The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Reduced anticipatory dopamine responses to food in rats exposed to high fat during early development.

We have previously demonstrated that exposure to high fat (HF) during early development alters the presynaptic regulation of mesolimbic dopamine (DA), and increases incentive motivation for HF food rewards. The goal of the present experiments was to examine the long-term consequences of early exposure to HF on anticipatory and consumatory nucleus accumbens (NAc) DA responses to HF food rewards. Mothers were maintained on a HF (30% fat) or control diet (CD; 5% fat) from gestation day 13 to postnatal day 22 when offspring from both diet groups were weaned and maintained on the CD until adulthood. In vivo NAc DA responses to food anticipation and consumption were measured in a Pavlovian conditioning paradigm using voltammetry in freely moving rats. HF-exposed offspring displayed reduced NAc DA responses to a tone previously paired with the delivery of HF food rewards. In an unconditioned protocol, consumatory NAc DA responses could be isolated, and were similar in HF and control offspring. These data demonstrate that exposure to HF through maternal diet during early development might program behavioral and functional responses associated with mesolimbic DA neurotransmission, thus leading to an increased HF feeding and obesity.

The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain.

Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out. We investigate here whether apoE is involved in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory reinnervation mechanisms. We examined the modifications in gene expression and protein levels of apoE and its key receptors, the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), as well as the reactive astrocyte marker glial fibrillary acidic protein (GFAP) in different brain structures throughout the degenerative and reactive regenerative period. In the striatum, upregulations of GFAP, apoE and LRP mRNAs at 1 day post-treatment were associated with marked decreases in dopamine (DA) levels, loss in tyrosine hydroxylase protein content, as well as to a compensatory increase in dopaminergic metabolism. Subsequent return to near control levels coincided with indications of reinnervation in the striatum: all consistent with a role of apoE during the degenerative process and regenerative period. We also found that this cascade was activated in the hippocampus and more so than in the striatum, with a particular contribution of LDLR expression. The hippocampal activation did not correlate with substantial neurochemical reductions but appears to reflect local subtle alteration of DA metabolism and the regulation of plasticity-related event in this structure. This study provides first evidence of an activation of the apoE/apoE receptors cascade in a mouse model of PD, specifically in the MPTP-induced deafferentation of the striatum. Results are also quite consistent with the postulated role of apoE in brain repair but, raise the issue of possible lesion- and region-specific alterations in gene expression.

Maternal high-fat intake alters presynaptic regulation of dopamine in the nucleus accumbens and increases motivation for fat rewards in the offspring.

High caloric intake during early postnatal development can have long term consequences for the offspring. We previously reported that the adult offspring of dams fed a high-fat diet during the last week of gestation and throughout lactation display blunted locomotor response to amphetamine (AMP) and reduced sensitization to the drug compared to offspring of control diet dams. Here, we report that the subsensitivity of high-fat offspring to AMP's locomotor stimulant action reflects, at least in part, altered regulation of nucleus accumbens (NAc) dopamine (DA) transmission. When compared to controls, the DA response of high-fat animals to AMP, as measured with microdialysis, was attenuated in the NAc, but unaffected in the prefrontal cortex (PFC). A relatively higher activity of NAc synaptosomal DA transporter sites without changes in vesicular monoamine transporter (VMAT) uptake capacity was also observed in high-fat offspring. Moreover, ventral tegmental area (VTA) D(2) receptor mRNA levels were decreased in high-fat offspring, suggesting a reduction in DA release-regulating D(2) autoreceptors in terminal regions such as the NAc. The magnitude of locomotor response to D(2/3) receptor activation (with quinpirole) was greater in high-fat than in control animals despite having comparable postsynaptic D(2) mRNA levels in the NAc. Finally, while operant responding for a sugar-enriched food reward did not differ between diet groups, high-fat offspring displayed increased operant responding for a fat-enriched reward compared to controls. These findings add to mounting evidence that early life exposure to elevated dietary maternal fat can lead to long lasting changes in DA-mediated behavioral responses to stimulant drugs and fat-enriched foods.

Influence of naturally occurring variations in maternal care on prepulse inhibition of acoustic startle and the medial prefrontal cortical dopamine response to stress in adult rats.

