Chronic social stress in adolescence influenced both amphetamine conditioned place preference and locomotor sensitization

We previously reported that chronic social stress (SS) in adolescence, but not in adulthood, increased the locomotor-activating effects of nicotine in females, and not males, when tested in adulthood. However, SS rats had decreased locomotor response to nicotine when tested in adolescence. Here, we investigated age-related changes in the effects of SS on both conditioned place preference (CPP) and locomotor sensitization to amphetamine. In the CPP experiment, SS females tested in adolescence had increased preference for the 1.0 mg/kg dose of amphetamine, whereas SS rats of both sexes showed a decrease in CPP for the 0.5 mg/kg dose when tested as adults. Irrespective of time of testing, SS males and females had enhanced locomotor sensitization compared to controls. Thus, adolescent SS produced both immediate and enduring effects on behavioral responses to amphetamine, likely by altering the development of the mesocorticolimbic dopamine system, which holds implications for vulnerability to addiction.     

Expression of cocaine sensitization: regulation by the medial prefrontal cortex.

Extracellular levels of dopamine are increased in response to systemic administration of cocaine in several brain areas including the nucleus accumbens and medial prefrontal cortex. While the cocaine-induced increase in extracellular dopamine levels in the nucleus accumbens is augmented after repeated daily cocaine, the response of extracellular dopamine levels in the medial prefrontal cortex is attenuated. Since dopamine in the medial prefrontal cortex has an inhibitory effect on nucleus accumbens dopamine levels and locomotor activity, the role of medial prefrontal cortex dopamine tolerance in the expression of sensitized locomotor behavior was further examined by injection of D-amphetamine sulfate into the prelimbic portion of the medial prefrontal cortex just prior to cocaine challenge in cocaine-sensitized rats. Male Sprague-Dawley rats were non-handled (naive) or injected with either saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) for five consecutive days. After a seven to 12 day withdrawal period, rats were microinjected with either saline or various doses of amphetamine into primarily the prelimbic region of the medial prefrontal cortex followed by systemic injection of saline or cocaine. In naive rats, intramedial prefrontal cortex amphetamine produced a trend toward decreased locomotor responding to cocaine challenge while no effect of amphetamine was evident in daily saline pretreated rats. Daily cocaine pretreated rats that received saline in the medial prefrontal cortex demonstrated a sensitized locomotor response compared to their daily saline pretreated counterparts. This sensitization was blocked by a low dose of amphetamine (0.175 microg/side) in the medial prefrontal cortex, an effect which disappeared in animals administered higher amphetamine doses. The results suggest that in rats sensitized to cocaine, decreased medial prefrontal cortex dopamine levels in response to cocaine challenge may contribute to behavioral sensitization. Furthermore, the data indicate the possibility that there is an optimal range at which medial prefrontal cortex amphetamine exerts maximal behavioral inhibition. These findings implicate a role for decreased cortical control in producing sensitized behavioral responding to cocaine.     

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder.     

Changes in hyporesponsiveness to acute amphetamine and age differences in tyrosine hydroxylase immunoreactivity in the brain over adolescence in male and female rats

We investigated hyposensitivity after amphetamine in early (postnatal Day 30; P30) and late (P45) adolescent rats compared to adults (P70) in experiment 1. Locomotor activity was measured for 1 hr after the first (acute) and second (24 hr later) injection of amphetamine (0.5 or 1.5 mg/kg). P30 and P45 rats were transiently hypoactive compared to adults, as indicated by reduced locomotor activity after acute amphetamine and enhanced activity after the second injection in adolescents only. In experiment 2, ovariectomy did not alter locomotor activity during habituation at any age compared to intact rats, and, as for intact adolescents, ovariectomized adolescents continued to be less active after amphetamine than adults, suggesting gonadal immaturity alone cannot account for age differences in experiment 1. However, ovariectomy attenuated the increase in activity after the second treatment. In experiment 3 involving untreated rats, tyrosine hydroxylase immunoreactivity was reduced in P30, P40, and P50 compared to P90 rats in the nucleus accumbens core and the medial prefrontal cortex. Thus, adolescents may have an increased threshold of behavioral activation that can be overcome with either a higher dose or with repeated amphetamine treatment, and may be related to changes in the dopamine system over development. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 417–428, 2009.     

Effects of 6-hydroxydopamine lesions of the prefrontal cortex on tyrosine hydroxylase activity in mesolimbic and nigrostriatal dopamine systems.

