caspase-dependent cascade following neonatal hypoxic and/or ischemic insults. Based on these combined data, the 'female protection' following HI injury may reflect the endogenous X-linked inhibitor of apoptosis (XIAP), which effectively binds effector caspases and halts downstream cleavage of effector caspases (thus reducing cell death). To test this theory, the current study utilized neonatal injections of vehicle or embelin (a small molecule inhibitor of XIAP) in male and female rats with or without induced HI injury on postnatal day 7 (P7). Subsequent behavioral testing using a clinically relevant task revealed that the inhibition of XIAP exacerbated HI-induced persistent behavioral deficits in females, with no effect on HI males. These results support sex differences in mechanisms of cell death following early HI injuries, and suggest a potential clinical benefit from the development of sex-specific neuroprotectants for the treatment of HI.

NAD+ depletion or PAR polymer formation: which plays the role of executioner in ischaemic cell death?

Multiple cell death pathways are activated in cerebral ischaemia. Much of the initial injury, especially in the core of the infarct where cerebral blood flow is severely reduced, is necrotic and secondary to severe energy failure. However, there is considerable evidence that delayed cell death continues for several days, primarily in the penumbral region. As reperfusion therapies grow in number and effectiveness, restoration of blood flow early after injury may lead to a shift towards apoptosis. It is important to elucidate what are the key mediators of apoptotic cell death after stroke, as inhibition of apoptosis may have therapeutic implications. There are two well described pathways that lead to apoptotic cell death; the caspase pathway and the more recently described caspase-independent pathway triggered by poly-ADP-ribose polymers (PARP) activation. Caspase-induced cell death is initiated by release of mitochondrial cytochrome c, formation of the cytosolic apoptosome, and activation of endonucleases leading to a multitude of small randomly cleaved DNA fragments. In contrast caspase-independent cell death is secondary to activation of apoptosis inducing factor (AIF). Mitochondrial AIF translocates to the nucleus, where it induces peripheral chromatin condensation, as well as characteristic high-molecular-weight (50 kbp) DNA fragmentation. Although caspase-independent cell death has been recognized for some time and is known to contribute to ischaemic injury, the upstream triggering events leading to activation of this pathway remain unclear. The two major theories are that ischaemia leads to nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure, or alternatively that cell death is directly triggered by a pro-apoptotic factor produced by activation of the DNA repair enzyme PARP. PARP activation is robust in the ischaemic brain producing variable lengths of poly-ADP-ribose (PAR) polymers as byproducts of PARP activation. PAR polymers may be directly toxic by triggering mitochondrial AIF release independently of NAD+ depletion. Recently, sex differences have been discovered that illustrate the importance of understanding these molecular pathways, especially as new therapeutics targeting apoptotic cell death are developed. Cell death in females proceeds primarily via caspase activation whereas caspase-independent mechanisms triggered by the activation of PARP predominate in the male brain. This review summarizes the current literature in an attempt to clarify the roles of NAD+ and PAR polymers in caspase-independent cell death, and discuss sex specific cell death to provide an example of the possible importance of these downstream mediators.

Delayed treatment of basilar thrombosis in a patient with a basilar aneurysm: a case report.

INTRODUCTION: Acute occlusion of the basilar artery is a neurological emergency that has a high risk of severe disability and mortality. Delayed thrombolysis or endovascular therapy has been performed with some success in patients who present after 3 hours of symptom onset. Here we present the first case of delayed intra-arterial thrombolysis of a basilar artery thrombosis associated with a large saccular aneurysm. CASE PRESENTATION: A 73-year-old Caucasian man with a history of smoking and alcohol abuse presented to the Emergency Department complaining of diplopia and mild slurred speech and who progressed over 12 hours to coma and quadriparesis. He was found to have a large basilar tip aneurysm putting him at high risk for hemorrhage with lytic treatment. CONCLUSION: The treatment options for basilar thrombosis are discussed. Aggressive treatment options should be considered despite long durations of clinical symptoms in basilar thrombosis, even in extremely high risk patients.

Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke.