In rats, naturally occurring variations in maternal care contribute to the development of individual differences in the behavioral and neuroendocrine responses to stress during adulthood. The dopamine (DA) projection to the medial prefrontal cortex (mPFC) plays an important role in mediating stress responsivity and is thought to be involved also in regulating sensorimotor gating. In the present study, we compared prepulse inhibition (PPI) of acoustic startle as well as the left and right mPFC DA stress responses in the adult offspring of high- and low-licking/grooming (LG) dams. Our data indicate that the offspring of low-LG animals are impaired on measures of PPI compared with high-LG animals. We also observed in low-LG animals a significant blunting of the mPFC DA stress responses that was lateralized to the right hemisphere, whereas in high-LG animals, the left and right mPFC DA stress responses were equally attenuated. Although mPFC levels of DA transporter did not differ between the two groups of animals, mPFC levels of catechol-O-methyl transferase immunoreactivity of low-LG animals were significantly lower than those of high-LG animals. These data provide evidence that variations in maternal care can lead to lasting changes in mPFC DA responsivity to stress and suggest the possibility that such changes in mesocorticolimbic DA function can also lead to deficits in sensorimotor gating.

Basolateral amygdala dopamine receptor antagonism modulates initial reactivity to but not habituation of the acoustic startle response.

Although the basolateral amygdala (BLA) plays a role in the habituation to sensory stimuli, the receptor mechanisms mediating this process remain unclear. In the present study, we investigated the role of BLA dopamine (DA) in the habituation of the acoustic startle response (ASR) with intra-BLA infusions of DA receptor antagonists. Male Long Evans rats were subjected to startle pulses over two consecutive once-daily sessions. Prior to testing on Day 1, separate groups of animals received bilateral intra-BLA infusions of a D1 (SCH 23390: 0, 3.2, 6.4 microg per side) or a D2/D3 (raclopride: 0, 2.5, 5.0 microg per side) receptor antagonist. Animals were retested 24h later (Day 2) without prior drug infusion in order to assess possible treatment effects on within- and between-session habituation of the ASR. As expected, within- and between-session habituation was observed in vehicle-treated controls. Within-session habituation was also seen in SCH 23390- and raclopride-treated animals both on Day 1 as well as 24h later (Day 2). Evidence of between-session habituation was observed in SCH 23390-treated animals. However, compared to vehicle, intra-BLA SCH 23390 or raclopride attenuated the initial startle response on Day 1, but not Day 2. No evidence of between-session habituation was found in raclopride-treated animals, although this probably reflected the attenuated initial response to the startling stimulus on Day 1 rather than a reduced rate of habituation on Day 2. The present study suggests that while BLA DA is not involved in habituation of the ASR, it may mediate the perceived aversive nature of the initially startling stimuli.

Basolateral amygdala modulation of the nucleus accumbens dopamine response to stress: role of the medial prefrontal cortex.

The basolateral amygdala (BLA) is involved in modulating affective responses to stress and, along with the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), receives a stress-responsive dopamine (DA) projection from the ventral tegmental area. The present study was undertaken to characterize the role of BLA DA D1 and D2/D3 receptor subtypes in modulating the NAc and mPFC DA responses to stress. Voltammetry was used to monitor, in freely behaving rats, stress-induced DA release in NAc or mPFC after injection of D1 (SCH 23390) or D2/D3 (raclopride) receptor antagonist into BLA. Intra-BLA SCH 23390 injection potentiated stress-induced NAc DA release but attenuated the mPFC DA stress response; raclopride had no effect on either the NAc or mPFC DA responses to stress. Based on these results, we also examined the possibility that BLA can indirectly modulate the NAc DA stress response via its projection to mPFC. To do so we studied the effects of intra-mPFC co-administration of D1 (SKF 38393) and D2/D3 (quinpirole) receptor agonists on the potentiated NAc DA stress response resulting from intra-BLA SCH 23390 injection. Alone, mPFC D1 and D2/D3 receptor co-activation had no effect on stress-induced NAc DA release, but did prevent the potentiated NAc DA stress response produced by BLA D1 receptor blockade. These findings indicate that BLA DA modulates the NAc and mPFC DA stress responses via activation of the D1 receptor subtype. They also suggest that BLA DA modulates stress-induced NAc DA release indirectly by modulating the mPFC DA response to stress.

Effects of basolateral amygdala dopamine depletion on the nucleus accumbens and medial prefrontal cortical dopamine responses to stress.

