Medial prefrontal cortex circuit dynamics involved in stage-specific addiction.

Neurobiology of Addiction

AMPA Receptor Synaptic Plasticity Induced by Psychostimulants: The Past, Present, and Therapeutic Future

Nicotine enhances responding for conditioned reinforcement via α4β2 nicotinic acetylcholine receptors in the ventral tegmental area, but not the nucleus accumbens or the prefrontal cortex

Dopamine (DA) neurons in the ventral tegmental area (VTA) are predicted to play important roles in reward. In pharmacological studies, the rewarding effects of methamphetamine are mediated by DA neurons localized in the VTA. The nucleus accumbens (NAc) and medial prefrontal cortices (mPFC) are the main projections from the VTA. However, the role of these projections remains unclear, particularly the mPFC projections. In the present study, DAT-Cre transgenic mice received an injection of adeno-associated viral vectors encoding channelrhodopsin2 (ChR2) or control vector into the VTA resulting in the selective expression of these opsins in DA neurons. Then, we stimulated the VTA, NAc (core and shell) or mPFC (prelimbic cortex (PL) and infralimbic cortex (IL)) via an optical fiber. The mice with ChR2 learned instrumental responses corresponding to the delivery of photostimulation into the VTA. The projections to the NAc core and shell from the VTA and stimulation of the NAc subregion both induced reinforcement. For projections to the mPFC (IL and PL), we verified that stimulation of the IL induced reinforcement dependent on DA from the VTA but not the PL. Furthermore, micro-infusion of methamphetamine into the NAc core and NAc shell also induced hyper-locomotion in a dose-dependent manner with a slight tendency of increased excitation of the IL but not PL. Taken together, excitation of the projection into the NAc core, NAc shell and IL elicited positive behavior during reward.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are predicted to play important roles in reward. In pharmacological studies, the rewarding effects of methamphetamine are mediated by DA neurons localized in the VTA. The nucleus accumbens (NAc) and medial prefrontal cortices (mPFC) are the main projections from the VTA. However, the role of these projections remains unclear, particularly the mPFC projections. In the present study, DAT-Cre transgenic mice received an injection of adeno-associated viral vectors encoding channelrhodopsin2 (ChR2) or control vector into the VTA resulting in the selective expression of these opsins in DA neurons. Then, we stimulated the VTA, NAc (core and shell) or mPFC (prelimbic cortex (PL) and infralimbic cortex (IL)) via an optical fiber. The mice with ChR2 learned instrumental responses corresponding to the delivery of photostimulation into the VTA. The projections to the NAc core and shell from the VTA and stimulation of the NAc subregion both induced reinforcement. For projections to the mPFC (IL and PL), we verified that stimulation of the IL induced reinforcement dependent on DA from the VTA but not the PL. Furthermore, micro-infusion of methamphetamine into the NAc core and NAc shell also induced hyper-locomotion in a dose-dependent manner with a slight tendency of increased excitation of the IL but not PL. Taken together, excitation of the projection into the NAc core, NAc shell and IL elicited positive behavior during reward.

The rat prelimbic prefrontal cortex and nucleus accumbens core are critical for initiating cocaine seeking. In contrast, the neural circuitry responsible for inhibiting cocaine seeking during extinction is unknown. The present findings using inhibition of selected brain nuclei with GABA agonists show that the suppression of cocaine seeking produced by previous extinction training required activity in the rat infralimbic cortex. Conversely, the reinstatement of drug seeking by a cocaine injection in extinguished animals was suppressed by increasing neuronal activity in infralimbic cortex with the glutamate agonist AMPA. The cocaine seeking induced by inactivating infralimbic cortex resembled other forms of reinstated drug seeking by depending on activity in prelimbic cortex and the basolateral amygdala. A primary efferent projection from the infralimbic cortex is to the nucleus accumbens shell. Akin to infralimbic cortex, inhibition of the accumbens shell induced cocaine seeking in extinguished rats. However, bilateral inhibition of the shell also elicited increased locomotor activity. Nonetheless, unilateral inhibition of the accumbens shell did not increase motor activity, and simultaneous unilateral inactivation of the infralimbic cortex and shell induced cocaine seeking, suggesting that an interaction between these two structures is necessary for extinction training to inhibit cocaine seeking. The infralimbic cortex and accumbens shell appear to be recruited by extinction learning because inactivation of these structures before extinction training did not alter cocaine seeking. Together, these findings suggest that a neuronal network involving the infralimbic cortex and accumbens shell is recruited by extinction training to suppress cocaine seeking.

Internet Sex Addiction Treated With Naltrexone

Leptin Regulation of the Mesoaccumbens Dopamine Pathway

Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies

If I do A, B will happen: Dissecting circuits detecting causal relations between actions and outcomes in marmoset prefrontal cortex

Chronic stress alters neural activity in medial prefrontal cortex during retrieval of extinction

Understanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine's conditioning, and the neutral states via saccharin extinction processes after morphine's conditioning. All rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus. The results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning. Altogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

The medial prefrontal cortex has been associated with diverse functions including attentional processes, visceromotor activity, decision-making, goal-directed behavior, and working memory. The present report compares and contrasts projections from the infralimbic (IL) and prelimbic (PL) cortices in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris-leucoagglutinin. With the exception of common projections to parts of the orbitomedial prefrontal cortex, olfactory forebrain, and midline thalamus, PL and IL distribute very differently throughout the brain. Main projection sites of IL are: 1) the lateral septum, bed nucleus of stria terminalis, medial and lateral preoptic nuclei, substantia innominata, and endopiriform nuclei of the basal forebrain; 2) the medial, basomedial, central, and cortical nuclei of amygdala; 3) the dorsomedial, lateral, perifornical, posterior, and supramammillary nuclei of hypothalamus; and 4) the parabrachial and solitary nuclei of the brainstem. By contrast, PL projects at best sparingly to each of these structures. Main projection sites of PL are: the agranular insular cortex, claustrum, nucleus accumbens, olfactory tubercle, the paraventricular, mediodorsal, and reuniens nuclei of thalamus, the capsular part of the central nucleus and the basolateral nucleus of amygdala, and the dorsal and median raphe nuclei of the brainstem. As discussed herein, the pattern of IL projections is consistent with a role for IL in the control of visceral/autonomic activity homologous to the orbitomedial prefrontal cortex of primates, whereas those of PL are consistent with a role for PL in limbic-cognitive functions homologous to the dorsolateral prefrontal cortex of primates.

SummaryMonoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Prefrontal Cortex Modulates Desire and Dread Generated by Nucleus Accumbens Glutamate Disruption