Perinatal diazepam exposure: alterations in exploratory behavior and mesolimbic dopamine turnover

Perinatal exposure to diazepam has been shown to lead to alterations in motor activity and exploratory behavior in neonatal animals. Exploratory and locomotor behavior have been associated with changes in mesotelencephalic dopamine function. We have therefore examined the effects of perinatal diazepam administration on both exploratory behavior and mesotelencephalic dopamine turnover in the adult rat. Animals exposed to the benzodiazepine during the perinatal period engaged in significantly less exploratory behavior than did control subjects. The diazepam-induced alterations in behavior were developmentally specific: decreased exploratory behavior was observed at 90, but not 60, days of age. At 90 days of age, specific changes in dopamine turnover in diazepam-treated animals were restricted to mesolimbic (nucleus accumbens and ventral tegmental area) sites; alterations in dopamine turnover were not seen in other mesotelencephalic sites examined. The findings indicate that perinatal exposure to benzodiazepines leads to behavioral changes that are present in adulthood. These changes in exploratory behavior may be associated with alterations in mesolimbic dopamine function.     

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.     

Glucocorticoid effects on mesotelencephalic dopamine neurotransmission.

Multiple neurochemical estimates were used to examine peripheral corticosterone (CORT) effects in dopaminergic terminal regions. Acute CORT administration, which elevated plasma CORT (5 h), slightly decreased dihydroxyphenylacetic acid (DOPAC) to dopamine (DA) ratios in the striatum but not in other regions examined. Two weeks of adrenalectomy (ADX) increased both medial prefrontal cortex DOPAC/DA and homovanillic acid (HVA)/DA and striatal HVA/DA. A reciprocal pattern of changes was observed with CORT replacement in ADX animals. In contrast, CORT replacement in ADX animals did not significantly influence tyrosine hydroxylase content, basal dihydroxyphenylalanine (DOPA) accumulation after NSD 1015 treatment or the decline in DA after alpha-methyl-para-tyrosine, suggesting that neither DA neuronal activity nor release are altered by CORT. Moreover, neither gamma-hydroxybutyric acid lactone-induced increases in DOPA accumulation or stress-induced increases in DA utilization were influenced by CORT replacement, indicating that neither autoreceptor regulation of DA synthesis nor acute stress regulation of DA utilization are changed by CORT. The findings are most consistent with direct inhibition of basal DA metabolism in the medial prefrontal cortex and striatum. The possible physiological and behavioral significance of this inhibition is being further explored.     

Inhibition of basal and stress-induced dopamine release in the cerebral cortex and nucleus accumbens of freely moving rats by the neurosteroid allopregnanolone

The neurosteroid allopregnanolone is a potent and efficacious modulator of γ-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 μg in 5 μl) on basal and stress-induced changes in the extracellular concentrations of dopamine were investigated by microdialysis in various brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 μg in 5 μl). Allopregnanolone reduced (by a maximum of 65 to 75%) basal dopamine content in the prefrontal cortex and nucleus accumbens in a dose-dependent manner, but had no effect on dopamine output in the striatum. Allopregnanolone (10 to 15 μg) also completely prevented the increase in extracellular dopamine concentrations in the nucleus accumbens and cerebral cortex induced by foot-shock stress. Midazolam reduced basal dopamine content in all three brain regions studied as well as the stress- induced increase in dopamine content in the nucleus accumbens and cerebral cortex with a greater potency than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of dopaminergic transmission in the rat cerebral cortex and nucleus accumbens, two brain areas which are important in the regulation of emotional processes. These agents do not appear to affect striatal dopaminergic transmission which modulates motor function.     

Clozapine normalizes prefrontal cortex dopamine transmission in monkeys subchronically exposed to phencyclidine.