In vivo voltammetry was used to study the effects of basolateral amygdala dopamine depletion on stress-induced dopamine release in the nucleus accumbens and medial prefrontal cortex. Male Long-Evans rats received bilateral microinjections of 6-hydroxydopamine or vehicle into the basolateral amygdala. Changes in dopamine signal were monitored in the nucleus accumbens and in the right and left hemispheres of medial prefrontal cortex, in lesioned animals and shams. Animals were subjected to a physical stressor (tail pinch) and a species-typical threat (fox odour); each stressor was presented twice over four consecutive daily sessions. The results indicate that the nucleus accumbens dopamine responses to both stressors are significantly potentiated by dopamine-depleting lesions to basolateral amygdala. In contrast, while the dopamine stress response in the left medial prefrontal cortex did not differ between lesioned animals and shams, the right medial prefrontal cortical dopamine response to tail pinch, but not fox odour stress, was significantly attenuated in lesioned animals. Therefore, basolateral amygdala dopamine depletion had opposite effects on the nucleus accumbens and medial prefrontal cortical dopamine responses to stress, although the effect on the latter is lateralized to the right hemisphere in a stressor-specific manner. These data indicate that stress-induced activation of meso-amygdaloid dopamine exerts an inhibitory influence on the nucleus accumbens dopamine response to stress. They also suggest the possibility that meso-amygdaloid dopamine influences the nucleus accumbens dopamine response to stress indirectly by modulating stress-induced dopamine release in medial prefrontal cortex. These findings add to a growing body of evidence of a preferential involvement of right medial prefrontal cortical dopamine in a wide range of physiological responses to stress.

Perinatal distress leads to lateralized medial prefrontal cortical dopamine hypofunction in adult rats.

Obstetric complications involving anoxia or prolonged hypoxia are suspected to increase the risk for such mental disorders as schizophrenia and attention deficit-hyperactivity disorder. In previous studies, we reported evidence of enhanced nucleus accumbens (NAcc) dopamine (DA) function in adult rats subjected to intrauterine anoxia during cesarean (C) section birth. In the present study, we used voltammetry and monoamine-sensitive electrodes to investigate the possibility that this functional hyperactivity of the meso-NAcc system is attributable to a loss of inhibitory control from the medial prefrontal cortex (PFC). We monitored the DA responses to repeated once-daily stress in the right or left PFC of adult male rats born vaginally (VAG) or by C-section, either with (C + 15) or without (C + 0) an additional 15 min of intrauterine anoxia. In C + 15 animals, we observed a pronounced and persistent blunting of stress-induced DA release in the right PFC but not in the left; with repeated testing, a similar pattern of dampened right PFC DA stress responses emerged in C + 0 animals. In addition, C + 15 animals were spontaneously more active than VAG and C + 0 animals and displayed an increase in PFC DA transporter density that was also lateralized to the right hemisphere. There was no evidence, however, that PFC D(1) and D(2) receptor levels differed between birth groups or hemisphere. These findings suggest a mechanism by which perinatal complications involving anoxia might contribute to the etiology of mental disorders that have been linked to disturbances in central DA transmission and lateralized PFC dysfunction.

Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex.

The medial prefrontal cortex modulates the nucleus accumbens dopamine response to stress and has been implicated in feedback regulation of hypothalamic-pituitary-adrenal axis activation by stress. Here we report on the effects of bilateral neonatal (postnatal day 7) ibotenate-induced lesions to the medial prefrontal cortex on nucleus accumbens dopamine and neuroendocrine function in adult rats. Voltammetry was used to monitor the dopamine response to each of five, once-daily exposures to tail-pinch stress whereas alterations in neuroendocrine function were determined from the plasma corticosterone response to a single 20-min episode of restraint stress. Potential lesion-induced deficits in sensory-motor gating were assessed by measuring prepulse inhibition of the acoustic startle response before and after repeated stress. Our data show that each daily stress episode elicited larger and longer-lasting dopamine increases in prefrontal cortex-lesioned animals than in sham-lesioned controls. Furthermore, greater stress-induced elevations in plasma corticosterone were seen in lesioned animals than in their sham-lesioned counterparts. However, while repeated stress potentiated startle responses in animals of both groups, there was no effect of lesion on the amplitude or on prepulse inhibition of the startle response.Together, these findings indicate that neonatal prefrontal cortex damage can lead to changes in mesolimbic dopamine and neuroendocrine function during adulthood. They also add to a growing body of experimental and clinical evidence implicating abnormal prefrontal cortex neuronal development in the pathophysiology of schizophrenia and other disorders linked to central dopamine dysfunction.

