Xiu-Ti Hu

Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice

The brain mesoaccumbens dopamine system is intricately involved in the psychomotor stimulant activities of cocaine. However, the extent to which different dopamine receptors mediate these effects has not yet been firmly established. The present study used dopamine D1 receptor mutant mice produced by gene targeting to investigate the role of this receptor in the effects induced by cocaine. In contrast with wild-type mice, which showed a dose-dependent increase in locomotion, D1 mutant mice exhibited a dose-dependent decrease. Electrophysiological studies of dopamine-sensitive nucleus accumbens neurons demonstrated a marked reduction in the inhibitory effects of cocaine on the generation of action potentials. In addition, the inhibitory effects of dopamine as well as D1 and D2 agonists were almost completely abolished, whereas those of serotonin were unaffected. D2-like dopamine receptor binding was also normal. These results demonstrate the essential role of the D1 receptor in the locomotor stimulant effects of cocaine and in dopamine-mediated neurophysiological effects within the nucleus accumbens.

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.

Loss of autoreceptor functions in mice lacking the dopamine transporter

Autoreceptors provide an important inhibitory feedback mechanism for dopamine neurons by altering neuronal functions in response to changes in extracellular levels of dopamine. Elevated dopamine may be a component of several neuropsychiatric disorders. However, evidence concerning the state of autoreceptors in such conditions has remained elusive. The function of dopamine autoreceptors was assessed in mice lacking the dopamine transporter (DAT). Genetic deletion of the DAT gene in mice results in a persistent elevation in levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and release-regulating autoreceptors in these mice reveals a nearly complete loss of function. These findings may provide insight into the neurochemical consequences of hyperdopaminergia.

Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations

Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK‐801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates. Synapse 34:169–180, 1999.

Dopamine Receptor Antagonists Fail to Prevent Induction of Cocaine Sensitization

We investigated the ability of dopamine D1 and D2 class receptor antagonists to prevent the induction of behavioral sensitization to cocaine. The D2 receptor antagonist eticlopride failed to prevent the induction of cocaine sensitization. An intermediate dose of the D1 receptor antagonist SCH 23390 (0.1 mg/kg) appeared to prevent the induction of cocaine sensitization when tested after 3 days of withdrawal, but sensitization was clearly evident after 10 days of withdrawal. High doses of SCH 23390 alone produced supersensitivity to the behavioral effects of cocaine and to the inhibitory effects of D1 receptor agonists on nucleus accumbens neurons. Co-administration of eticlopride and SCH 23390 also failed to prevent the induction of cocaine sensitization. SCH 23390, but not eticlopride, prevented the expression of cocaine sensitization. We conclude that dopamine receptors are either not involved in the induction of cocaine sensitization or that redundant mechanisms exist to produce the same neuroadaptations.

Cocaine-Induced Plasticity of Intrinsic Membrane Properties in Prefrontal Cortex Pyramidal Neurons: Adaptations in Potassium Currents

Drug-induced adaptations in the prefrontal cortex (PFC) contribute to several core aspects of addictive behaviors, but the underlying neuronal processes remain essentially unknown. Here, we demonstrate that repeated in vivo exposure to cocaine persistently reduces the voltage-gated K+ current (VGKC) in PFC pyramidal neurons, resulting in enhanced membrane excitability. Analysis of dopamine D1-class receptor (D1R)-mediated modulation of VGKC indicates that, despite the absence of direct D1R stimulation, downstream D1 signaling (the cAMP/protein kinase A pathway) is increased during withdrawal from chronic cocaine treatment and plays a central role in the drug-induced membrane plasticity in PFC. This long-lasting, cocaine-induced plasticity of membrane excitability in PFC pyramidal neurons may contribute to the impaired decision making and drug craving that characterize cocaine withdrawal.

Dopamine enhances glutamate-induced excitation of rat striatal neurons by cooperative activation of D1 and D2 class receptors

Although dopamine (DA) usually inhibits firing of rat striatal neurons in vivo, iontophoresis of DA with low ejection currents can also potentiate glutamate-evoked activity. We used extracellular single cell recording to examine the DA receptor subtypes involved in such potentiation. At low iontophoretic currents (1-8 nA), both the DA D1 class receptor agonist SKF 38393 and the DA D2 class receptor agonist quinpirole mimicked the ability of DA to facilitate glutamate-induced activity. Acute depletion of DA abolished the excitatory modulation produced by either D1 or D2 agonists but not by DA. Co-administration of SKF 38393 and quinpirole restored the facilitation of glutamate effects in DA-depleted rats. Stimulation of both D1 and D2 class receptors appears to be required for DA to enhance glutamate-induced firing of striatal neurons.

