Until recently, most modern neuroscience research on addiction using animal models did not incorporate manipulations of social factors. Social factors play a critical role in human addiction: social ...isolation and exclusion can promote drug use and relapse, while social connections and inclusion tend to be protective. Here, we discuss the state of the literature on social factors in animal models of opioid and psychostimulant preference, self-administration, and relapse. We first summarize results from rodent studies on behavioral, pharmacological, and circuit mechanisms of the protective effect of traditional experimenter-controlled social interaction procedures on opioid and psychostimulant conditioned place preference, self-administration, and relapse. Next, we summarize behavioral and brain-mechanism results from studies using newer operant social-interaction procedures that inhibit opioid and psychostimulant self-administration and relapse. We conclude by discussing how the reviewed studies point to future directions for the addiction field and other neuroscience and psychiatric fields, and their implications for mechanistic understanding of addiction and development of new treatments.
In this review, we propose that incorporating social factors into modern neuroscience research on addiction could improve mechanistic accounts of addiction and help close gaps in translating discovery to treatment. We first summarize rodent studies on behavioral, pharmacological, and circuit mechanisms of the protective effect of both traditional experimenter-controlled and newer operant social-interaction procedures. We then discuss potential future directions and clinical implications.
The dorsal raphe nucleus (DRN) contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that ...serotonin inhibits reward seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and nonserotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via nonserotonergic neurons, for which the main projection target is the ventral tegmental area (VTA). Furthermore, these nonserotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.
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•Stimulation of nonserotonergic neurons in the DRN is highly rewarding•The majority of projections from DRN to VTA are nonserotonergic•Nonserotonergic DRN neurons provide glutamatergic input to VTA dopamine neurons•Optogenetic/pharmacological stimulation of DRN serotonin is not highly rewarding
The majority of the brain’s serotonin neurons are found in the dorsal raphe nucleus, a brain region in which the influence over reward learning has proven enigmatic. Although drugs that enhance serotonin function have minimal abuse liability, laboratory rats will work vigorously to earn electrical stimulation of the dorsal raphe nucleus. In this study, McDevitt et al. explore nonserotonergic cell populations of the dorsal raphe nucleus, examining their ability to reinforce behavior and control the firing of midbrain dopamine neurons.
Individuals suffering from substance use disorder often experience relapse events that are attributed to drug craving. Insular cortex (IC) function is implicated in processing drug‐predictive cues ...and is thought to be a critical substrate for drug craving, but the downstream neural circuit effectors of the IC that mediate reward processing are poorly described. Here, we uncover the functional connectivity of an IC projection to the ventral bed nucleus of the stria terminalis (vBNST), a portion of the extended amygdala that has been previously shown to modulate dopaminergic activity within the ventral tegmental area (VTA), and investigate the role of this pathway in reward‐related behaviors. We utilized ex vivo slice electrophysiology and in vivo optogenetics to examine the functional connectivity of the IC‐vBNST projection and bidirectionally control IC‐vBNST terminals in various reward‐related behavioral paradigms. We hypothesized that the IC recruits mesolimbic dopamine signaling by activating VTA‐projecting, vBNST neurons. Using slice electrophysiology, we found that the IC sends a glutamatergic projection onto vBNST‐VTA neurons. Photoactivation of IC‐vBNST terminals was sufficient to reinforce behavior in a dopamine‐dependent manner. Moreover, silencing the IC‐vBNST projection was aversive and resulted in anxiety‐like behavior without affecting food consumption. This work provides a potential mechanism by which the IC processes exteroceptive triggers that are predictive of reward.
This work provides a potential mechanism by which the insular cortex (IC) modulates reward‐related behavior through a projection to the ventral bed nucleus of the stria terminalis (vBNST).
Glutamate has been implicated in a wide range of brain pathologies and is thought to be metabolized via the astrocyte-specific enzyme glutamine synthetase (GS). We show here that oligodendrocytes, ...the myelinating glia of the central nervous system, also express high levels of GS in caudal regions like the midbrain and the spinal cord. Selective removal of oligodendrocyte GS in mice led to reduced brain glutamate and glutamine levels and impaired glutamatergic synaptic transmission without disrupting myelination. Furthermore, animals lacking oligodendrocyte GS displayed deficits in cocaine-induced locomotor sensitization, a behavior that is dependent on glutamatergic signaling in the midbrain. Thus, oligodendrocytes support glutamatergic transmission through the actions of GS and may represent a therapeutic target for pathological conditions related to brain glutamate dysregulation.