The mechanism responsible for the therapeutic effects of the prototypical atypical antipsychotic drug, clozapine, is still not understood; however, there is persuasive evidence from in vivo studies in normal rodents and primates that the ability to elevate dopamine neurotransmission preferentially in the prefrontal cortex is a key component to the beneficial effects of clozapine in schizophrenia. Theoretically, such an effect of clozapine would counteract the deficient dopaminergic innervation of the prefrontal cortex that appears to be part of the pathophysiology of schizophrenia. We have previously shown that following repeated, intermittent administrations of phencyclidine to monkeys there is lowered prefrontal cortical dopamine transmission and impairment of cognitive performance that is dependent on the prefrontal cortex; these biochemical and behavioral changes therefore model certain aspects of schizophrenia. We now investigate the effects of clozapine on the dopamine projections to prefrontal cortex, nucleus accumbens, and striatum in control monkeys and in those withdrawn from repeated phencyclidine treatment, using a dose regimen of clozapine that ameliorates the cognitive deficits described in the primate phencyclidine (PCP) model. In normal monkeys, clozapine elevated dopamine turnover in all prefrontal cortical, but not subcortical, regions analyzed. In the primate PCP model, clozapine normalized dopamine (DA) turnover in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex. Thus, the present data support the hypothesis that the therapeutic effects of clozapine in this primate model and perhaps in schizophrenia may be related at least in part to the restoration of DA tone in the prefrontal cortex.     

Phasic alterations in dopamine and serotonin release in striatum and prefrontal cortex in response to cocaine predictive cues in behaving rhesus macaques.

The ability of environmental cues associated with cocaine availability to cause relapse may result from conditioned activation of dopamine (DA) release. We examined this hypothesis in macaque monkeys by conducting microdialysis studies in animals during exposure to a cocaine predictive compound cue. In addition to studying DA release in mesolimbic and sensorimotor striatum, both DA and serotonin levels were determined in the prefrontal cortex (medial orbitofrontal and anterior cingulate). The compound cue employed visual, auditory, and olfactory components, and was salient to the animals as demonstrated by anticipatory lever pressing in the absence of cocaine. During a 10-min period of exposure prior to cocaine availability, there was no significant increase in striatal or cortical DA. The addition of a DA uptake inhibitor to the striatal perfusate to reduce the potential interference of neuronal uptake did not alter the results. In contrast to the lack of any change in striatal DA, a significant decrease in extracellular serotonin in the prefrontal cortex during the 10 min of cue exposure was observed.     

Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence

 Acute administration of phencyclidine to rats potently activates mesocorticolimbic dopaminergic neurons. The activation of dopamine release and utilization in the prefrontal cortex and nucleus accumbens are associated with profound cognitive impairment and hyperlocomotion, respectively. This dopaminergic activation by phencyclidine is not mediated by direct effects on the cell body regions of the dopamine neurons; however, phencyclidine augments dopamine release locally in the terminal fields. In the present study, the possible involvement of the prefrontal cortex in mediating activation of the mesolimbic dopamine system by phencyclidine was examined. Ibotenic acid lesions of the prefrontal cortex attenuated the biochemical activation of the mesolimbic dopamine neurons by PCP, and prefrontal lesions sharply blunted phencyclidine-, but not amphetamine- or novelty-, induced hyperlocomotion. In addition, injection of phencyclidine directly into the prefrontal cortex increased dopamine utilization in the nucleus accumbens and induced hyperlocomotion. In summary, these studies show that phencyclidine activates the mesolimbic pathway through a mechanism in the prefrontal cortex, possibly by disinhibiting the cortical circuit and activating corticofugal glutamatergic release in the ventral tegmental area. Received: 15 October 1997 / Final version: 13 January 1998     

Effects of prenatal and postnatal exposure to amitraz on norepinephrine, serotonin and dopamine levels in brain regions of male and female rats