The effects of prefrontal cortical dopamine depletion on subcortical dopamine function in the rat were examined. 6-Hydroxydopamine lesions of the dopaminergic innervation of the prefrontal cortex did not alter concentrations of dopamine or its metabolite 3,4-dihydroxyphenylacetic acid in either the striatum or nucleus accumbens. Similarly, the activity of the catecholamine biosynthetic enzyme tyrosine hydroxylase in the striatal complex was not changed in animals with prefrontal cortical lesions. Animals sustaining neurotoxic lesions of the prefrontal cortex were challenged with haloperidol in order to activate submaximally tyrosine hydroxylase activity. The magnitude of the haloperidol-induced increase in enzyme activity in the nucleus accumbens was significantly greater in lesioned subjects than in control animals. These data suggest that lesions of the prefrontal cortical dopamine innervation do not result in significant alterations in basal dopaminergic function in the striatal complex. However, lesions of the dopaminergic innervation of the prefrontal cortex significantly increase the responsiveness of mesolimbic dopamine afferents to pharmacological challenge.     

The effects of ibotenic acid lesions of the medial and lateral prefrontal cortex on latent inhibition, prepulse inhibition and amphetamine-induced hyperlocomotion

Hypofunction of prefrontal cortical regions, such as dorsolateral and orbital regions, has been suggested to contribute to the symptomatology of schizophrenia. In the rat, the medial and the lateral prefrontal cortices are considered as homologs of the primate dorsolateral and orbital prefrontal cortices, respectively. The present study investigated in rats the effects of lesions of the medial and lateral prefrontal cortices on latent inhibition, prepulse inhibition and amphetamine-induced activity. These paradigms are known to be modulated by the mesolimbic dopaminergic system, a system that has been suggested to be involved in the symptomatology of schizophrenia. Latent inhibition and prepulse inhibition are disrupted in schizophrenic patients as well as in rats treated with amphetamine. Amphetamine-induced activity was tested under dim light (low stress) and bright light (high stress) because stressful situations selectively increase mesocortical dopamine activity. Lateral prefrontal cortex lesioned animals did not differ in their behavior from control animals in any of the paradigms used in this study. Medial prefrontal cortex lesions did not affect latent inhibition but increased prepulse inhibition. In the amphetamine-induced activity experiment, prior to drug administration, open field locomotion was reduced under bright illumination for all lesion groups. After amphetamine administration, medial prefrontal cortex lesions attenuated the hyperlocomotor effect of the drug under the dim light condition and potentiated it under the bright light condition.The results indicate that medial and lateral prefrontal cortex can be functionally differentiated by their involvement in the modulation of behavior requiring mesocorticolimbic dopamine activation. The results in amphetamine induced activity suggest that the behavioral outcomes associated with medial prefrontal cortex depend on the background (stress) against which the evaluation is made. The results also support the notion that prepulse inhibition may be a better model than latent inhibition of the symptoms of schizophrenia associated with dysfunctional prefrontal activity.     

Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: a comparative study in the Roman high- and low-avoidance rat lines

The selectively bred Roman high- and low-avoidance rats differ in emotionality and responsiveness to the motor effects of acute and repeated psychostimulant administration. These lines also show drastic differences in the neurochemical responses of their mesolimbic dopamine systems to addictive drugs. The nucleus accumbens is critically involved in the locomotor activation produced by psychostimulants and in the augmentation of this effect observed upon repeated drug administration (i.e. behavioral sensitization), although there is not a general consensus as to whether the nucleus accumbens-core or the nucleus accumbens-shell is preferentially involved in such alterations. This study was designed to evaluate the effects of acute amphetamine (0.20mg/kg, s.c.) on dopamine output in the nucleus accumbens-shell and nucleus accumbens-core of the Roman lines under basal conditions (i.e. naïve rats) and after the repeated administration of amphetamine (1mg/kg, s.c.×10 days) or saline. We show that (1) in naïve rats, amphetamine caused a larger increment in dopamine output in the nucleus accumbens-shell vs the nucleus accumbens-core only in the Roman high-avoidance line; (2) repeated amphetamine elicits behavioral sensitization in Roman high-avoidance, but not Roman low-avoidance, rats; (3) in sensitized Roman high-avoidance rats, amphetamine provokes a larger increment in dopamine output in the nucleus accumbens-core, and an attenuated dopaminergic response in the nucleus accumbens-shell, as compared with Roman high-avoidance rats repeatedly treated with saline; and (4) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant Roman low-avoidance line. We propose that (1) Roman high-avoidance and Roman low-avoidance rats differ in the vulnerability to develop psychostimulant sensitization, (2) the nucleus accumbens-core and nucleus accumbens-shell subserve distinct functional roles in this phenomenon, and (3) comparative studies in the Roman lines may provide insight into the influence of neural substrates and genetic background on the individual vulnerability to addiction.     

