Janet M. Finlay

Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex.

Abstract: Noradrenergic and dopaminergic projections converge in the medial prefrontal cortex and there is evidence of an interaction between dopamine (DA) and norepinephrine (NE) terminals in this region. We have examined the influence of drugs known to alter extracellular NE on extracellular NE and DA in medial prefrontal cortex using in vivo microdialysis. Local application of the NE uptake inhibitor desipramine (1.0 µM) delivered through a microdialysis probe increased extracellular DA (+149%) as well as NE (+201%) in medial prefrontal cortex. Furthermore, desipramine potentiated the tail shock‐induced increase in both extracellular DA (stress alone, +64%; stress + desipramine, +584%) and NE (stress alone, +55%; stress + desipramine, +443%). In contrast, local application of desipramine did not affect extracellular DA in striatum, indicating that this drug does not influence DA efflux directly. Local application of the α2‐adrenoceptor antagonist idazoxan (0.1 or 5.0 mM) increased extracellular NE and DA in medial prefrontal cortex. Conversely, the α2‐adrenoceptor agonist clonidine (0.2 mg/kg; i.p.) decreased extracellular NE and DA in medial prefrontal cortex. These results support the hypothesis that NE terminals in medial prefrontal cortex regulate extracellular DA in this region. This regulation may be achieved by mechanisms involving an action of NE on receptors that regulate DA release (heteroreceptor regulation) and/or transport of DA into noradrenergic terminals (heterotransporter regulation).

Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increase in extracellular dopamine in the nucleus accumbens core and shell

In the present study we examined whether depletion of dopamine in the medial prefrontal cortex alters the neurochemical activity of mesoaccumbens dopamine neurons and/or their behavioral correlate, motor behavior. Infusion of 6-hydroxydopamine (1 microgram) into the medial prefrontal cortex of rats pretreated with a norepinephrine uptake blocker produced a 70% loss of tissue dopamine, with relative sparing of the norepinephrine content (-23%) in that region. Using in vivo microdialysis, we monitored basal and evoked extracellular dopamine in the nucleus accumbens core and shell of control and lesioned rats. The concentration of basal extracellular dopamine in the nucleus accumbens core was similar in control and lesioned rats; however, basal dopamine efflux in the nucleus accumbens shell was approximately 30% higher in lesioned rats than in controls. Lesions did not alter the ability of systemic D-amphetamine (1.5 mg/kg, i.p.) to increase extracellular dopamine in the nucleus accumbens shell, in contrast, the dopamine depletion in the medial prefrontal cortex attenuated the amphetamine-induced increase in extracellular dopamine in the nucleus accumbens core, as well as the amphetamine-induced increase in locomotor activity. Lesions did not significantly alter the effects of tail pressure (30 min) on extracellular dopamine in the nucleus accumbens core. However, the depletion of dopamine in the medial prefrontal cortex potentiated the stress-induced increase in extracellular dopamine in the nucleus accumbens shell. These data demonstrate that mesocortical dopamine neurons influence (i) amphetamine-induced dopamine efflux in the nucleus accumbens core and (ii) stress-evoked dopamine efflux in the nucleus accumbens shell. It has been proposed that a disruption in the interaction between cortical and subcortical dopamine neurons is involved in the pathophysiology of schizophrenia. The present data raise the possibility that a disruption in the interaction between mesocortical dopamine neurons and dopamine neurons projecting to the nucleus accumbens shell is involved in those symptoms of schizophrenia that are influenced by stress.

The Effects of Stress on Central Dopaminergic Neurons: Possible Clinical Implications

The response of the central nervous system to stress is often critical to the adaptation of an organism to its environment. However, in humans the response to stress also can be maladaptive, resulting in the expression or exacerbation of many neurological and psychiatric disorders. In this review, we examine the impact of stress on the synthesis and release of dopamine within mesocortical, mesoaccumbens, and nigrostriatal dopamine projections. We note that whereas stress increases the neurochemical activity of each of these populations of dopamine neurons, heterogeneities do exist. Specifically, acute stress evokes a greater increase in dopamine metabolism and release within the prefrontal cortex than the subcortical sites. Furthermore, whereas prior exposure to chronic stress enhances the response of mesocortical dopamine neurons to an acute novel stressor, this does not occur in the subcortical sites. In addition to these regional heterogeneities, we also note that even within a single dopamine projection there can be heterogeneous regulation of dopamine synthesis and release. Specifically, whereas stress-induced dopamine release in the neostriatum is mediated by an action of glutamate on the dopamine cell body, stress-induced dopamine synthesis in the neostriatum is mediated by an action of glutamate on the dopamine nerve terminal. Finally, we propose that regional heterogeneities in the responsiveness of central dopamine neurons to stress may ultimately play a role in the expression and exacerbation of symptoms associated with schizophrenia.