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•Oligodendrocytes (OLs) express glutamine synthetase (GS)•OL GS expression is low in rostral regions and high in caudal regions of the brain•OLs do not require GS for survival or myelination•Loss of OL GS disrupts neuronal glutamate signaling and glutamate-dependent behavior
Xin et al. show that mature oligodendrocytes, the myelinating cells of the brain, express the glutamine-synthesizing enzyme glutamine synthetase (GS). Oligodendrocyte-specific GS deletion does not impair myelination but disrupts neuronal glutamatergic transmission, thus demonstrating a myelin-independent role for oligodendrocytes in supporting glutamate signaling in the brain.
Modifications in brain regions that govern reward-seeking are thought to contribute to persistent behaviors that are heavily associated with alcohol-use disorder (AUD) including binge ethanol ...drinking. The bed nucleus of the stria terminalis (BNST) is a critical node linked to both alcohol consumption and the onset, maintenance and progression of adaptive anxiety and stress-related disorders. Differences in anatomy, connectivity and receptor subpopulations, make the BNST a sexually dimorphic region. Previous work indicates that the ventral BNST (vBNST) receives input from the insular cortex (IC), a brain region involved in processing the body's internal state. This IC-vBNST projection has also been implicated in emotional and reward-seeking processes. Therefore, we examined the functional properties of vBNST-projecting, IC neurons in male and female mice that have undergone short-term ethanol exposure and abstinence using a voluntary Drinking in the Dark paradigm (DID) paired with whole-cell slice electrophysiology. First we show that IC neurons projected predominantly to the vBNST. Next, our data show that short-term ethanol exposure and abstinence enhanced excitatory synaptic strength onto vBNST-projecting, IC neurons in both sexes. However, we observed diametrically opposing modifications in excitability across sexes. In particular, short-term ethanol exposure resulted in increased intrinsic excitability of vBNST-projecting, IC neurons in females but not in males. Furthermore, in females, abstinence decreased the excitability of these same neurons. Taken together these findings show that short-term ethanol exposure, as well as the abstinence cause sex-related adaptations in BNST-projecting, IC neurons.
•Binge ethanol consumption and abstinence enhances excitatory synaptic strength in vBNST-projecting IC neurons.•Binge ethanol consumption increases the excitability of vBNST-projecting IC neurons only in female mice.•Abstinence from binge ethanol consumption decreases the excitability of vBNST-projecting IC neurons only in female mice.
Binge ethanol drinking is an increasingly problematic component of alcohol use disorder costing the United States approximately over $150 billion every year and causes progressive neuroplasticity ...alterations in numerous brain regions. However, the precise nature or machinery that underlies binge drinking has not yet been elucidated. Corticotropin releasing factor (CRF) neurons in the central amygdala (CeA) are thought to modulate binge drinking, but the specific circuit mechanisms remain poorly understood. Here, we combined optogenetics with in vivo electrophysiology to identify and record from CeA CRF neurons in mice during a repeated binge ethanol drinking task. First, we found that CeA CRF neurons were more active than CeA non-CRF cells during our binge drinking paradigm. We also observed that CeA CRF neurons displayed a heterogeneous spectrum of responses to a lick of ethanol including, pre-lick activated, lick-excited, lick-inhibited, and no response. Interestingly, pre-lick activated CeA CRF neurons exhibited higher frequency and burst firing during binge drinking sessions. Moreover, their overall tonic and phasic electrical activity enhances over repeated binge drinking sessions. Remarkably, CeA CRF units and pre-lick activated CeA CRF neurons did not show higher firing rate or bursting activity during water and sucrose consumption, suggesting that ethanol may “hijack” or plastically alter their intrinsic excitability.
This article is part of the special issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse’.
•Optical identification and recording of CeA CRF neurons in freely behaving mice.•CeA CRF neurons display heterogeneous firing profiles in response to ethanol.•CeA CRF pre-lick neurons show enhanced excitability and bursting compared to other CeA CRF and CeA non CRF cells.
•Early environmental experience and behavioral reactivity in female rats.•Early handling manipulation interferes positively with the acquisition of declarative memory.•A brief early manipulation ...induces an improvement in reference and working memory.•Early handling increases maternal care thus ameliorating behavioral flexibility and cognitive performance.