Differential expression of arc mRNA and other plasticity-related genes induced by nicotine in adolescent rat forebrain

Relatively little attention has been focused on mechanisms related to neural plasticity and drug abuse in adolescence, compared with abundant research using adult animal models. As smoking is typically initiated in adolescence, an important question to address is whether the adolescent brain responds differently to nicotine compared with the adult. To investigate this question, we examined the expression of a number of early response genes (arc, c-fos and NGFI-B) that have been implicated in synaptic plasticity and addiction, following acute nicotine in adolescent and adult rats. Baseline expression of arc and c-fos was higher in adolescent brains compared with adults. Following acute nicotine treatment (0.1, 0.4mg/kg), we found a marked induction of arc mRNA in the prefrontal cortex of nicotine-treated adolescents compared with a less pronounced increase of arc in the adult. c-fos and NGFI-B were also upregulated by nicotine, but not in an age-related manner. In contrast, nicotine induced less arc, c-fos, and NGFI-B expression in the somatosensory cortex of adolescents compared with adults. A fourth gene, quinoid dihydropteridine reductase was expressed at lower levels in white matter of the adolescent forebrain compared with the adult, but was not affected by nicotine. These results suggest that in adolescence, the activity of specific early response genes is higher in brain regions critical for emotional regulation and decision-making. Further, nicotine affects key plasticity molecules in these areas in a manner different from the adult. Thus, adolescence may represent a neurobiologically vulnerable period with regard to nicotine exposure.     

Dopamine and noradrenaline efflux in the prefrontal cortex in the light and dark period: effects of novelty and handling and comparison to the nucleus accumbens

We used on-line microdialysis measurements of dopamine and noradrenaline extracellular concentrations in the medial prefrontal cortex of awake, freely moving rats during the dark and the light period of the day to study whether (i) basal efflux would be higher in the active, dark period than in the inactive, light period; (ii) the activation induced by environmental stimuli would be dependent on these conditions. When determined one day after cannula placement, noradrenaline and dopamine levels were higher during the dark. Maximal relative increases induced by novelty and handling were 150% and 175–200%, respectively, and were very similar in the light and the dark, but the net increases were higher in the dark. Separate groups were tested one week after cannula placement to ensure recovery of possibly disturbed circadian rhythms. While basal levels in the dark were now approximately twice those in the light, the maximal relative and net increases after both novelty and handling were very similar. Basal levels of dopamine in the nucleus accumbens (one day after cannula placement) were not different in the light or dark, but were increased by novelty and handling to about 130% only in the light period, not in the dark.

Thus, in the prefrontal cortex, dopamine strongly resembles noradrenaline, in that basal efflux was state dependent, whereas activation by stimuli was not. In the nucleus accumbens, basal dopamine efflux was not state dependent, but activation by stimuli was. These results suggest that there are differential effects of circadian phase on basal activity and responsiveness of the mesolimbic vs the mesocortical dopamine system.     

Effects of electrical or chemical stimulation of the prefrontal cortex on arrhythmias induced in cats by electrical stimulation of the anteromedial hypothalamus

When the anteromedial hypothalamus is stimulated with a chronically implanted electrode in conscious cats, negative emotional behaviors such as restlessness and escape occur during stimulation and ventricular extrasystoles occur in rapid succession immediately after the end of stimulation. It has been shown in the lightly anesthetized cat that the activity of the sympathetic nervous system becomes predominant during stimulation of the anteromedial hypothalamus thereby causing the rises in blood pressure and heart rate. However, immediately after the cessation of the stimulation, this 'sympathetic dominant' state was observed to be switched to the 'parasympathetic dominant' state with falls in blood pressure and heart rate which was very frequently followed by the appearance of the ventricular extrasystoles (Poststimulus Arrhythmia: PSA). The purpose of this experiment was to examine how the electric and pharmacological stimulation of the prefrontal cortex modulate the rise in the blood pressure and heart rate and PSA caused by electric stimulation of the anteromedial hypothalamus. When the prefrontal cortex was electrically stimulated simultaneously with stimulation of the anteromedial hypothalamus in 24 lightly anesthetized cats, PSA was inhibited or facilitated or remained unchanged depending on the site of stimulation in the prefrontal cortex. When dopamine or noradrenaline was microinjected into the site of prefrontal cortex where PSA was inhibited, PSA was suppressed and this effect was blocked by microinjection of haloperidol or phenoxybenzamine, respectively. Dopamine was ineffective when injected in the site where PSA was facilitated; PSA was facilitated by microinjection of noradrenaline and this effect was inhibited by microinjection of propranolol. Although changes in blood pressure and heart rate were observed when the inhibition or facilitation of PSA was elicited by prefrontal injection of noradrenaline, no changes in cardiovascular parameters occurred when dopamine injection caused the inhibition of PSA. These results suggest (1) that activation of the dopamine receptor or alpha adrenoceptor in the prefrontal cortex is involved in the inhibition of PSA, and activation of beta adrenoceptor is concerned with facilitation of PSA and (2) that the mechanisms of dopamine receptor mediated inhibition of PSA appear to be different from those of inhibition of PSA by activation of the alpha adrenoceptor in the prefrontal cortex.     

Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults

Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium-activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction.     

Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome

Rearing rats in isolation has been shown to be a relevant paradigm for studying early life stress and understanding the genesis of depression and related affective disorders. Recent studies from our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging conditions. Accordingly, the present series of experiments assessed the contribution of each condition to the expression of the prepulse inhibition of the acoustic startle, food hoarding and spontaneous locomotor activity. In addition, ex vivo neurochemical changes in the brains of isolated and grouped rats reared either in sawdust-lined or in grid-floor cages were determined by measuring dopamine and serotonin as well as their major metabolites in a “psychosis circuit” that includes mainly the hippocampus and selected hippocampal efferent pathways projecting towards the anterior cingulate and infralimbic cortices, nucleus accumbens, dorsolateral caudate nucleus, amygdala and entorhinal cortex. The results of the present study demonstrate that rearing rats in isolation (i) produces a syndrome of generalized locomotor hyperactivity; (ii) increases the startle response; (iii) impairs prepulse inhibition; (iv) tends to increase food hoarding behavior; (v) increases basal dopamine turnover in the amygdaloid complex; (vi) decreases basal dopamine turnover in the infralimbic part of the medial prefrontal cortex; and (vii) decreases basal turnover of serotonin in the nucleus accumbens. In the entorhinal cortex, dopamine neurotransmission seemed to be more sensitive to the caging conditions since a decreased basal turnover of dopamine was observed in grid-reared animals. Plasma corticosterone levels were also increased in grid-reared animals compared with rats reared in sawdust cages. Finally, isolates reared on grids showed a significant positive correlation between plasma corticosterone levels and dopamine in the left nucleus accumbens.

Altogether, these results support the contention that there is a link between social isolation, attention deficit, spontaneous locomotor hyperactivity and reduced dopamine turnover in the medial prefrontal cortex. Furthermore, our data demonstrate that rearing rats in grid-floor cages represents a form of chronic mild stress associated with increased corticosterone levels, decreased basal turnover of entorhinal dopamine and increased dopamine activity in the left nucleus accumbens. Finally, a significant and selective decrease in the basal turnover of serotonin in the nucleus accumbens of isolated rats may be linked to the isolation-induced locomotor hyperactivity.     

Nicotine-induced increases of noradrenaline turnover in discrete noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their relationship to changes in the secretion of adenohypophyseal hormones

The effects of acute single doses (0.3 and 1 mg/kg) of nicotine on various hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal hormones in the rat were studied. Nicotine, in a dose of 1.0 mg/kg, increased noradrenaline turnover in the median eminence and in the peri- and paraventricular hypothalamic regions. The dopamine and noradrenaline nerve terminal systems in the median eminence and the dorsomedial hypothalamic nucleus respectively were unaffected. Serum GH levels were decreased and serum prolactin levels increased after a dose of 1 mg/kg. In the presence of tyrosine hydroxylase inhibition, nicotine in a dose of 1 mg/kg, instead increased GH and also LH secretion. It is suggested that the preferential increases of noradrenaline turnover in various hypothalamic noradrenaline nerve terminal systems by nicotine may be partly responsible for the nicotine induced increases of serum prolactin, GH and LH levels observed.     

Smoking, nicotine and psychiatric disorders: evidence for therapeutic role, controversies and implications for future research.

