Stephanie F. Bishop

Cannabinoid Transmission in the Basolateral Amygdala Modulates Fear Memory Formation via Functional Inputs to the Prelimbic Cortex

The cannabinoid CB1 receptor system is critically involved in the control of associative fear memory formation within the amygdala–prefrontal cortical pathway. The CB1 receptor is found in high concentrations in brain structures that are critical for emotional processing, including the basolateral amygdala (BLA) and the prelimbic division (PLC) of the medial prefrontal cortex (mPFC). However, the precise role of CB1 receptor transmission within the BLA during the processing of fear memory is not fully understood. We examined the potential role of BLA CB1 receptor transmission during an olfactory fear-conditioning procedure in rats by pharmacologically modulating CB1 cannabinoid transmission directly within the BLA. We report that blockade of BLA CB1 receptor transmission prevents the acquisition of associative fear memory, while having no effect on the recall or consolidation of these memories. In contrast, intra-BLA activation of CB1 receptor transmission or blockade of endocannabinoid reuptake strongly potentiated the emotional salience of normally subthreshold fear-conditioning stimuli. In addition, pharmacological inactivation of the mPFC before intra-BLA CB1 activation blocked CB1-receptor-mediated potentiation of fear memory formation. In vivo single-unit electrophysiological recordings within the PLC revealed that modulation of BLA CB1 receptor transmission strongly influences neuronal activity within subpopulations of PLC neurons, with blockade of intra-BLA CB1 receptor transmission inhibiting spontaneous PLC neuronal activity and activation of CB1 receptors producing robust activation, in terms of neuronal firing frequency and bursting activity. Thus, cannabinoid transmission within the BLA strongly modulates the processing of associative fear memory via functional interactions with PLC neuronal populations.

Integrated Cannabinoid CB1 Receptor Transmission within the Amygdala–Prefrontal Cortical Pathway Modulates Neuronal Plasticity and Emotional Memory Encoding

The cannabinoid CB1 receptor system is functionally involved in the processing and encoding of emotionally salient sensory information, learning and memory. The CB1 receptor is found in high concentrations in brain structures that are critical for emotional processing, including the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC). In addition, synaptic plasticity in the form of long-term potentiation (LTP) within the BLA > mPFC pathway is an established correlate of exposure to emotionally salient events. We performed a series of in vivo LTP studies by applying tetanic stimulation to the BLA combined with recordings of local field potentials within prelimbic cortical (PLC) region of the rat mPFC. Systemic pretreatment with AM-251 dose dependently blocked LTP along the BLA-PLC pathway and also the behavioral acquisition of conditioned fear memories. We next performed a series of microinfusion experiments wherein CB1 receptor transmission within the BLA > PLC circuit was pharmacologically blocked. Asymmetrical, interhemispheric blockade of CB1 receptor transmission along the BLA > PLC pathway prevented the acquisition of emotionally salient associative memory. Our results indicate that coordinated CB1 receptor transmission within the BLA > PLC pathway is critically involved in the encoding of emotional fear memories and modulates neural plasticity related to the encoding of emotionally salient associative learning.

Identification of a Dopamine Receptor-Mediated Opiate Reward Memory Switch in the Basolateral Amygdala–Nucleus Accumbens Circuit

The basolateral amygdala (BLA), ventral tegmental area (VTA), and nucleus accumbens (NAc) play central roles in the processing of opiate-related associative reward learning and memory. The BLA receives innervation from dopaminergic fibers originating in the VTA, and both dopamine (DA) D1 and D2 receptors are expressed in this region. Using a combination of in vivo single-unit extracellular recording in the NAc combined with behavioral pharmacology studies, we have identified a double dissociation in the functional roles of DA D1 versus D2 receptor transmission in the BLA, which depends on opiate exposure state; thus, in previously opiate-naive rats, blockade of intra-BLA D1, but not D2, receptor transmission blocked the acquisition of associative opiate reward memory, measured in an unbiased conditioned place preference procedure. In direct contrast, in rats made opiate dependent and conditioned in a state of withdrawal, intra-BLA D2, but not D1, receptor blockade blocked opiate reward encoding. This functional switch was dependent on cAMP signaling as comodulation of intra-BLA cAMP levels reversed or replicated the functional effects of intra-BLA D1 or D2 transmission during opiate reward processing. Single-unit in vivo extracellular recordings performed in neurons of the NAc confirmed an opiate-state-dependent role for BLA D1/D2 transmission in NAc neuronal response patterns to morphine. Our results characterize and identify a novel opiate addiction switching mechanism directly in the BLA that can control the processing of opiate reward information as a direct function of opiate exposure state via D1 or D2 receptor signaling substrates.