BACKGROUND AND PURPOSE: Estrogen is a known neuroprotective and vasoprotective agent in experimental cerebral ischemia. Preischemic steroid treatment protects animals of both sexes from focal cerebral ischemia. This study determined whether intravenous estrogen acts as a vasodilator when administered on reperfusion and whether the resulting increase in cerebral blood flow (CBF) provides tissue protection from middle cerebral artery occlusion. METHODS: Adult male Wistar rats were treated with reversible middle cerebral artery occlusion (2 hours), then infused with intravenous estrogen (Premarin; 1 mg/kg) or vehicle during the first minutes of reperfusion (n=15 per group). Cortical laser-Doppler flowmetry was used to assess adequacy of occlusion. Ischemic lesion volume was determined at 22 hours after occlusion by 2,3,5-triphenyltetrazolium chloride staining and image analysis. Cortical and striatal CBF was measured by (14)[C]iodoantipyrine autoradiography at 10 (n=10) or 90 (n=11) minutes of reperfusion. RESULTS: As expected, supraphysiological plasma estrogen levels were achieved during reperfusion (estrogen, 198+/-45 pg/mL; vehicle, 6+/-5; P:=0.001). Physiological variables were controlled and not different between groups. Total hemispheric infarction was reduced in estrogen-treated rats (estrogen, 49+/-4% of ipsilateral structure; vehicle, 33+/-5%; P:=0.02), which was most pronounced in striatum (estrogen, 40+/-6% of ipsilateral striatum; vehicle, 60+/-3%; P:=0.01). CBF recovery was strikingly increased by estrogen infusion at 10 minutes in frontal (estrogen, 102+/-12 mL/100 g per minute; vehicle, 45+/-15; P:=0.01) and parietal cortex (estrogen, 74+/-15 mL/100 g per minute; vehicle, 22+/-13; P:=0.028) and throughout striatum (estrogen, 87+/-13 mL/100 g per minute; vehicle, 25+/-20; P:=0.02). Hemispheric volume with low CBF recovery (eg, <20 mL/100 g per minute) was smaller in estrogen-treated animals (estrogen, 73+/-18 mm(3); vehicle, 257+/-46; P:=0.002). However, differences in CBF recovery could not be appreciated between groups by 90 minutes of reperfusion. CONCLUSIONS: Acute estrogen therapy during reperfusion improves tissue outcome from experimental stroke. The steroid rapidly promotes CBF recovery and reduces hemispheric no-reflow zones. This beneficial effect appears only during early reperfusion and likely complements other known mechanisms by which estrogen salvages brain from focal necrosis.

Recent advances in the diagnosis and treatment of stroke.

Stroke is defined as an abnormality in brain function resulting from disruption of cerebral circulation. It is the third leading cause of death in the United States and the primary cause of long-term disability. The economic burden of stroke will only increase as the population ages, making prevention and treatment of stroke one of the most important public health issues of the upcoming millennium. New therapies for the treatment of acute stroke, especially thrombolysis, have turned what was once considered an inevitable deficit into a potentially treatable illness. It is increasingly important for all physicians to be able to identify symptoms of cerebral ischemia. Neurons have a very limited tolerance for ischemia, making the rapid evaluation and diagnosis of stroke critical. This is particularly relevant for the ophthalmologist, who may be the first physician to see individuals presenting with visual deficits. Trials are underway to look specifically at central retinal artery and basilar artery ischemia and their response to thrombolytic therapy. This review will focus on description of recent advances in treatment and diagnosis of stroke, including thrombolytic trials and the expanding role of neuroimaging.

The effects of nucleus accumbens dopamine depletions on continuously reinforced operant responding: contrasts with the effects of extinction.

Two experiments were undertaken to study the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement schedule (CRF). In the first experiment, the neurotoxic agent 6-hydroxydopamine was infused directly into the nucleus accumbens to investigate the effects of DA depletion on lever pressing performance. DA depletion had only a modest effect on the total number of lever presses, and there was a significant effect on total lever presses only on the first test day (third day postsurgery). Analyses also were performed on responding across the 45-min session by breaking down the session into three 15-min periods. During the test session on day 3 postsurgery, there was a significant group x time interaction, with DA-depleted rats showing a significant reduction in the numbers of responses in the first 15-min period, but no significant effects over the second or third 15-min period within the session. Although control rats showed a within-session decline in responding, the DA-depleted rats did not. In addition, analysis of interresponse times (IRTs) indicated that accumbens DA depletions produced a slowing of the local rate of responding as indicated by a significant decrease in high rate (i.e., short-duration IRT) responses and an increase in low rate (i.e., long-duration IRT) responses. In a second experiment, the effects of extinction on CRF performance were investigated. Unlike the effects of nucleus accumbens DA depletion, extinction produced lower levels of responding throughout the entire test session.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleus accumbens dopamine release increases during instrumental lever pressing for food but not free food consumption.