Stress-Induced Sensitization of Dopamine and Norepinephrine Efflux in Medial Prefrontal Cortex of the Rat

Abstract: We examined whether prior exposure to chronic cold (17–28 days, 5°C) alters basal or stress‐evoked (30‐min tail shock) catecholamine release in medial prefrontal cortex, nucleus accumbens, and striatum, using in vivo microdialysis. Basal norepinephrine (NE) concentrations in medial prefrontal cortex did not differ between chronically cold‐exposed rats and naive control rats (2.7 ± 0.3 vs. 2.5 ± 0.2 pg/20 µl, respectively). Basal dopamine (DA) efflux in any of the brain regions was not significantly different between chronically cold‐exposed rats and naive rats. However, a trend for lower basal DA efflux in the cold‐exposed relative to naive rats was observed in medial prefrontal cortex (1.5 ± 0.2 vs. 2.2 ± 0.3 pg/20 µl, respectively), nucleus accumbens (3.7 ± 0.8 vs. 5.4 ± 0.9 pg/20 µl, respectively), and striatum (4.4 ± 0.5 vs. 7.2 ± 1.5 pg/20 µl, respectively). In medial prefrontal cortex of rats previously exposed to cold, tail shock elicited a greater increase from baseline in both DA and NE efflux relative to that measured in naive rats (DA, 2.3 ± 0.3 vs. 1.2 ± 0.1 pg, respectively; NE, 3.8 ± 0.4 vs. 1.4 ± 0.2 pg, respectively). However, in nucleus accumbens or striatum of rats previously exposed to cold, the stress‐induced increase in DA efflux was not significantly different from that of naive rats (nucleus accumbens, 1.8 ± 0.7 vs. 1.5 ± 0.3 pg, respectively; striatum, 1.9 ± 0.4 vs. 2.6 ± 0.7 pg, respectively). Thus, both cortical NE projections and cortically projecting DA neurons sensitize after chronic exposure to cold. In contrast, subcortical DA projections do not sensitize under these conditions.

Chronic cold exposure potentiates CRH-evoked increases in electrophysiologic activity of locus coeruleus neurons

BACKGROUND Chronic stress exposure can produce sensitization of norepinephrine release in the forebrain in response to subsequent stressors. Furthermore, the increase in norepinephrine release in response to the stress-related peptide corticotropin-releasing hormone (CRH) is potentiated by prior chronic stress exposure. To explore possible mechanisms underlying these alterations in norepinephrine release, we examined the effect of chronic stress on the electrophysiologic activity of locus coeruleus (LC) neurons in response to centrally applied CRH. METHODS Single-unit recordings of LC neurons in halothane-anesthetized rats were used to compare the effect of intraventricular administration of CRH (0.3-3.0 microg) in control and previously cold-exposed (2 weeks at 5 degrees C) rats. RESULTS The CRH-evoked increase in LC neuron activity was enhanced following chronic cold exposure, without alteration in basal activity of LC neurons. The enhanced CRH-evoked activation was apparent at higher doses of CRH but not at lower ones, resulting in an increased slope of the dose-response curve for CRH in previously cold-exposed rats. CONCLUSIONS These data, in combination with previous data, suggest that the sensitivity of LC neurons to excitatory inputs is increased following chronic cold exposure. The altered functional capacity of LC neurons in rats after continuous cold exposure may represent an experimental model to examine the role of central noradrenergic neurons in anxiety and mood disorders.

Sensitization of norepinephrine release in medial prefrontal cortex: effect of different chronic stress protocols.

Previously, we demonstrated that continuous exposure of rats to cold (5 degrees C) for 2-3 weeks potentiates the increase in extracellular norepinephrine in the medial prefrontal cortex produced by acute tail shock. In the present study, we used in vivo microdialysis to examine whether this sensitization of evoked norepinephrine release also occurs in the medial prefrontal cortex following exposure to other chronic stress protocols. Rats exposed to 30 min of intermittent foot shock (0.6 mA) each day for 14 days, did not exhibit a greater increase in extracellular norepinephrine in response to acute tail shock. To determine whether this discrepancy between cold exposure and foot shock might be related to differences in the nature or the pattern of exposure to the chronic stressor, we also examined the effect of intermittent exposure to cold or continuous exposure to a foot shock protocol on tail shock-evoked norepinephrine release. Sensitized norepinephrine release did not develop following either intermittent exposure to cold (5 degrees C; 4 h/day for 14 days) or continuous exposure to a foot shock protocol (0.6 mA trains at random intervals 24 h/day for 14 days), suggesting that both the nature of the stressor as well as the pattern of exposure to the chronic stressor play a role in the development of sensitized norepinephrine release.

Impact of corticotropin-releasing hormone on extracellular norepinephrine in prefrontal cortex after chronic cold stress.