Researchers interested in investigating the possible therapeutic effects and the mechanisms of action of nicotine in neuropsychiatric disorders face a social-scientific-ethical dilemma. This dilemma comprises three components: (1) the known addictive potential of nicotine makes careful evaluation of the therapeutic potential of this compound socially unattractive; (2) the potential misuse of scientifically determined data by the tobacco 'lobby' creates ethical concerns; and (3) the possible confusion between the differential effects of nicotine in human smokers versus non-smokers creates difficulties in study designs in voluntary human subjects. Therefore, it is imperative that, at the onset of this review, the authors stress that they do not advocate cigarette-smoking as a route of nicotine intake under any circumstances on the basis that controlled dosing of nicotine may be of potential benefit in some neuropsychiatric disorders. In this article, we review the psychopharmacology of nicotine and its effects in a variety of neuropsychiatric disorders including schizophrenia, depression, anxiety and Tourette's syndrome. Possible mechanisms of action of nicotine directly or indirectly via its interaction with other neurotransmitter systems (i.e. serotonin, dopamine and noradrenaline) in relation to its potential role in these disorders are discussed. It is postulated that new drugs may need to be developed that selectively interact with nicotinic receptors without addiction potential.     

Systemic and intra-accumbens administration of amphetamine differentially affects cortical acetylcholine release

The present experiments tested the hypothesis that the amphetamine-induced increase in dopamine release in the nucleus accumbens represents a necessary and sufficient component of the ability of systemically administered amphetamine to stimulate cortical acetylcholine release. The effects of systemic or intra-accumbens administration of amphetamine on accumbens dopamine release and cortical acetylcholine release were assessed simultaneously in awake animals equipped with dialysis probes inserted into the shell of the nucleus accumbens and the medial prefrontal cortex. Additionally, the ability of intra-accumbens administration of dopamine D(1) and D(2) receptor antagonists to attenuate the effects of systemic amphetamine on cortical acetylcholine was tested. The effects of all treatments were assessed in interaction with a stimulus-induced activation of cortical acetylcholine release to account for the possibility that the demonstration of the trans-synaptic effects of accumbens dopamine requires pre-activation of basal forebrain circuits. Systemic amphetamine resulted in increases in basal cortical acetylcholine and accumbens dopamine efflux. Intra-accumbens administration of amphetamine substantially increased accumbens dopamine efflux, but did not significantly affect cortical acetylcholine efflux. Furthermore, intra-accumbens administration of sulpiride or SCH 23390 did not attenuate the systemic amphetamine-induced increase in cortical acetylcholine efflux. Collectively, the present data suggest that increases in accumbens dopamine release are neither sufficient nor necessary for the effects of systemically administered amphetamine on cortical acetylcholine release. The systemic amphetamine-induced increase in cortical acetylcholine may be mediated via multiple, parallel pathways and may not be attributable to a single afferent pathway of the basal forebrain.     

Postnatal alterations in dopaminergic markers in the human prefrontal cortex

Dopamine in the prefrontal cortex plays a critical role in normal cognition throughout the lifespan and has been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and attention deficit disorder. Little is known, however, about the postnatal development of the dopaminergic system in the human prefrontal cortex. In this study, we examined pre- and post-synaptic markers of the dopaminergic system in postmortem tissue specimens from 37 individuals ranging in age from 2 months to 86 years. We measured the levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine biosynthesis, using Western immunoblotting. We also examined the gene expression of the three most abundant dopamine receptors (DARs) in the human prefrontal cortex: DAR1, DAR2 and DAR4, by in situ hybridization. We found that tyrosine hydroxylase concentrations and DAR2 mRNA levels were highest in the cortex of neonates. In contrast, the gene expression of DAR1 was highest in adolescents and young adults. No significant changes across age groups were detected in mRNA levels of DAR4. Both DAR1 and DAR2 mRNA were significantly lower in the aged cortex. Taken together, our data suggest dynamic changes in markers of the dopamine system in the human frontal cortex during postnatal development at both pre-and post-synaptic sites. The peak in DAR1 mRNA levels around adolescence/early adulthood may be of particular relevance to neuropsychiatric disorders such as schizophrenia in which symptoms manifest during the same developmental period.     

