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Opioid signaling in the nucleus accumbens shell (sNAcc) has been implicated in hedonic feeding and binge eating behavior. The sNAcc projects to the lateral hypothalamus (LH), and this pathway has been suggested to modulate palatability-driven feeding behavior. In this study, we investigated the effects of sNAcc mu opioid receptor (MOR) stimulation on firing rates of LH neurons in previously sated rats. Neural firing in the LH was recorded while food-deprived rats performed an operant task to obtain sweetened Intralipid (a 4% fat emulsion containing 5% sucrose) before and after bilateral sNAcc infusion of either a MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) or a saline control solution. During sessions in which saline was infused into the sNAcc, the number of trials completed after infusion were significantly lower than the number completed before infusion, likely reflecting animals' increased satiety state. During sessions in which DAMGO was infused into the sNAcc, the decrease in the number of trials completed (comparing post- vs. pre-infusion trials) was significantly attenuated. Electrophysiological recording showed that the percentage of LH neurons showing an excitatory response due to behavioral events (cue presentation, lever press, lever retraction, and consumption) was reduced in post vs. pre-saline infusion period. However, the percentage of LH neurons showing excitatory responses to the same behavioral events was similar in pre- and post-DAMGO infusion periods. These findings suggest that MOR stimulation in sNAcc leads to an increase in stimulus-evoked excitatory signaling in LH neurons which could contribute to preventing satiety-induced decline in palatable food intake.

Ethanol, like other drugs of abuse, has both rewarding and aversive properties. Previous work suggests that sensitivity to ethanol's aversive effects negatively modulates voluntary alcohol intake and thus may be important in vulnerability to developing alcohol use disorders. We previously found that rats with lesions of the lateral habenula (LHb), which is implicated in aversion-mediated learning, show accelerated escalation of voluntary ethanol consumption. To understand neural encoding in the LHb contributing to ethanol-induced aversion, we recorded neural firing in the LHb of freely behaving, water-deprived rats before and after an ethanol-induced (1.5 g kg−1 20% ethanol, IP) conditioned taste aversion (CTA) to saccharin taste. Ethanol-induced CTA strongly decreased motivation for saccharin in an operant task to obtain the tastant. Comparison of LHb neural firing before and after CTA induction revealed four main differences in firing properties. First, baseline firing after CTA induction was significantly higher. Second, firing evoked by cues signalling saccharin availability shifted from a pattern of primarily inhibition before CTA to primarily excitation after CTA induction. Third, CTA induction reduced the magnitude of lever press-evoked inhibition. Finally, firing rates were significantly higher during consumption of the devalued saccharin solution after CTA induction. Next, we studied sham- and LHb-lesioned rats in our operant CTA paradigm and found that LHb lesion significantly attenuated CTA effects in the operant task. Our data demonstrate the importance of LHb excitation in regulating expression of ethanol-induced aversion and suggest a mechanism for its role in modulating escalation of voluntary ethanol intake. This article is protected by copyright. All rights reserved

The goal of the present research was to assess the degree to which a pattern completion process operates in cue-induced relapse to cocaine-seeking behavior. Using a novel cue-preference version of the place preference task, rats were administered cocaine or saline, which resulted in a preference for the cocaine-paired cues. After 21 days of abstinence and prior to the preference test, for one group, PBS or naloxone was injected into the CA3 subregion of the hippocampus and for a second group, saline or naloxone was injected systemically. The results indicated that infusions of naloxone into CA3 or systemic injections produced a marked disruption for one and two cues, but had minimal disruptive effect for three or four cues, suggesting that naloxone injections disrupt CA3 function and trigger a deficit in a pattern completion process. Thus, it appears that cue-based activation of the dorsal CA3 might be a critical trigger via a pattern completion process. Based on additional analyses it appears that there is a disruption primarily for object touches for one cue naloxone injections into the CA3 or systemic injections, but no effect on time (spatial context). © 2016 Wiley Periodicals, Inc.

Preclinical studies demonstrate that repeated, high-dose methamphetamine administrations rapidly decrease plasmalemmal dopamine uptake, which may contribute to aberrant dopamine accumulation, reactive species generation, and long-term dopaminergic deficits. The present study extends these findings by demonstrating a heretofore unreported, epitope-specific modification in the dopamine transporter caused by a methamphetamine regimen that induces these deficits. Specifically, repeated, high-dose methamphetamine injections (4 × 10 mg/kg/injection, 2-h intervals) rapidly decreased immunohistochemical detection of striatal dopamine transporter as assessed 1 h after the final methamphetamine exposure. In contrast, neither a single high dose (1 × 10 mg/kg) nor repeated injections of a lower dose (4 × 2 mg/kg/injection) induced this change. The high-dose regimen-induced alteration was only detected using antibodies directed against the N-terminus. Immunohistochemical staining using antibodies directed against the C-terminus did not reveal any changes. The high-dose regimen also did not alter dopamine transporter expression as assessed using [(125) I]RTI-55 autoradiography. These data suggest that the repeated, high-dose methamphetamine regimen alters the N-terminus of the dopamine transporter. Further, these data may be predictive of persistent dopamine deficits caused by the stimulant. Future studies of the signaling cascades involved should provide novel insight into potential mechanisms underlying the physiological and pathophysiological regulation of the dopamine transporter.