The effects of maternal exposure to amitraz on brain region monoamine levels of male and female offspring rats at 60 days of age were observed. Maternal and offspring body weight, physical and general activity development were unaffected by the exposure of dams to amitraz (20mg/kgbw, orally on days 6-21 of pregnancy and 1-10 of lactation). Male and female offspring were sacrificed at 60 days of age and possible alterations in the content and metabolism of NE, DA and 5-HT were determined in brain regions by HPLC. The results showed that all these neurotransmitter systems were altered in a brain regional-related manner. In male and female offspring, amitraz induced a significant decrease in the prefrontal cortex 5-HT and its metabolite 5-HIAA and DA and its metabolites DOPAC and HVA levels with interaction of sex. Nevertheless, we verified that striatum DA and 5-HT and corresponding metabolite contents decreased in male and female offspring without statistical distinction of sex. In contrast, amitraz did not modify 5-HT content, but caused an increase in 5-HIAA content in the medulla oblongata and hippocampus in male and female offspring. Alterations in the hippocampus DA, DOPAC and HVA levels after amitraz exposure were also observed displaying a sex interaction. NE levels also showed a decrease after amitraz treatment in the prefrontal cortex and striatum without statistical sex interaction, but MHPG levels decreased in both regions with a sex interaction. Amitraz evoked increases in 5-HT turnover in the prefrontal cortex as well as in DA turnover in the striatum and hippocampus but decreases in NE turnover in the hypothalamus, prefrontal cortex and striatum. The present findings indicated that maternal exposure to amitraz altered noradrenergic, serotonergic and dopaminergic neurochemistry in their offspring in the prefrontal cortex, striatum and hippocampus, and those variations could be related to several alterations in the functions in which these brain regions are involved.     

Impairment of dopaminergic system function after chronic treatment with corticotropin-releasing factor

Mounting evidence suggests that chronic stress may have a detrimental effect on dopaminergic function and, in certain individuals, could contribute to the pathophysiology of central nervous system disorders like depression, schizophrenia, and Parkinson's disease. Therefore, the effects of chronic elevated brain levels of corticotropin-releasing factor (CRF), a crucial mediator of the behavioral stress response, on dopaminergic function were investigated. Rats treated intracerebroventricularly (i.c.v.) with 1 microg of CRF per day for 13 days displayed a decreased stereotyped response to D-amphetamine 1 day after chronic CRF and 1 month post-CRF. These rats also displayed an increased cataleptic response to eticlopride at 2 days post-CRF, consistent with decreased functional activity in the dopaminergic systems. CRF treatment induced a transient decrease of dopamine tissue levels in the prefrontal cortex at 1 day and 1 week post-CRF, an increase in the nucleus accumbens 1 week post-CRF and no change in the striatum. An increase of the dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio, an indicator of dopamine turnover, also was seen in the prefrontal cortex and striatum in CRF-treated animals at 1 week post-CRF. The dopaminergic system is very sensitive to oxidative insults. Levels of malondialdehyde, a membrane lipid peroxidation marker, also were measured in the same brain areas. In the prefrontal cortex, we observed a decrease of malondialdehyde at 1 week after chronic CRF treatment. This result may indicate an activation of the antioxidant system in response to chronic stress. These results show that chronic hyperactivity of the CRF system leads to a transient dysfunction of the dopaminergic systems, possibly through oxidative mechanisms, and suggest that stress could be a cofactor in the pathogenesis and/or progression of disorders of the dopaminergic systems.     

Ro 15-4513, like anxiogenic beta-carbolines, increases dopamine metabolism in the prefrontal cortex of the rat

The effects of Ro 15-4513, FG 7142 and beta-CCM on the activity of the mesocortical dopaminergic system were examined by measuring the changes in the content of the principal dopamine (DA) metabolite, dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex of the rat. Ro 15-4513 increased the DOPAC content in the prefrontal cortex in a dose-dependent manner (5-40 mg/kg i.p.) but had no effect on DA concentrations. A similar increase in DOPAC content was induced by FG 7142 (40 mg/kg i.p.) and beta-CCM (8 mg/kg s.c.), two beta-carboline derivatives that interact with benzodiazepine recognition sites as partial inverse agonists. These effects of Ro 15-4513, FG 7142 and beta-CCM on DA metabolism in the prefrontal cortex are mediated via benzodiazepine recognition sites, since they were prevented by the administration of the benzodiazepine antagonists Ro 15-1788 and ZK 93426. These data indicate that Ro 15-4513 is an inverse agonist at benzodiazepine recognition sites.     