Repeated Cocaine Administration Increases Voltage-Sensitive Calcium Currents in Response to Membrane Depolarization in Medial Prefrontal Cortex Pyramidal Neurons

The medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction. However, evidence to elucidate how the mPFC is functionally involved in cocaine addiction remains incomplete. Recent studies have revealed that repeated cocaine administration induces various neuroadaptations in pyramidal mPFC neurons, including a reduction in voltage-gated K+ currents (VGKCs) and a possible increase in voltage-sensitive Ca2+ currents (ICa). Here, we performed both current-clamp recordings in brain slices and voltage-clamp recordings in freshly dissociated cells to determine whether ICa is altered in mPFC pyramidal neurons after chronic cocaine treatment with a short-term or long-term withdrawal. In addition, a critical role of VGKCs in regulating the generation of Ca2+ plateau potential was also studied in mPFC neurons. Repeated cocaine administration significantly prolonged the duration of evoked Ca2+ plateau potentials and increased the whole-cell ICa in mPFC neurons after a 3 d withdrawal. Selective blockade of L-type Ca2+ channels by nifedipine not only significantly increased the threshold but also reduced the duration and amplitude of Ca2+ plateau potentials in both saline- and cocaine-withdrawn mPFC neurons. However, there was no significant difference in the increased threshold, reduced duration, and decreased amplitude of Ca2+ potentials between saline- and cocaine-withdrawn neurons after blockade of L-type Ca2+ channels. Moreover, an increase in amplitude was also observed, whereas the prolonged duration persisted, in Ca2+ potentials after 2-3 weeks of withdrawal. These findings indicate that chronic exposure to cocaine facilitates the responsiveness of ICa, particularly via the activated L-type Ca2+ channels, to excitatory stimuli in rat mPFC pyramidal neurons.

Homeostatic Synapse-Driven Membrane Plasticity in Nucleus Accumbens Neurons

Stable brain function relies on homeostatic maintenance of the functional output of individual neurons. In general, neurons function by converting synaptic input to output as action potential firing. To determine homeostatic mechanisms that balance this input–output/synapse–membrane interaction, we focused on nucleus accumbens (NAc) neurons and demonstrated a novel form of synapse-to-membrane homeostatic regulation, homeostatic synapse-driven membrane plasticity (hSMP). Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input. Furthermore, hSMP was triggered by synaptic NMDA receptors (NMDARs) and expressed by the modification of SK-type Ca2+-activated potassium channels. Moreover, hSMP in NAc neurons was abolished in rats during a short- (2 d) or long- (21 d) term withdrawal from repeated intraperitoneal injections of cocaine (15 mg/kg/d, 5 d). These results suggest that hSMP is a novel form of synapse-to-membrane homeostatic plasticity and dysregulation of hSMP may contribute to cocaine-induced cellular alterations in the NAc.

Adaptations in the mesoaccumbens dopamine system resulting from repeated administration of dopamine D1 and D2 receptor-selective agonists : relevance to cocaine sensitization

Abstract The mesoaccumbens dopamine (DA) system is intricately involved in sensitization to the locomotor stimulant effects of cocaine. Among the adaptations implicated in cocaine sensitization are transient subsensitivity of impulse-regulating DA D2 autoreceptors on ventral tegmental area (VTA) DA neurons leading to hyperactivity of the mesoaccumbens DA pathway, and persistently enhanced DA D1 receptor responses of nucleus accumbens (NAc) neurons. We have tested the hypothesis that both of these adaptations are necessary to produce cocaine sensitization. We injected rats twice daily for 2 weeks with the selective DA D1 class receptor agonist SKF 38393, the DA D2 class receptor agonist quinpirole, or both. We then used single-cell recording procedures to determine possible alterations in VTA DA autoreceptor sensitivity and NAc D1 receptor sensitivity at three withdrawal times: 1 day, 1 week and 1 month. We also tested whether these treatments produced cross-sensitization to cocaine at each withdrawal time. Repeated quinpirole treatment produced a reduction in VTA autoreceptor sensitivity and cross-sensitization to cocaine, but these effects lasted for less than 1 week. Repeated SKF 38393 treatment produced enhanced NAc D1 responses which lasted for 1 week and cross-sensitization to cocaine which was only evident after 1 week of withdrawal. Repeated treatment with the combination of the two agonists transiently down-regulated autoreceptor sensitivity, enhanced and prolonged D1 receptor supersensitivity (lasting 1 month), and produced enduring cross-sensitization to cocaine. These results suggest that neuroadaptations within both the VTA and NAc may be necessary for the induction of enduring cocaine sensitization.