Neurotoxic doses of methamphetamine (METH) are known to cause depletions in striatal dopamine (DA) tissue content. However, the effects of METH-induced insults on dopaminergic neurotransmission are not fully understood. Here, we employed fast-scan cyclic voltammetry at a carbon-fiber microelectrode in the anesthetized rat striatum to assess the effects of a neurotoxic regimen of METH on phasic and tonic modes of dopaminergic signaling and underlying mechanisms of DA release and uptake. Extracellular DA was electrically evoked by stimulation of the medial forebrain bundle mimicking tonic and phasic firing patterns for dopaminergic cells and was monitored simultaneously in both the dorsomedial and dorsolateral striatum. Kinetic analysis of evoked recordings determined parameters describing DA release and uptake. Striatal DA tissue content was quantified by high performance liquid chromatography with electrochemical detection. METH-pretreatment (four doses of 7.5 or 10.0 mg/kg s.c.) induced DA depletions of ~40% on average, which are reported in both striatal subregions. METH pretreatment significantly decreased the amplitude of signals evoked by phasic, but not tonic, stimulation. Parameters for DA release and uptake were also similarly reduced by ~40%, consistent with effects on evoked phasic-like responses and DA tissue content. Taken together, these results suggest that METH-pretreatment selectively diminishes phasic, but not tonic, dopaminergic signaling in the dorsal striatum.

The dorsal striatum is involved in motor-response learning, but the extent to which distinct populations of striatal efferent neurons are differentially involved in such learning is unknown. Activity-regulated, cytoskeleton-associated (Arc) protein is an effector immediate– early gene implicated in synaptic plasticity. We examined arc mRNA expression in striatopallidal vs. striatonigral efferent neurons in dorsomedial and dorsolateral striatum of rats engaged in reversal learning on a T-maze motor-response task. Male Sprague–Dawley rats learned to turn right or left for 3 days. Half of the rats then underwent reversal training. The remaining rats were yoked to rats undergoing reversal training, such that they ran the same number of trials but ran them as continued-acquisition trials. Brains were removed and processed using double-label fluorescent in situ hybridization for arc and preproenkephalin (PPE) mRNA. In the reversal, but not the continued-acquisition, group there was a significant relation between the overall arc mRNA signal in dorsomedial striatum and the number of trials run, with rats reaching criterion in fewer trials having higher levels of arc mRNA expression. A similar relation was seen between the numbers of PPE + and PPE – neurons in dorsomedial striatum with cytoplasmic arc mRNA expression. Interestingly, in behaviourally activated animals significantly more PPE – neurons had cytoplasmic arc mRNA expression. These data suggest that Arc in both striatonigral and striatopallidal efferent neurons is involved in striatal synaptic plasticity mediating motorresponse learning in the T-maze and that there is differential processing of arc mRNA in distinct subpopulations of striatal efferent neurons.

Substance P (SP) is a neuropeptide closely associated with basal ganglia dopaminergic neurons. Because some neuropeptide systems in the basal ganglia (i.e. neurotensin and metenkephalin) are differentially affected by treatment with low or high doses of methamphetamine, we determined if basal ganglia SP pathways were also differentially influenced in a dose-dependent manner by this psychostimulant. Employing in vivo microdialysis, it was observed that the lowdose (0.5 mg/kg) of methamphetamine increased the extracellular concentration of SP in the substantia nigra, but not in globus pallidus or striatum. In contrast, the high dose (10 mg/kg) of methamphetamine did not increase extracellular SP content in any of these structures. The effect of the low-dose methamphetamine treatment on nigral extracellular SP levels was blocked by pre-treatment with either a D1 or D2 antagonist. In addition, 12 h after similar methamphetamine treatments, a dose-dependent differential response in SP tissue levels occurred in some of the regions examined. When these changes occurred, the low dose of methamphetamine usually reduced, whereas the high dose increased, SP tissue content. This study demonstrated opposite responses of the basal ganglia SP system to low and high doses of methamphetamine and suggested that a combination of dopamine D1 and D2 receptor activity contributed to these effects.

We and others previously reported that equimolar doses of methamphetamine and cocaine differentially increase preprodynorphin mRNA in striatum: methamphetamine causes a patchy increase, whereas cocaine produces a more homogenous one. The current study directly examined whether this effect reflects differential induction in the patch–matrix division of striatum, as identified by µ opioid receptor immunohistochemistry. In addition, we determined whether doses of cocaine (30 mg/kg) and methamphetamine (2 mg/kg) that produced equivalent increases in extracellular dopamine differentially affected preprodynorphin mRNA expression in striatum of male, Sprague–Dawley rats. In both experiments, methamphetamine and cocaine differentially affected preprodynorphin mRNA in striatum after 3 h. The high, equimolar dose of methamphetamine selectively increased preprodynorphin mRNA in the patch division of rostral striatum, whereas cocaine increased preprodynorphin mRNA throughout patch and matrix divisions of striatum. In contrast, a dose of methamphetamine (2.0 mg/kg) that caused an increase in extracellular dopamine similar to that produced by 30 mg/kg cocaine did not significantly affect preprodynorphin mRNA in any region of striatum. These data provide further evidence that cocaine and amphetamines exert distinct effects on the patch–matrix division of striatum and suggest further that the post-synaptic consequences of elevated extracellular dopamine produced by methamphetamine and cocaine are distinct.

Microdialysis was used to assess extracellular dopamine in striatum, nucleus accumbens, and medial frontal cortex of unanesthetized rats both under resting conditions and in response to intermittent tail-shock stress. The dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid also were measured. The resting extracellular concentration of dopamine was estimated to be approximately 10 nM in striatum, 11 nM in nucleus accumbens, and 3 nM in medial frontal cortex. In contrast, the resting extracellular levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid were in the low micromolar range. Intermittent tail-shock stress increased extracellular dopamine relative to baseline by 25% in striatum, 39% in nucleus accumbens, and 95% in medial frontal cortex. 3,4-Dihydroxyphenylacetic acid and homovanillic acid also were generally increased by stress, although there was a great deal of variability in these responses. These data provide direct in vivo evidence for the global activation of dopaminergic systems by stress and support the concept that there exist regional variations in the regulation of dopamine release.