Stress activation of limbic and cortical dopamine release is prevented by ICS 205-930 but not by diazepam

Systemic administration of the 5-HT3 receptor antagonist ICS 205-930, but not of the benzodiazepine diazepam, was able to prevent the stimulation of dopamine release in the nucleus accumbens and prefrontal cortex induced by restraint stress. These findings suggest that stress is not simply co-extensive with anxiety and that 5-HT3 receptors could regulate the dopaminergic response to stress.     

Dopamine in the basal ganglia and benzodiazepine-induced sedation

The effects of the anxiolytic benzodiazepine flurazepam on motor activity and the turnover of dopamine were measured in rats. Changes in motor activity were measured using a doppler-shift device; changes in extracellular homovanillic acid (HVA), monitored by linear sweep voltammetry with carbon paste electrodes implanted in the striatum and nucleus accumbens and ex vivo measurements of changes in 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios in the striatum and nucleus accumbens were used as indices of changes in the turnover of dopamine. Injection of vehicle increased the nocturnal rise in the concentration of HVA and the ex vivo DOPAC/DA ratio in the nucleus accumbens. Injection of flurazepam decreased the nocturnal rise in HVA and DOPAC/DA ratio in the nucleus accumbens below control levels. There was also a decrease in the nocturnal rise in motor activity. Neither injection of vehicle nor injection of flurazepam caused changes in either the concentration of HVA or the DOPAC/DA ratio in the striatum. The correlation coefficient for motor activity compared to concentration of HVA remained high for the nucleus accumbens but was reduced for the striatum after administration of flurazepam. The results suggest that the sedative effect of flurazepam may be due to an action on the mesolimbic but not the nigrostriatal dopaminergic pathway.     

Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress.

Preclinical studies have shown that stress and glucocorticoids increase mesolimbic dopamine (DA) and thereby facilitate psychostimulant self-administration. The relationship between stress-induced cortisol and mesolimbic DA responses to psychostimulants has not been studied in humans. To test the hypotheses that glucocorticoid responses to psychological stress are correlated with DA and subjective responses to psychostimulants in humans, 25 healthy adults (18-29 years) completed the Trier Social Stress Test (TSST) and two positron emission tomography (PET) scans with high-specific [11C]raclopride. The first scan was preceded by intravenous saline and the second by amphetamine (AMPH). Findings showed that stress-induced cortisol levels were positively associated with AMPH-induced DA release in the ventral striatum and other striatal regions. Subjects with higher cortisol responses to stress also reported more positive subjective drug effects with AMPH than subjects with lower responses. The results are consistent with preclinical findings showing an interrelationship between glucocorticoids and mesolimbic DA dynamics, which may influence psychostimulant self-administration in humans.     

Stress-induced increase of cortical dopamine metabolism: attenuation by a tachykinin NK1 receptor antagonist

The present study examined the potential role of tachykinin NK1 receptors in modulating immobilisation stress-induced increase of dopamine metabolism in rat medial prefrontal cortex. In agreement with previous studies, 20 min immobilisation stress significantly increased medial prefrontal cortex dopamine metabolism as reflected by the concentration of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC). Pretreatment with the high affinity, selective, tachykinin NK1 receptor antagonist (3(S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethyl amino)-2(S)-phenylpiperidine) ((S)-GR205171, 10 mg/kg, s.c.), a dose that in ex vivo binding studies extensively occupied rat brain tachykinin NK1 receptors for approximately 60 min, significantly attenuated the stress-induced increase of mesocortical DOPAC concentration without affecting cortical DOPAC levels per se. In contrast, pretreatment of animals with the less active enantiomer (R)-GR205171 (10 mg/kg, s.c.), which demonstrated negligible tachykinin NK1 receptor occupancy ex vivo, failed to affect either basal or stress-induced DOPAC concentration in medial prefrontal cortex. Furthermore, pretreatment of animals with the benzodiazepine/GABAA receptor antagonist, flumazenil (15 mg/kg, i.p.), did not affect the ability of (S)-GR205171 to attenuate the increase of medial prefrontal cortex DOPAC concentration by acute stress. Results demonstrate that the selective tachykinin NK1 receptor antagonist, (S)-GR205171, attenuated the stress-induced activation of mesocortical dopamine neurones by a mechanism independent of the benzodiazepine modulatory site of the GABAA receptor.     