Neonatal ventral hippocampal lesions attenuate the nucleus accumbens dopamine response to stress: an electrochemical study in the adult rat.

Neonatal damage to the ventral hippocampus (VH) can lead, during adulthood, to behaviours that are believed to reflect enhanced mesocorticolimbic dopamine (DA) transmission. In the present study, the effects of neonatal excitotoxic lesions to the VH on spontaneous locomotor activity and stress-elicited increases in extracellular nucleus accumbens (NAcc) DA levels were examined in adult rats. Male pups received, on postnatal day 7, bilateral injections of either an ibotenic acid solution (lesioned) or vehicle (sham-lesioned) into the VH. At 3-4 months of age, animals were assessed during five daily sessions for changes in spontaneous locomotor activity associated with habituation to a novel environment. Voltammetry was used in separate groups of sham- and VH-lesioned animals to monitor the NAcc DA response to each of five once-daily exposures to tail-pinch stress. The results indicate that while VH-lesioned animals seem to habituate to novelty, they remain hyperactive relative to sham-lesioned controls. In contrast, however, stress consistently elicited in VH-lesioned animals smaller and shorter-lasting increases in NAcc DA than in sham-lesioned controls. These data suggest that neonatal excitotoxic damage to VH leads to changes in DA function that persist into adulthood. The blunted response to stress seen in VH-lesioned animals indicates that one consequence of such damage is a functional hyporeactivity in meso-NAcc DA neurons. The fact that these animals are spontaneously more active suggests compensatory changes in DA function that are efferent to DA terminals in NAcc.

Effects of medial prefrontal cortical injections of GABA receptor agonists and antagonists on the local and nucleus accumbens dopamine responses to stress.

Stress stimulates dopamine (DA) release in nucleus accumbens (NAcc) but will do so more strongly in medial prefrontal cortex (PFC). Evidence indicates, however, that the cortical DA response to stress acts to dampen the concurrent increase in NAcc DA release. In the present study, we used voltammetry to investigate the role of PFC GABA in regulating the NAcc DA response to stress. The results of Experiment 1 show that the NAcc stress response is inhibited following bilateral cortical microinjections of baclofen (GABAB receptor agonist). While phaclofen (GABAB receptor antagonist) blocked the effect of baclofen, it had no significant effect of its own. Intra-PFC injections of muscimol (GABAA receptor agonist) and bicuculline (GABAA receptor antagonist) had no effect on the DA stress response in NAcc. In Experiment 2, we explored the possibility that GABA influences the NAcc DA stress response indirectly by modulating stress-induced DA release in PFC. None of the drugs tested had an effect on the PFC stress response at a dose (1 nmol) that produced reliable effects on the NAcc stress response. At an order of magnitude higher dose, however, locally applied phaclofen and muscimol enhanced and attenuated, respectively, the DA stress response in PFC. These results were validated in Experiment 3 by showing that intra-PFC injections of GBR-12395 (DA uptake blocker) and quinpirole (D2/D3 receptor agonist) dose-dependently enhanced and inhibited, respectively, the local DA stress response. Together, these findings indicate that increased GABA transmission in PFC exerts an inhibitory influence on the NAcc DA response to stress, and that this action is mediated primarily but not exclusively by GABAB receptors which may be located both on cortical output neurons and on DA terminals.

Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.

The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function.

Changes in medial prefrontal cortical dopamine levels associated with response-contingent food reward: an electrochemical study in rat.

Voltammetry was used to monitor in rats changes in medial prefrontal cortex (PFC) dopamine (DA) levels associated with response-contingent presentation of a condensed milk reward. During two initial training sessions, minor DA signal fluctuations were seen when animals consumed a standard 30 sec (0.2 ml) meal earned on a continuous reinforcement schedule. There was no evidence of experience-dependent changes in these fluctuations. Under delayed reinforcement conditions, lever-presses were followed by DA signal increases that were time-locked to the delay duration, and these were followed by signal decreases when animals eventually received the reward. Such decreases became more pronounced when the standard rate of milk delivery was tripled, but were attenuated when milk delivery was reduced to half the usual rate. Withholding earned milk resulted in signal increases. In contrast, DA signal increases were observed during milk consumption when the standard meal duration was unexpectedly shortened to 15 sec or lengthened to 60 or 90 sec. Orderly changes in DA signal were also observed under partial reinforcement conditions. Unreinforced responses were associated with DA signal decreases, whereas transient increases were seen during the 30 sec meal that followed reinforced responses. These findings indicate that response-contingent reward presentation elicits synchronous changes in PFC DA transmission. They also suggest that the DA input to PFC is activated when rewards are presented under conditions that deviate from those that the animals had come to expect, particularly so when the temporal structure of learned associations is altered.