Regulation of medial prefrontal cortex dopamine by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors

In the medial prefrontal cortex, repeated cocaine produces tolerance of the extracellular dopamine response to subsequent cocaine injection. These studies characterized the influence of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors on the medial prefrontal cortex dopamine response to acute cocaine, amphetamine and potassium chloride as a first step to assess whether these receptor subtypes may be candidates for mediating dopamine tolerance after repeated cocaine. Local infusion of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) produced an approximate 40% increase in dopamine levels in the medial prefrontal cortex, while a 30 microM dose did not alter basal levels infused over a 3-h period. Thus, 30 microM CNQX was chosen for the remaining experiments, and was infused for 1 h prior to and during all in vivo treatments. Local medial prefrontal cortex infusion of the 30 microM dose blocked the small increase in dopamine levels elicited by systemic saline injection (maximum of 26%), as well as the much larger increase in response to acute cocaine injection (maximum of 340%). Local infusion of D-amphetamine (3 and 30 microM) through the probe increased dopamine to 300 and 600% of basal levels, respectively. Co-infusion of CNQX partially blocked the response for the first 40 min, but dopamine levels recovered by 60 min later. Local infusion of 100 mM potassium chloride elicited a 600% increase in dopamine levels, which was attenuated approximately 50% by CNQX co-infusion. Potassium-stimulated release of dopamine was also measured in vitro in medial prefrontal cortical and striatal tissue. By 30 s after potassium addition, dopamine levels increased to 800% above baseline in the medial prefrontal cortex, and this increase was blocked by the presence of 30 microM CNQX. In contrast, potassium-stimulated dopamine release in striatal tissue was approximately 250% above basal levels, with no effect of CNQX on dopamine release. Locomotor behavior collected during dialysis experiments demonstrated that increased activity induced by local infusion of potassium chloride was severely attenuated by co-infusion of 30 microM CNQX, while no effects of this drug were found for cocaine-elicited behavior. These results suggest a potent influence of glutamate via alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors on extracellular dopamine in the medial prefrontal cortex, and these receptors may regulate dopamine release through a presynaptic mechanism. The findings may help elucidate the role of medial prefrontal cortex dopamine-glutamate interactions in drug abuse and stress- and drug-precipitated psychosis.     

Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission

Sex differences in behavioral and neurobiological responses to stress are considered to modulate the prevalence of some psychiatric disorders, including major depression. In the present study, we compared dopaminergic neurotransmission and behavior in response to two different stress paradigms, the Forced Swim Test (FST) and the Chronic Mild Stress (CMS). Male and female rats were subjected to one session of swim stress for two consecutive days (FST) or to a variety of mild stressors alternating for six weeks (CMS). Subsequently, the tissue levels of dopamine (DA) and its metabolites (HVA and DOPAC) in the hippocampus, the hypothalamus, the prefrontal cortex and the striatum were measured using high-performance liquid chromatography (HPLC). The ratios HVA/DA and DOPAC/DA were also calculated as indices of the dopaminergic activity. Results from the FST determined that males exhibited lower immobility, higher climbing duration and increased dopaminergic activity in the prefrontal cortex and the hippocampus compared to females. CMS induced alterations in sucrose intake in both sexes, while it only decreased dopaminergic activity in the prefrontal cortex of females. These findings show that FST and CMS have different effects on the dopaminergic activity of discrete brain regions depending on the sex of the animal. These data support the growing evidence that females display a differential response and adaptation to stress than males.     

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.     

Cortisol secretion patterns in addiction and addiction risk.

Addiction to alcohol or nicotine involves altered functioning of the brain's motivational systems. Altered functioning of the hypothalamic-pituitary-adrenocortical (HPA) axis may hold clues to the nature of the motivational changes accompanying addiction and vulnerability to addiction. Alcohol and nicotine show at least three forms of interaction with HPA functioning. Acute intake of both substances causes stress-like cortisol responses. Their persistent use may dysregulate the HPA. Finally, the risk for dependence and for relapse after quitting may be associated with deficient cortisol reactivity to a variety of stressors. The HPA is regulated at the hypothalamus by diurnal and metabolic signals, but during acute emotional states, its regulation is superseded by signals from the limbic system and prefrontal cortex. This top-down organization makes the HPA responsive to inputs that reflect motivational processes. The HPA is accordingly a useful system for studying psychophysiological reactivity in persons who may vary in cognitive, emotional, and behavioral tendencies associated with addiction and risk for addiction. Chronic, heavy intake of alcohol and nicotine may cause modifications in these frontal-limbic interactions and may account for HPA response differences in seen in alcoholics and smokers. In addition, preexisting alterations in frontal-limbic interactions with the HPA may reflect addiction-proneness, as shown in studies of offspring of alcohol- and drug-abusing parents. Continuing research on the relationship between HPA function, stress responsivity, and the addictions may yield insights into how the brain's motivational systems support addictions and risk for addictions.