Holly Moore

Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission

The mesolimbic dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which dopamine participates in these activities requires comprehension of the dynamics of dopamine release. Here we report dissociable regulation of dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal dopamine efflux. After blockade of dopamine reuptake, however, enhanced bursting increased dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate dopamine system function: burst firing induces massive synaptic dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic dopamine levels that are less influenced by reuptake.

Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs

Antipsychotic drugs used in the treatment of schizophrenia have in common the property of being dopamine-receptor antagonists. However, the rapid timecourse of receptor blockade produced upon drug administration does not correlate with the emergence of clinical actions, which typically require weeks of treatment to become manifest. Studies in rats have shown that repeated antipsychotic drug treatment results in a delayed inactivation of dopamine-neuron firing in the midbrain due to depolarization block. Furthermore, the therapeutic efficacy of antipsychotic drugs in humans correlates with their ability to induce depolarization block of mesolimbic dopamine neurons, whereas their potential to produce extrapyramidal side effects correlates with their propensity for inducing depolarization block in the nigrostriatal dopamine system. Therefore, dopamine-cell depolarization block is an effective model for evaluating antipsychotic drug efficacy, and provides a potential mechanism to account for their therapeutic impact on a dysregulated dopamine system.

A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia

BACKGROUNDnAs a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus.nnnMETHODSnIn offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed.nnnRESULTSnAdult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven bistable membrane states in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype.nnnCONCLUSIONSnThe MAM-E17 rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.

The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia

Since the discovery that the therapeutic efficacy of antipsychotic drugs was significantly correlated to their ability to block dopamine D2 receptors, abnormal dopamine transmission in the forebrain has been postulated to underlie psychosis in schizophrenia. In the past 15 years, an impressive amount of clinical and basic research aimed at the study of schizophrenia has indicated that prefrontal and temporal cortical abnormalities may be more important in the etiology of many of the symptoms of schizophrenia, including psychosis. However, the cortical systems that appear to have structural and/or metabolic abnormalities in schizophrenia patients potently regulate forebrain dopamine transmission through a number of mechanisms. In turn, dopamine modulates excitatory transmission mediated by frontal and temporal cortical projections to the basal ganglia and other regions. The present review summarizes the multiple interactions between forebrain DA systems and frontal and temporal corticostriatal transmission. It then examines the role of these interactions in normal behaviors and the psychopathology of schizophrenia.

Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons.

The dopamine (DA) neurons in the ventral tegmental area and medial substantia nigra (VTA/mSN) projecting to the limbic forebrain and prefrontal cortex have long been postulated to play a major role in cognitive and behavioral effects of stress. In this study, the effects of a chronic stressor (prolonged exposure to cold) on the spontaneous activity of DA neurons in the VTA/mSN were examined. Extracellular single-unit recordings of DA neurons were performed in rats following a 17-day continuous exposure to a cold (4°C) environment. Compared to controls, cold-exposed rats displayed 64% fewer spontaneously active DA neurons. The average spike activity (average firing rate, average spikes fired in bursts) of the DA cells that remained active in the cold-exposed rats did not differ significantly from controls. However, a significantly larger proportion of those cells showed excessive burst activity, compared to the DA cell population in controls. These results show that chronic stress can lead to the cessation of spontaneous activity in a subpopulation of VTA/mSN DA cells. These changes may indicate that unlike acute stress, which can potently activate the mesolimbic/mesocortical DA systems, chronic stress leads to an adaptive reduction in the number of active DA cells, perhaps altering the response of these systems to subsequent stressors.

Prenatal disruption of neocortical development alters prefrontal cortical neuron responses to dopamine in adult rats

A growing body of evidence suggests that structural changes in the cortex may disrupt dopaminergic transmission in circuits involving the prefrontal cortex (PFC) and may contribute to the etiology of schizophrenia. In this study, we utilize a rodent model of neonatal disruption of cortical development using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM). Using intracellular recordings in vivo, we compare the physiology of prefrontal cortical neurons and their responses to topical administration of dopamine (DA) in intact animals and adult rats treated prenatally with MAM. Topical administration of DA hyperpolarized the membrane potential (MP) and decreased the firing rate of neurons recorded in deep layers of the PFC in intact animals. Furthermore, electrical stimulation of the VTA evoked fast onset epsps or long-lasting depolarizations in PFC neurons. In comparison, PFC neurons recorded in MAM-treated animals had significantly faster baseline firing rates. Moreover, topical administration of DA did not affect the MP or firing rate of the neurons in MAM-treated animals. However, MAM-treated animals exhibited an increase in the percentage of neurons responding with long-lasting depolarizations to stimulation of the VTA. The results of this study indicate that PFC neurons in the MAM-treated rats are not responsive to DA administered superficially, while at the same time exhibit greater responsiveness to VTA stimulation. These results are consistent with a rewiring of the corticolimbic system in response to neurodevelopmental insults.