Abstract: We have previously demonstrated that exposing rats to cold (5°C) for 3–4 weeks potentiates the increase in extracellular norepinephrine (NE) in the medial prefrontal cortex produced by acute tail shock. In the present study, we used microdialysis to determine the duration of cold exposure required to produce this sensitization and explored the mechanism of the phenomenon. Tail shock elicited a twofold greater increase in extracellular NE in the medial prefrontal cortex of rats exposed to cold for 2 weeks than in naive control rats or in rats exposed to cold for 1 week and tested either immediately or after a 2‐week delay. Local infusion of 10 µMd‐amphetamine or 30 mM K+ increased extracellular NE in the medial prefrontal cortex (∼350 and 190%, respectively) comparably in control rats and rats exposed to cold for 3 weeks. In contrast, intraventricular administration of 3.0 µg of corticotropin‐releasing hormone increased extracellular NE in the medial prefrontal cortex by 65% in rats exposed to cold for 2 weeks, but only 35% in control rats. These results indicate that an enhanced responsiveness of noradrenergic neurons to acute tail shock (1) requires ∼2 weeks of cold exposure to develop and (2) may be mediated by a change at the level of the noradrenergic cell bodies rather than the nerve terminals.

Effects of selective dopamine depletion in medial prefrontal cortex on basal and evoked extracellular dopamine in neostriatum

In this study, we demonstrate that 6-hydroxydopamine (6-OHDA) can be used to produce a lesion of dopamine (DA) terminals in medial prefrontal cortex (mPFC) while sparing the noradrenergic innervation in this region. Furthermore, we determined the impact of these lesions on both extracellular DA in neostriatum, using in vivo microdialysis, and locomotor activity. Our results demonstrate that, whereas higher doses of 6-OHDA (> or = 4 micrograms) depleted both DA and norepinephrine (NE) in mPFC, 1 micrograms 6-OHDA produced a depletion of DA (-79%) without significantly affecting NE content (-13%). Selective depletion of DA content in mPFC did not alter basal levels of extracellular DA in neostriatum determined 14 days after the lesion. The lesion also did not alter the ability of acute tail pressure (30 min) to increase extracellular DA in neostriatum or to stimulate locomotor activity. Depletion of DA in mPFC did not alter the ability of d-amphetamine (1.5 mg/kg, i.p.) to increase intracellular DA in neostriatum. In contrast, the maximum amphetamine-induced increase in locomotor activity was attenuated in lesioned rats as compared with control rats (670 and 280 locomotor counts/15 min, respectively). These data suggest that in the intact system, DA terminals in mPFC do not regulate extracellular DA in neostriatum. In addition, these data confirm that DA terminals in mPFC can influence stimulant-induced locomotion.

Depletion of dopamine in the prefrontal cortex decreases the basal electrophysiological activity of mesolimbic dopamine neurons

One hypothesis regarding the etiology of schizophrenia proposes that disruption of the dopaminergic innervation of the prefrontal cortex leads to an increase in dopamine (DA) transmission in subcortical regions. In the present study, we examined the effect of 6-hydroxydopamine lesions of the medial prefrontal cortex (mPFC) dopamine innervation on the spontaneous electrophysiological activity of ventral tegmental DA neurons recorded in vivo. DA cell activity was assessed along three dimensions: (1) the relative proportion of DA neurons exhibiting spontaneous activity, (2) their basal firing rate, and (3) the mean percentage of spikes fired in bursts. In lesioned rats, DA neurons in the ventral tegmental area (VTA) exhibited a significantly slower mean firing rate, as well as a significant reduction in the percentage of spikes fired in bursts relative to controls. In contrast, depletion of DA in the mPFC did not have a significant effect on the relative proportion of VTA DA neurons exhibiting spontaneous activity. We suggest that by reducing the basal electrophysiological activity of VTA DA neurons, mPFC DA depletion may lead to an increase in the level of responsivity of the system to excitatory stimuli. Thus, the magnitude of increase in action potential-dependent DA release that occurs in response to a challenge may be augmented in lesioned rats.

Loss of dopamine terminals in the medial prefrontal cortex increased the ratio of DOPAC to DA in tissue of the nucleus accumbens shell: role of stress

We examined whether dopamine depletion in the medial prefrontal cortex of the rat differentially affects basal and evoked dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content in the subareas of the neostriatum and nucleus accumbens. Loss of approximately 80% of tissue dopamine content in the medial prefrontal cortex did not significantly alter basal tissue concentrations of dopamine or DOPAC or the DOPAC:dopamine ratio in either the nucleus accumbens core or shell or the medial or lateral neostriatum. However, tail pressure stress significantly increased the DOPAC:dopamine ratio in the nucleus accumbens shell of lesioned rats. Because dorsal and ventral areas of the medial prefrontal cortex preferentially innervate the core and shell, respectively, we sought to determine whether the selective effect of lesions on dopamine terminals in the shell of the nucleus accumbens are paralleled by greater dopamine loss in the ventral medial prefrontal cortex. 6-Hydroxydopamine decreased tissue concentrations of dopamine in both the dorsal (-74%) and ventral medial prefrontal cortex (-68%). In lesioned rats, few tyrosine hydroxylase-immunoreactive fibers remained in the dorsal medial prefrontal cortex whereas a dense innervation remained in the ventralmost area. The present data suggest that the influence of mesocortical dopamine neurons on the dopamine projection to the nucleus accumbens shell is expressed only under conditions of stress. Furthermore, lesion-induced alterations in dopamine neurons projecting to the nucleus accumbens shell are not due to a more extensive loss of dopamine terminals in the ventral than in the dorsal medial prefrontal cortex.