This experiment was undertaken to investigate the role of nucleus accumbens dopamine (DA) in instrumental and consummatory responses for food. In vivo microdialysis methods were used to study DA release and metabolism in the nucleus accumbens of behaving rats. Four behavioral conditions were used: performance on a fixed ratio 5 (FR 5) schedule of food reinforcement, consumption of Bioserve food pellets, consumption of laboratory chow, and food deprivation control. Groups of rats that were previously exposed to these conditions were implanted with dialysis probes in the nucleus accumbens and tested the day after implantation. The rats that pressed a lever on a FR 5 schedule showed significant increases in extracellular DA and DA metabolites compared to food-deprived control rats. In further analyses, rats that responded on the FR5 schedule were divided into three groups based upon their response rates. The rats with low response rates did not significantly differ from control rats, whereas rats with medium and high rates of responding showed significant increases in DA release relative to the control group. Rats that received massed presentation of food pellets or laboratory chow consumed large quantities of food, but showed no significant increases in DA release. This experiment demonstrated that performance of lever pressing behavior is accompanied by an increase in accumbens DA release and metabolism, and that DA release in nucleus accumbens is more closely related to the performance of highly active instrumental responses than it is to consumption of large quantities of food.

Effects of dopamine depletions in the medial prefrontal cortex on active avoidance and escape in the rat.

Dopamine systems have been implicated in the performance of avoidance behavior, and the dopaminergic innervation of medial prefrontal cortex is known to be responsive to stressful stimuli. In the present investigation, injections of 6-hydroxydopamine were used to produce moderate depletions of dopamine in the medial prefrontal cortex of rats trained to perform an active avoidance/escape task. In this task, 0.5 mA shock was presented for 5 s every 30 s, and the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. Depletion of dopamine in the medial prefrontal cortex did not affect total number of responses, and did not impair avoidance responding (i.e. responding when the shock was off), and in fact dopamine-depleted animals tended to make slightly more avoidance responses than control animals. Prefrontal dopamine depletions did result in a significant decrease in the number of escape responses (i.e. responding to terminate shock when the shock was on). Moreover, dopamine depletions significantly decreased response efficiency, which is an index of the reduction of shock time produced per lever pressing response. Previous work has indicated that dopamine antagonists and accumbens dopamine depletions have dramatic effects on avoidance behavior; thus, the present results indicate that prefrontal cortex dopamine depletions do not mimic the effects of interference with subcortical dopamine systems. The selective effects of dopamine depletions on escape behavior in the present study suggest that rats with medial prefrontal dopamine depletions have an impairment in the ability to respond appropriately to the direct presentation of footshock.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of nucleus accumbens dopamine in responding on a continuous reinforcement operant schedule: a neurochemical and behavioral study.

Two experiments were undertaken to investigate the role of nucleus accumbens dopamine (DA) in instrumental lever pressing on a continuous reinforcement (CRF) schedule. Rats trained to press a lever for food reinforcement on a CRF schedule, and food-deprived control rats, were implanted with dialysis probes in the nucleus accumbens. The day after implantation, rats were tested and dialysis samples were assayed for DA and the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Performance of the lever-pressing task resulted in significant increases in extracellular levels of DA and DOPAC relative to control rats. The increases in extracellular DA were significantly correlated (r = 0.92) with the number of lever press responses committed. In the second experiment, the neurotoxic agent 6-hydroxydopamine was infused directly into the nucleus accumbens to investigate the effects of DA depletion on lever-pressing performance. DA depletion had only a modest effect on the total number of lever presses, and there was a significant effect on total lever presses only on the first test day (third day postsurgery). Analyses also were performed on responding across the 45-min session by breaking down the session into three 15-min periods. There was a significant group x time interaction, with DA-depleted rats showing a significant reduction in the numbers of responses in the first 15-min period, but no significant effects over the second or third 15 min in the session. This initial slowing of response rate was present across all 5 test days. These results indicate that DA release and metabolism increases in rats performing on a CRF schedule, and that DA depletion produces a slowing of initial response rate.