Dopamine D1 versus D4 Receptors Differentially Modulate the Encoding of Salient versus Nonsalient Emotional Information in the Medial Prefrontal Cortex

Dopamine (DA) transmission plays a critical role in the processing of emotionally salient information and in associative learning and memory processes. Within the mammalian brain, neurons within the medial prefrontal cortex (mPFC) are involved critically in the encoding, expression, and extinction of emotionally salient learned information. Within the mPFC, dopaminergic transmission is involved importantly in controlling attentional and motivational processes, particularly within the context of emotionally salient sensory information. Considerable evidence suggests differential roles for DA D1-like versus D2-like receptors, including the D4 receptor subtype, in the regulation of neuronal activity and emotional processing within the mPFC. Using an olfactory fear-conditioning assay in rats, we compared the roles of DA D1 versus D4 receptor activation during the encoding and recall phases of emotional learning and memory. We report that specific activation of DA D4 receptors within the mPFC strongly potentiates the salience of normally nonsalient emotional associative fear memories and blocks the encoding of suprathreshold conditioned fear associations. However, D4 receptor activation has no effect on the recall of previously learned emotionally salient conditioned memories. In contrast, intra-mPFC D1 receptor activation failed to increase the emotional salience of subthreshold fear stimuli but completely blocked the expression of previously learned emotionally relevant information, demonstrating that DA D4 versus D1 subtype receptor transmission within the mPFC plays distinct functional roles in the processing of emotionally salient versus nonsalient associative information and differentially modulates the encoding versus recall phases of emotional memory within the mPFC.

Dopamine Signaling through D1-Like versus D2-Like Receptors in the Nucleus Accumbens Core versus Shell Differentially Modulates Nicotine Reward Sensitivity

Considerable evidence implicates the mesolimbic dopamine (DA) system in the processing of nicotines reinforcing properties, specifically the ventral tegmental area (VTA) and the terminal fields of VTA DAergic projections to the “core” (NAcore) and “shell” (NAshell) subdivisions of the nucleus accumbens (NAc). However, the specific roles of DA D1-like and D2-like receptor subtypes in nicotine reward processing within these NAc subregions have not been elucidated. We report that microinfusions of DA D1-like or D2-like receptor-specific antagonists into NAcore or NAshell double dissociate the rewarding and aversive properties of systemic or intra-VTA nicotine, and differentially regulate sensitivity to the rewarding properties as well as the motivational valence of either intra-VTA or systemic nicotine administration. Using a place conditioning procedure, NAshell infusions of a D2-like receptor antagonist switched the motivational valence of intra-VTA nicotine from aversive to rewarding and potentiated nicotine reward sensitivity to sub-reward threshold intra-VTA nicotine doses. In contrast, NAcore infusions of a D1-like receptor antagonist switched intra-VTA nicotine aversion to reward, and potentiated reward sensitivity to sub-reward threshold nicotine doses. Thus, D1-like versus D2-like receptors in NAcore versus NAshell subdivisions play functionally dissociable roles in modulating systemic or intra-VTA nicotine motivational processing.

NMDA Receptor Hypofunction in the Prelimbic Cortex Increases Sensitivity to the Rewarding Properties of Opiates via Dopaminergic and Amygdalar Substrates

The medial prefrontal cortex (mPFC) plays a significant role in associative learning and memory formation during the opiate addiction process. Various lines of evidence demonstrate that glutamatergic (GLUT) transmission through the N-methyl D-aspartate (NMDA) receptor can modulate neuronal network activity within the mPFC and influence dopaminergic signaling within the mesocorticolimbic pathway. However, little is known about how modulation of NMDA receptor signaling within the mPFC may regulate associative opiate reward learning and memory formation. Using a conditioned place preference (CPP) procedure, we examined the effects of selective NMDA receptor blockade directly within the prelimbic cortex (PLC) during the acquisition of associative opiate reward learning. NMDA receptor blockade specifically within the PLC caused a strong potentiation in the rewarding effects of either systemic or intra-ventral tegmental area (intra-VTA) morphine administration. This reward potentiation was dose dependently blocked by coadministration of dopamine D1 or D2 receptor antagonists and by blockade of presynaptic GLUT release. In addition, pharmacological inactivation of the basolateral amygdala (BLA) also prevented intra-PLC NMDA receptor blockade-induced potentiation of opiate reward signals, demonstrating a functional interaction between inputs from the VTA and BLA within the PLC, during the encoding and modulation of associative opiate reward information.