Blockade by diazepam of conditioned fear-induced activation of rat mesoprefrontal dopamine neurons

The effect of diazepam on activation of the mesoprefrontal dopamine (DA) system by an emotional stress model without direct physical stimuli was examined. Environmental stimuli previously paired with inescapable footshock (conditioned fear) elicited increases in levels of the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the medial prefrontal cortex and of plasma corticosterone in rats. The increases in both levels were blocked by pretreatment with diazepam (5 mg/kg, IP); such blocking effects were reversed by Ro 15-1788 (15 mg/kg, IP), the benzodiazepine (BZD) receptor antagonist. These data suggest that diazepam can block activation of mesoprefrontal DA neurons as well as hypothalamo-pituitary-adrenocortical system elicited by the conditioned fear paradigm. This action appears to be a specific action of BZDs mediated through BZD receptors. We suggest that blocking effects of BZDs on the hyperactivity of the mesoprefrontal DA neurons may be one neural mechanism of their anxiolytic actions.     

The activation of mesoprefrontal dopamine neurons by FG 7142 is absent in rats treated chronically with diazepam

Administration of methyl-beta-carboline-3-carboxamide (FG 7142, 15 mg/kg i.p.) to rats has previously been shown to cause a selective increase in the levels of 3,4-dihydroxy-phenylacetic acid (DOPAC) in the prefrontal cortex and ventral tegmental area (VTA) via an interaction with benzodiazepine receptors. On withdrawal 3 days following chronic treatment with diazepam for 21 days, FG 7142 no longer increased DOPAC levels in either the prefrontal cortex or the VTA. Chronic diazepam treatment alone was ineffective in altering dopamine metabolism in the eight brain regions examined. The present findings indicate that chronic diazepam treatment may cause changes at the level of GABA/benzodiazepine receptor macromolecular complex, which is normally functionally integrated with the mesoprefrontal dopaminergic neurons, so that FG 7142 can no longer exert its intrinsic actions.     

Noradrenaline, dopamine, serotonin: different effects of psychological stress on brain biogenic amines in mice and rats.

The effect of restraint stress on central neurotransmission was evaluated in mice and rats. Noradrenaline (NA), dopamine (DA) and serotonin (5-HT) levels and their primary metabolites were measured in discrete brain regions following exposure to stress. Mice and rats demonstrated a similar response to stress in some brain regions. Both species responded to stress with lower NA and 5-HT in the locus coeruleus compared to non-stressed controls. Dopaminergic activity, assessed by DA turnover, was elevated in the hypothalamus. While DA turnover was suppressed in the amygdala, 5-HT turnover was similarly elevated in both species. In most cases, however, there were differences in biogenic neurotransmission between mice and rats in response to stress. In particular, NA levels were suppressed by stress in the dorsal cortex of mice, but in the rats NA levels were decreased in the hypothalamus. While stress produced lower DA levels in the hypothalamus, DA levels demonstrated a marked increase in the amygdala of mice. Stress was also associated with a decrease in DA levels in the rat striatum and with an increase of DA turnover in the locus coeruleus of mice. On the other hand, 5-HT was suppressed in the mouse striatum and in the rat hypothalamus and amygdala, while 5-HT turnover was markedly decreased in the hippocampus and dorsal cortex of rats alone. In conclusion, the changes in the central neurotransmission which are evoked by stress appear to be species-specific in most cases, a fact which may trigger discrete alterations in homeostatic mechanisms.     

Idazoxan preferentially increases dopamine output in the rat medial prefrontal cortex at the nerve terminal level.