The role of brain dopamine in response initiation: effects of haloperidol and regionally specific dopamine depletions on the local rate of instrumental responding.

Two experiments were undertaken to investigate dopaminergic involvement in the local rate of responding on a fixed ratio 5 (FR5) instrumental lever pressing schedule. Rats were trained to press a lever for food reinforcement on a FR5 schedule, and a computer program was used to record the interresponse time (IRT) for each response. The IRT is the time between each lever pressing response, which is equal to the reciprocal of the local response rate. After several weeks of training, rats received i.p. injections of the dopamine antagonist haloperidol (HP; 0.1, 0.2 and 0.4 mg/kg). HP produced a dose-related decline in overall response number. In addition, HP dramatically altered the IRT distribution. HP-treated rats showed a dose-related reduction in the proportion of IRTs with low time values (high local rates of responding), and a corresponding increase in the relative number of IRTs with high time values (low local rates of responding). In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the nucleus accumbens, medial neostriatum or ventrolateral neostriatum in order to determine the effects of DA depletion on lever pressing performance. Dopamine depletion in all regions significantly reduced lever pressing, and dopamine-depleted rats had substantial changes in their IRT distributions. Rats with dopamine depletions showed significant reductions in the proportion of IRTs with low time values, and increases in the relative number of IRTs with high time values. The greatest reductions in response number and the most pronounced alterations of the IRT distribution were shown by rats with ventrolateral neostriatal dopamine depletions.(ABSTRACT TRUNCATED AT 250 WORDS)

A neurochemical and behavioral investigation of the involvement of nucleus accumbens dopamine in instrumental avoidance.

Two experiments were conducted to investigate the role of nucleus accumbens dopamine in the performance of a lever press avoidance task in the rat. In this task, 0.5 mA shock was presented for 5 s every 30 s, but the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. In the first experiment, dialysis probes were implanted into the nucleus accumbens of rats previously trained on the avoidance procedure, and also two groups of untrained rats. On the day after dialysis probe implantation, rats trained to press a lever to avoid shock (n = 10) were exposed to a 45 min avoidance test session. Untrained rats were either exposed to periodic shock (n = 9) or the control procedure in which lights were dimmed but no shock was presented (n = 8). Performance of the avoidance task led to significant increases in extracellular dopamine and dopamine metabolites. There was a significant positive correlation between increases in extracellular dopamine and the number of avoidance responses emitted. In the second experiment, groups of rats were trained on the lever press avoidance procedure. After training, rats received intra-accumbens injections of the neurotoxic agent 6-hydroxydopamine or ascorbic acid vehicle. Dopamine depletion produced by 6-hydroxydopamine injection led to a substantial decrease in lever pressing to avoid or escape shock. These results indicate that dopamine in nucleus accumbens is important for operant avoidance responding, and that the involvement of accumbens dopamine in instrumental behavior is not unique to positively reinforced responses.

Involvement of nucleus accumbens dopamine in the motor activity induced by periodic food presentation: a microdialysis and behavioral study.

Two experiments were undertaken to investigate the role of accumbens dopamine (DA) in food-related motor activities. Although presentation of large amounts of food elicits feeding behavior, periodic food presentation (PFP; e.g. a 45-mg pellet every 45 s) induces considerable locomotion, rearing and other motor activities in food-deprived rats. In the first experiment, in vivo microdialysis methods were used to study DA release and metabolism in the nucleus accumbens of behaving rats exposed to periodic food presentation. Four behavioral conditions were used: high rate of PFP (one pellet per 45 s), low rate of PFP (one pellet per 4 min), massed food presentation and food deprivation control. The rats that received a high rate of PFP showed substantial increases in locomotor activity, and also showed significant increases in extracellular DA and DA metabolites. Rats that received massed presentation of food pellets consumed large quantities of food, but showed no significant increases in locomotor activity or DA release. Although the group that received the high rate of PFP showed the highest motor activity and the largest increase in DA release, there was only a modest correlation (r = 0.34) between motor activity and increased DA release. In the second experiment, the neurotoxic agent 6-hydroxydopamine (6-OHDA) was injected into the nucleus accumbens in order to assess the effects of DA depletion of PFP-induced motor activity. DA depletion significantly reduced PFP-induced motor activity in the first week after surgery, but by the second week DA-depleted rats had recovered normal levels of motor activity.(ABSTRACT TRUNCATED AT 250 WORDS)