A Role for Electrotonic Coupling in the Striatum in the Expression of Dopamine Receptor-mediated Stereotypies

Stimulation of dopamine (DA) receptors in the striatum evokes a number of alterations in motor behavior in rats, as well as causing several alterations in cellular physiology, including changes in membrane potential, cell excitability, afferent drive, and electrotonic coupling. One cellular property that is potently modulated by DA stimulation is electrotonic coupling, a process shown to subserve motor pattern generation. To examine whether electrotonic coupling plays a role in mediating a specific set of DA receptor-mediated motor behaviors, we tested the effects of two inhibitors of gap junction conductance, carbenoxolone (CARB) and anandamide (AEA), on apomorphine (APO)-induced motor responses. We then used intra-striatal infusions of CARB to determine the role of electrotonic coupling specifically in the ventral striatum in the expression of APO-induced behaviors. APO (2.5–3.0 mg/kg, i.p.) significantly increased motor activity (a composite score) and the frequencies of oral and sniffing stereotypies. APO also disrupted grooming initiation and completion. APO-induced oral stereotypies were selectively blocked by systemic administration of CARB (7.0, 35.0 mg/kg). Moreover, although CARB alone disrupted the initiation and completion of grooming sequences, it also partially normalized APO-induced disruptions in grooming. AEA (0.5, 1.5 mg/kg) also blocked APO-induced oral stereotypies at the higher dose, but differed from CARB in that it did not restore normal grooming behaviors but, instead, appeared to “release” locomotion. Bilateral infusion of carbenoxolone (50 pmol) into the ventral striatum also blocked the oral stereotypies induced by systemic APO. We conclude from these and previous experiments that gap junctions play an important role in normal motor behavior, and furthermore that disruption of motor behavior in the form of oral and sniffing stereotypies associated with systemic APO administration may be a consequence of this heightened electrotonic coupling in the striatum. These results may be relevant to diseases and pharmacotherapies associated with disruptions of motor and possibly cognitive sequencing.

THE MODULATION OF CORTICOACCUMBENS TRANSMISSION BY LIMBIC AFFERENTS AND DOPAMINE : A MODEL FOR THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA

Publisher Summary The prefrontal cortex (PFC) throughput in the accumbens is dependent on two systems: it is gated by depolarizations arising from the hippocampal input, and it is attenuated by dopamine (DA) acting presynaptically on PFC terminals and on accumbens neurons by decreasing excitability. Systemic administration of DA agonists also appears to interfere with PFC transmission in another manner-by affecting the transitions to the depolarized state. The chapter shows that systemic administration of D1 and D2 DA agonists causes a decrease in the frequency of transitions to the depolarized state in bistable neurons. Furthermore, systemic administration of the psychotomimetic phenycyclidine (PCP) also causes a potent suppression of the bistable state. As the primary action of these drugs is a slowing of the frequency of the bistable state rather than a decrease in its amplitude, these drugs are most likely acting directly or indirectly on the hippocampus. Therefore, administration of DA agonists and PCP or damage to the hippocampus has a similar impact in the accumbens. The ability of the hippocampus to gate the PFC has implications of relevance to schizophrenia. It has been suggested that a deficit in hippocampal function may be involved in the etiology of schizophrenia. In addition, afferents from the amygdala to the nucleus accumbens also appear to exert a unique modulatory influence over the PFC inputs. During in vivo intracellular recording, stimulation of the amygdala evoked a long-latency depolarization of the membrane of accumbens neurons. Therefore, the amygdala appears to exert a narrow, time-locked facilitation that may be selective for specific stimuli. These systems are likely to exert both a context-dependent (hippocampal) and affect-selective (amygdalar) gating of PFC throughput in the accumbens.