The effects of the alpha2-adrenoceptor antagonist idazoxan on extracellular concentrations of dopamine in major dopaminergic terminal regions in the brain were investigated by means of microdialysis in freely moving rats. Systemic administration of idazoxan markedly increased dopamine output in the medial prefrontal cortex, whereas it failed to affect dopamine efflux in the striatum or in the nucleus accumbens. Local perfusion of idazoxan via reversed dialysis markedly enhanced dopamine efflux in cortical but not subcortical areas, in which dopamine output was but little affected. Infusion of idazoxan into the ventral tegmental area did not alter the dopamine efflux in the medial prefrontal cortex. Moreover, the increase in cortical dopamine efflux induced by systemic administration of idazoxan was unaffected by tetrodotoxin perfusion of the ventral tegmental area. These data show that the alpha2-adrenoceptor antagonist idazoxan preferentially increases basal dopamine output in the medial prefrontal cortex through a local mechanism, an effect which appears largely independent of dopaminergic neuronal activity. An enhanced output of cortical dopamine may contribute to the purported augmentation by alpha2-adrenoceptor antagonists of the therapeutic effects of both antidepressant and antipsychotic drugs.     

Effects of subchronic methamphetamine exposure on basal dopamine and stress-induced dopamine release in the nucleus accumbens shell of rats

Rationale Subchronic administration of stimulants reduces basal dopamine (DA) concentrations and blocks stress-induced DA release in the nucleus accumbens (NA) of rats during withdrawal. However, no studies have attempted to relate early withdrawal from chronic drug exposure to stress reactivity and changes in DA transmission. Objectives The effects of subchronic low-dose methamphetamine (METH) administration on regional changes in dopamine transporter (DAT) and norepinephrine transporter (NET) immunoreactivity and function during early withdrawal were examined. The effects of subchronic METH on stress responsivity measured by DA release in the nucleus accumbens shell (NA SHELL) and core (NA CORE) during acute restraint stress were also examined. Methods Male rats received single injections of METH (2.0 mg/kg i.p.) or saline (SAL) for 10 days and then were killed 24 h after the last injection. DAT and NET protein in NA, striatum (STR), medial prefrontal cortex (mPFC), and hippocampus were assayed by Western blot analysis. Experiment 2 measured basal extracellular DA concentrations and restraint-stress-induced DA release in vivo in the NA SHELL and CORE of SAL- and METH-pretreated rats after 24-h withdrawal. Experiment 3 examined the in vivo regulation of extracellular DA in the NA SHELL and/or CORE after local administration of GBR12909 (50 μM) or nisoxetine (100 μM; NA SHELL). Results Subchronic METH increased DAT but not NET immunoreactivity in the NA compared to the STR and mPFC. METH reduced basal extracellular DA and blocked restraint-stress-induced DA release in the NA SHELL. DA uptake blockade increased extracellular DA more in the NA SHELL of METH rats, whereas NE uptake blockade increased basal DA concentrations to a similar extent in METH and SAL rats. Conclusions These results suggest that subchronic METH exposure selectively increases NA DAT and consequently reduces basal and stress-induced DA release in the NA SHELL during early withdrawal.     

Psychostimulant treatment of combat-related posttraumatic stress disorder

The objective of this paper is to describe three cases of combat-related posttraumatic stress disorder (PTSD), largely refractory to standard medication treatment who responded well to psychostimulant treatment. Symptoms of PTSD potentially result from chronic, stress-induced dopaminergic dysfunction in the prefrontal cortex/basal ganglia system. Psychostimulants, by their relative propensity to enhance dopamine (DA) activity within these brain regions, may have particular value in targeting this dysfunction. Evidence of dopaminergic dysfunction following chronic stress is reviewed and possible mechanism of action of psychostimulants is explored. Psychostimulants appeared to be well tolerated and beneficial in the treatment of the cases of combat-related PTSD reported. General applicability of the use of psychostimulants in combat- and non-combat-related PTSD awaits further study. The potential implications of these findings in further delineating pathophysiology and treatment in PTSD deserve further exploration.