Psychoactive substance use is a nearly universal human behavior, but a significant minority of people who use addictive substances will go on to develop an addictive disorder. Similarly, though ∼90% of people experience traumatic events in their lifetime, only ∼10% ever develop post-traumatic stress disorder (PTSD). Substance use disorders (SUD) and PTSD are highly comorbid, occurring in the same individual far more often than would be predicted by chance given the respective prevalence of each disorder. Some possible reasons that have been proposed for the relationship between PTSD and SUD are self-medication of anxiety with drugs or alcohol, increased exposure to traumatic events due to activities involved in acquiring illegal substances, or addictive substances altering the brain's stress response systems to make users more vulnerable to PTSD. Yet another possibility is that some people have an intrinsic vulnerability that predisposes them to both PTSD and SUD. In this review, we integrate clinical and animal data to explore these possible etiological links between SUD and PTSD, with an emphasis on interactions between dopaminergic, adrenocorticotropic, GABAergic, and glutamatergic neurobehavioral mechanisms that underlie different emotional learning styles.

Rationale: Prior research suggests that inputs from the lateral hypothalamic area (LHA) to the paraventricular nucleus of the thalamus (PVT) contribute to the attribution of incentive salience to Pavlovian-conditioned reward cues. However, a causal role for the LHA in this phenomenon has not been demonstrated. In addition, it is unknown which hypothalamic neurotransmitter or peptide system(s) are involved in mediating incentive salience attribution.Objectives: To examine: 1) the role of the LHA in the propensity to attribute incentive salience to reward cues, and 2) the role of orexinergic signaling in the PVT on the expression of Pavlovian conditioned approach (PavCA) behavior, a reflection of incentive salience attribution. Methods: Male Sprague-Dawley rats received bilateral excitotoxic lesions of the LHA prior to the acquisition of Pavlovian conditioned approach (PavCA) behavior. A separate cohort of male rats acquired PavCA behavior and were characterized as sign-trackers (STs) or goal-trackers (GTs) based on their conditioned response. The orexin 1 receptor (OX1r) antagonist SB-334867, or the orexin 2 receptor (OX2r) antagonist TCS-OX2-29, were then administered directly into the PVT to assess the effects of these pharmacological agents on the expression of PavCA behavior and on the conditioned reinforcing properties of the Pavlovian reward cue. Results: Lesions of the LHA before training attenuated the development of leverdirected (sign-tracking) behaviors in the PavCA paradigm, without affecting magazinedirected (goal-tracking) behaviors. In STs, administration of the OX1r antagonist into the PVT reduced lever-directed behaviors and increased magazine-directed behaviors; while administration of the OX2r antagonist only reduced lever-directed behaviors.Further, OX2r, but not OX1r, antagonism was able to reduce the incentive motivational value of the conditioned stimulus on a conditioned reinforcement test in STs. The behavior of GTs was unaffected by orexinergic antagonism in the PVT. Conclusions:The LHA is necessary for the attribution of incentive salience to reward cues and, thereby, the development of a sign-tracking conditioned response..

The I h is a mixed depolarizing current present in neurons which, upon activation by hyperpolarization, modulates neuronal excitability in the mesocorticolimbic (MCL) system, an area which regulates emotions such as pleasure, reward, and motivation. Its biophysical properties are determined by HCN protein expression profiles, specifically HCN subunits 1-4. Previously, we reported that cocaine-induced behavioral sensitization increases HCN2 protein expression in all MCL areas with the Ventral Tegmental Area (VTA) showing the most significant increase. Recent evidence suggests that HCN4 also has an important expression in the MCL system. Although there is a significant expression of HCN channels in the MCL system their role in addictive processes is largely unknown. Thus, in this study we aim to compare HCN2 and HCN4 expression profiles and their cellular compartmental distribution in the MCL system, before and after cocaine sensitization. Surface/intracellular (S/I) ratio analysis indicates that VTA HCN2 subunits are mostly expressed in the cell surface in contrast to other areas tested. Our findings demonstrate that after cocaine sensitization, the HCN2 S/I ratio in the VTA was decreased whereas in the Prefrontal Cortex it was increased. In addition, HCN4 total expression in the VTA was decreased after cocaine sensitization, although the S/I ratio was not altered. Together, these results demonstrate differential cocaine effects on HCN2 and HCN4 protein expression profiles and therefore suggest a diverse I h modulation of cellular activity during cocaine addictive processes.

Chronic cocaine exposure produces enduring neuroadaptations in the brain’s reward system. Persistence of early cocaine evoked neuroadaptations in the ventral tegmental area (VTA) are necessary for later synaptic alterations in the nucleus accumbens (NAc), suggesting a temporal sequence of neuroplastic changes between these two areas. However, the molecular nature of the signal that mediates this sequential event is unknown. Here we used the behavioral sensitization model and the aPKC inhibitor of late-phase LTP maintenance, ZIP, to investigate if a persistent increase in AMPA/NMDA ratio plays a role in the molecular mechanism that allows VTA neuroadaptations to induce changes in the NAc. Results showed that intra-VTA ZIP microinfusion successfully blocked cocaine evoked synaptic enhancement in the VTA and the expected AMPA/NMDA ratio decrease in the NAc following cocaine sensitization. ZIP microinfusions also blocked the expected AMPA/NMDA ratio increase in the NAc following cocaine withdrawal. These results suggest that a persistent increase in AMPA/NMDA ratio, mediated by aPKC’s, could be the molecular signal that enables the VTA to elicit synaptic alterations in the NAc following cocaine administration.

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