Relationships between stress-induced increases in medial prefrontal cortical dopamine and plasma corticosterone levels in rats: role of cerebral laterality.

In the present study, in vivo voltammetry was used to monitor changes in dopamine levels in the left and right medial prefrontal cortex of rats exposed to mild physical and psychological stress. These were 2 min of tail-pinch and 15 min exposure to cat odour, respectively. Fourteen male Long Evans rats with bilateral carbon fibre recording electrodes were tested on four consecutive days, and records obtained in each medial prefrontal cortex for each stressor. A week later, animals underwent a 20 min restraint stress, with plasma samples taken at 0, 20 and 80 min to determine stress-induced corticosterone responses. It was found that dopamine responses to tail-pinch were significantly longer-lasting in the left hemisphere than in the right, while this asymmetry was not present for the dopamine response to cat odour. Stress-induced dopamine increases elicited by the two stressors were significantly correlated only in the right medial prefrontal cortex. Restraint stress-induced increases in plasma corticosterone were positively correlated with dopaminergic responses to tail-pinch, but were only related to dopamine cat odour responses when individual asymmetries favoured the right medial prefrontal cortex. The data suggest that asymmetric mesocortical dopamine activation depends on the type of stress, and that regulation of dopamine responses to both types of stress is most tightly coupled in the right hemisphere. While neuroendocrine and dopaminergic stress responses are positively linked, this relationship is only asymmetrical for the psychological stressor, suggesting a specialized role for right cortical mechanisms in the integration of emotional and physiological responses to stressful situations. A preliminary report of this work was presented at the Society for Neuroscience meeting in Washington DC, November, 1996.

NMDA receptors in nucleus accumbens modulate stress-induced dopamine release in nucleus accumbens and ventral tegmental area.

Converging evidence suggests that dopamine (DA) transmission in nucleus accumbens (NAcc) is modulated locally by an excitatory amino acid (EAA)-containing input possibly originating in medial prefrontal cortex (PFC). In the present study, we examined the effects of intra-NAcc administration of EAA receptor antagonists on stress-induced increases of NAcc DA levels and of dendritically released DA in the ventral tegmental area (VTA). Local injection of the NMDA receptor antagonist-AP-5 (0.05, 0.5, and 5.0 nmoles)-dose-dependently potentiated increases in NAcc DA levels elicited by 15 min of restraint stress. In contrast, local application of equivalent doses of the kainate/AMPA receptor antagonist-DNQX-failed to alter the NAcc DA stress response reliably. In a separate experiment, we found that intra-NAcc injection of AP-5 also potentiated stress-induced increases in VTA DA levels. These results indicate that EAAs acting at NMDA receptors in NAcc can modulate stress-induced DA release in this region. Our data indicate, however, that this action exerts an inhibitory influence on the NAcc DA stress response, suggesting that the relevant population of NMDA receptors are not located on NAcc DA terminals. The fact that intra-NAcc AP-5 injections also potentiated the DA stress response in VTA suggests instead an action mediated by NMDA receptors located on NAcc neurons that feedback, directly or indirectly, to cell bodies of the mesocorticolimbic DA system.

Influence of perinatal factors on the nucleus accumbens dopamine response to repeated stress during adulthood: an electrochemical study in the rat.