This study aims at providing an insight into early handling procedures on learning and memory performance in adult female rats. Early handling procedures were started on post-natal day 2 until 21, and consisted in 15min, daily separations of the dams from their litters. Assessment of declarative memory was carried out in the novel-object recognition task; spatial learning, reference- and working memory were evaluated in the Morris water maze (MWM). Our results indicate that early handling induced an enhancement in: (1) declarative memory, in the object recognition task, both at 1h and 24h intervals; (2) reference memory in the probe test and working memory and behavioral flexibility in the “single-trial and four-trial place learning paradigm” of the MWM. Short-term separation by increasing maternal care causes a dampening in HPA axis response in the pups. A modulated activation of the stress response may help to protect brain structures, involved in cognitive function. In conclusion, this study shows the long-term effects of a brief maternal separation in enhancing object recognition-, spatial reference- and working memory in female rats, remarking the impact of early environmental experiences and the consequent maternal care on the behavioral adaptive mechanisms in adulthood.
Electrical or optogenetic stimulation of lateral hypothalamic (LH) GABA neurons induces rapid vigorous eating in sated animals. The dopamine system has been implicated in the regulation of feeding. ...Previous work has suggested that a subset of LH GABA neurons projects to the ventral tegmental area (VTA) and targets GABA neurons, inhibiting them and thereby disinhibiting dopaminergic activity and release. Furthermore, stimulation-induced eating is attenuated by dopamine lesions or receptor antagonists. Here we explored the involvement of dopamine in LH stimulation-induced eating. LH stimulation caused sated mice to pick up pellets of standard chow with latencies that varied based on stimulation intensity; once food was picked up, animals ate for the remainder of the 60-s stimulation period. However, lesion of VTA GABA neurons failed to disrupt this effect. Moreover, direct stimulation of VTA or substantia nigra dopamine cell bodies failed to induce food approach or eating. Looking further, we found that some LH GABA fibers pass through the VTA to more caudal sites, where they synapse onto neurons near the locus coeruleus (LC). Similar eating was induced by stimulation of LH GABA terminals or GABA cell bodies in this peri-LC region. Lesion of peri-LC GABA neurons blocked LH stimulation-induced eating, establishing them as a critical downstream circuit element for LH neurons. Surprisingly, lesions did not alter body weight, suggesting that this system is not involved in the hunger or satiety mechanisms that govern normal feeding. Thus, we present a characterization of brain circuitry that may promote overeating and contribute to obesity.
Methamphetamine (METH) is a highly addictive psychostimulant. The continuous use of METH may lead to its abuse and neurotoxicity that have been associated with METH-induced increases in release of ...dopamine (DA) and glutamate in the brain. METH action in DA has been shown to be mediated by redistribution of DA from vesicles into cytoplasm via vesicular monoamine transporter 2 (VMAT2) and the subsequent reversal of membrane DA transporter (DAT), while little is known about the mechanisms underlying METH-induced glutamate release. Recent studies indicate that a subpopulation of midbrain DA neurons co-expresses VMAT2 and vesicular glutamate transporter 2 (VGLUT2). Therefore, we hypothesized that METH-induced glutamate release may in part originate from such a dual phenotype of DA neurons. To test this hypothesis, we used Cre-LoxP techniques to selectively delete VGLUT2 from midbrain DA neurons, and then examined nucleus accumbens (NAc) DA and glutamate responses to METH using in vivo brain microdialysis between DA-VGLUT2-KO mice and their VGLUT2-HET littermates. We found that selective deletion of VGLUT2 from DA neurons did not significantly alter basal levels of extracellular DA and glutamate, but attenuated METH-induced increases in extracellular levels of DA and glutamate. In addition, DA-VGLUT2-KO mice also displayed lower locomotor response to METH than VGLUT2-HET control mice. These findings, for the first time, suggest that cell-type specific VGLUT2 expression in DA neurons plays an important role in the behavioral and neurochemical effects of METH. Glutamate corelease from DA neurons may in part contributes to METH-induced increase in NAc glutamate release.
•Methamphetamine co-releases DA and glutamate, while the underlying mechanisms are unclear.•VGLUT2 and VMAT2 are colocalized in a subpopulation of DA neurons and promote DA and glutamate update into vesicles.•Deletion of VGLUT2 from DA neurons attenuates behavioral and neurochemical responses to methamphetamine.•These findings suggest that methamphetamine-enhanced DA/glutamate release may be in part derived from DA neurons.
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