Inputs from the basolateral amygdala to the nucleus accumbens shell control opiate reward magnitude via differential dopamine D1 or D2 receptor transmission

The basolateral amygdala (BLA), ventral tegmental area and nucleus accumbens (NAc) form a functionally connected neural circuit involved in the processing of opiate‐related reward and memory. Dopamine (DA) projections from the ventral tegmental area to the BLA modulate associative plasticity mechanisms within the BLA. However, the role of DA receptor signaling in the BLA and its functional outputs to the NAc during opiate reward processing is not currently understood. Using an unbiased place conditioning procedure, we measured the rewarding effects of morphine following intra‐BLA microinfusions of specific DA D1 or D2 receptor agonists in either opiate‐naive or opiate‐dependent/withdrawn rats. Activation of intra‐BLA D1 receptors strongly potentiated the behaviorally rewarding effects of opiates, only in the opiate‐naive state. However, once opiate dependence and withdrawal occurred, the intra‐BLA DA‐mediated potentiation of opiate reward salience switched to a D2 receptor‐dependent substrate. We next performed single‐unit, in‐vivo extracellular neuronal recordings in the NAc shell (NA shell), to determine if intra‐BLA D1/D2 receptor activation may modulate the NA shell neuronal response patterns to morphine. Consistent with our behavioral results, intra‐BLA D1 or D2 receptor activation potentiated NAc ‘shell’ (NA shell) neuronal responses to sub‐reward threshold opiate administration, following the same functional boundary between the opiate‐naive and opiate‐dependent/withdrawn states. Finally, blockade of N‐methyl‐d‐aspartate transmission within the NA shell blocked intra‐BLA DA D1 or D2 receptor‐mediated opiate reward potentiation. Our findings demonstrate a novel and functional DA D1/D2 receptor‐mediated opiate reward memory switch within the BLA→NA shell circuit that controls opiate reward magnitude as a function of opiate exposure state.

Acquisition, extinction, and recall of opiate reward memory are signaled by dynamic neuronal activity patterns in the prefrontal cortex.

The medial prefrontal cortex (mPFC) comprises an important component in the neural circuitry underlying drug-related associative learning and memory processing. Neuronal activation within mPFC circuits is correlated with the recall of opiate-related drug-taking experiences in both humans and other animals. Using an unbiased associative place conditioning procedure, we recorded mPFC neuronal populations during the acquisition, recall, and extinction phases of morphine-related associative learning and memory. Our analyses revealed that mPFC neurons show increased activity both in terms of tonic and phasic activity patterns during the acquisition phase of opiate reward-related memory and demonstrate stimulus-locked associative activity changes in real time, during the recall of opiate reward memories. Interestingly, mPFC neuronal populations demonstrated divergent patterns of bursting activity during the acquisition versus recall phases of newly acquired opiate reward memory, versus the extinction of these memories, with strongly increased bursting during the recall of an extinction memory and no associative bursting during the recall of a newly acquired opiate reward memory. Our results demonstrate that neurons within the mPFC are involved in both the acquisition, recall, and extinction of opiate-related reward memories, showing unique patterns of tonic and phasic activity patterns during these separate components of the opiate-related reward learning and memory recall.

Chronic nicotine exposure switches the functional role of mesolimbic dopamine transmission in the processing of nicotine's rewarding and aversive effects

The mammalian ventral tegmental area (VTA) and associated mesolimbic dopamine (DA) system are critical neural substrates for processing nicotines motivational effects. Considerable evidence suggests that the role of DA transmission may be altered as a function of nicotine exposure. Using a combination of in vivo neuronal recording and behavioral conditioning, we report that chronic nicotine exposure induces a functional switch in the role of mesolimbic DA transmission. Thus, in nicotine-naive subjects, blockade of DA transmission potentiates the rewarding effects of sub-reward-threshold doses of nicotine and reverses the motivational valence of nicotine from aversive to rewarding. However, in animals treated chronically with nicotine, DA blockade switches previously sub-reward-threshold or rewarding doses of nicotine into aversion signals. Neuronal VTA recordings similarly revealed a functional switch in this DAergic neuronal circuit resulting in strongly increased sensitivity of the VTA DAergic system to nicotine administration and a tonic reduction in the baseline activity of VTA DAergic neurons. These results demonstrate a functional switch in the role of DAergic transmission during the acute versus chronic phases of nicotine exposure and suggest that mesolimbic DA transmission plays qualitatively distinct roles in the processing of nicotines motivational effects as a function of drug exposure.