Evidence from animal studies suggests that a period of anoxia to the fetus, a consequence common to many birth complications, results in long-term alterations in ventral mesencephalic dopamine function. Long-term functional changes in these dopamine neurons, in particular those that innervate the nucleus accumbens, also occur when animals are repeatedly stressed. In the present study, we examined the possibility that a period of anoxia during a Cesarean section birth can later alter the development of stress-induced sensitization of dopamine transmission in the nucleus accumbens. Dams were decapitated on the last day of gestation and the entire uterus was removed by Cesarean section. Pups were then delivered either immediately (Cesarean section group) or were immersed in a 37 degrees C saline bath for 3.5 or 13.5 min (Cesarean section+anoxia groups) before delivery of the pups. A fourth group of pups that were born vaginally served as controls (Vaginal group). Three to four months postnatally, animals from each group were implanted with monoamine-selective carbon-fiber electrodes into the nucleus accumbens. Voltammetry was used to monitor the dopamine response to each of five consecutive, once daily, 15-min exposures to tail-pinch stress. The results show that the first exposure to stress elicited dopamine signal increases of comparable amplitudes and durations in all animals. However, when compared to the initial stress response, the fourth and fifth exposures to tail-pinch elicited significantly longer-lasting dopamine responses in animals born by Cesarean section, either with or without added anoxia. In contrast, there was no significant day-to-day enhancement of the stress response in control, vaginally born animals. The findings reported here provide experimental support for the idea that birth complications may contribute to the pathophysiology of psychiatric disorders, in particular those that involve central dopamine dysfunction, such as schizophrenia. Specifically, our results suggest that subtle alterations in birth procedure may be sufficient to increase the sensitivity of mesolimbic dopamine neurons to the effects of repeated stress in the adult animal.

Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats.

We examined the possibility that anoxia at birth can alter behavioral sensitization to amphetamine during adulthood. Male rats born either vaginally or by Cesarean section with or without an additional 15-min period of anoxia received five once-daily injections of either d-amphetamine (2.0 mg/kg, i.p.) or vehicle or no pretreatment. One week later, all animals received a challenge injection of amphetamine (0.5 mg/kg, i.p.). The data indicate that all three birth groups of animals pretreated with amphetamine had sensitized equally to the drug's behavioral effect. Of animals pretreated with saline, however, only those born by Cesarean section with added anoxia displayed a sensitized response to amphetamine, suggesting that the stress of daily injection was sufficient to sensitize these animals to amphetamine. These findings provide experimental support for clinical evidence implicating obstetric complications, such as perinatal anoxia, in the pathophysiology of schizophrenia.

Behavior-relevant changes in nucleus accumbens dopamine transmission elicited by food reinforcement: an electrochemical study in rat.

Voltammetry was used to monitor dopamine (DA) transmission in nucleus accumbens (NAcc) of rats lever-pressing for food. Under standard conditions, animals responded on a fixed ratio 1 (FR1) schedule for 0.2 ml of milk delivered over 30 sec; milk delivery was paired with a 30 sec cue light. Consumption of the initial few milk rewards of the session caused DA signal increases. These initial signal increases were typical of the first and, at times, the second test days. On subsequent days, the most pronounced initial signal increases coincided with presentation of conditioned stimuli that marked the start of the session. Biphasic changes in DA signal that were time-locked to each reinforced lever-press were also observed; responses were preceded by increases and were followed, during milk consumption, by decreases in DA signal. At the end of milk delivery, the signal increased again in apparent anticipation of the next lever-press. Delaying milk delivery caused a corresponding delay in DA signal decreases, and the amount of time signals remained depressed was bound by the duration of milk consumption. Greater decreases in DA signal were observed when the rate of milk delivery was doubled or tripled, and such increases in reward value were associated with more pronounced signal increases during the period that preceded each lever-press. In contrast, DA signal increases were seen when milk was delivered at half the usual rate or was withheld altogether or when animals were denied access to the lever. Under partial reinforcement conditions, reinforced lever-presses were preceded by more pronounced signal increases and decreases of comparable magnitude accompanied milk consumption. These results suggest that meso-NAcc DA neurons are activated primarily in response to the incentive rather than to the reinforcing properties of rewards.

In vivo analysis of the role of dopamine in stimulant and opiate self-administration.

Stimulants and opiates increase synaptic dopamine (DA) transmission in nucleus accumbens (NAcc), and this action is thought to underlie the habit-forming properties of these and several other abused drugs, Much of the experimental support for this idea comes from drug self-administration studies. The fact that animals will learn an arbitrary response when it is followed by an intravenous cocaine or heroin injection has been taken to suggest that these and other such drugs act as potent rewards. It is widely assumed that the resulting increase in NAcc levels of DA is what reinforces operant-responding in animals and drug-seeking in humans. Recent evidence from a variety of sources, however, including our group, appears to challenge the validity of this assumption. In this article we review some of the findings that have emerged thus far from our in vivo electrochemical recording studies. The conclusions suggested by our research are discussed in relation to those derived from other lines of evidence.