Substance abuse costs the United States over $740 billion annually in healthcare, law enforcement, rehabilitation, and decreased work productivity costs. While there are certain clinical treatments for nicotine, opioid, and alcohol addiction, there is yet an equivalent treatment for psychostimulant addiction. The 5-HT7 receptor (5-HT7R) is one of the more recently discovered members of the serotonin receptor family. The involvement of 5-HT7Rs in thermoregulation, memory, and circadian rhythms, suggests that the receptor also plays a role in mood regulation, making it a potential target in the treatment of psychiatric disorders. Given’ the distribution of the 5-HT7Rs in the brain and its known cellular functions, the receptor has also been implicated in addiction processes. Most studies to date have mainly focused on psychiatric conditions like depression, having yet to explore the role of 5-HT7Rs in psycho-stimulant behaviors. In our study, the effects of SB 269970(SB), a selective antagonist for 5-HT7Rs, were tested on 8-OH-DPAT induced hypothermia, cocaine-induced locomotion, and fos expression in the nucleus accumbens. We found that SB effectively reversed 8-OH-DPAT induced hypothermia, indicating the drug is indeed binding to the 5-HT7R. However, while cocaine did increase locomotor activity and fos expression in the nucleus accumbens in rats, SB had no effect on either measure. These results suggest that 5-HT7Rs may work through pathways other than motor and should be explored through additional behavioral tests. Other brain regions should also be studied for fos expression to see if there is a region-specific effect of 5-HT7Rs and fos expression. The efficacy of SB to 5-HT7Rs and results of past studies on the drug suggests its potential as a pharmacological treatment for psychostimulant disorders.

Previous findings from our lab have demonstrated that nicotine and social reward have synergistic effects when experienced together versus when experienced separately. The purpose of this experiment is to understand the neural mechanisms underlying this synergistic effect by quantifying Fos protein, a marker for neural activation, in various brain regions. We utilized the conditioning place preference (CPP) model to assess reward. Four groups of adolescent male rats (n=120) were given either nicotine (Nic) (0.1 mg/kg/mL) or saline (Sal) and were placed in the CPP apparatus either with a social partner (Soc) or alone (Iso). Thus, groups were: 1.)Sal+Iso, 2).Sal+Soc, 3).Nic+Iso, 4).Nic+Soc. Brains of some the rats (n=40) were collected for Fos staining 90 minutes after the last conditioning session to obtain Fos data in response to direct exposure to the stimuli. The following regions were analyzed for Fos expression: central amygdala (CeA), medial amygdala (MeA), basolateral amygdala (BLA), nucleus accumbens core (NAcCore), and nucleus accumbens shell (NAcShell). Place preference changes occurred in socially-conditioned groups reflecting social reward and in nicotine-conditioned groups reflecting nicotine reward. As expected, the Sal+Iso control group failed to display a preference change. Fos data revealed a significant increase in Fos expression in the CeA, MeA, NAcCore and NAcShell for socially-conditioned animals and a significant decrease in the NAcCore for nicotine-conditioned groups. Experiencing both social and nicotine rewards together appeared to produce greater activation in the BLA. However, there was an increase in Fos expression in the negative control group relative to Nic+Iso group. The results of CPP suggest that social, nicotine and their combination are rewarding. The combination of the nicotine and social reward could have been more rewarding than social and nicotine separately, but the test was not sensitive to reward magnitude. The increase in Fos expression in the negative control group in the BLA could be due to isolation stress. Overall, these results suggest that these brain regions had greater activation to social reward.

Patients with schizophrenia have impaired cognitive flexibility, as evidenced by behaviors of perseveration. Cognitive impairments may be due to dysregulation of glutamate and/or loss of neuronal plasticity in the medial prefrontal cortex (mPFC). The purpose of these studies was to examine the effects of mGluR5 positive allosteric modulators (PAMs) alone and in combination with the NMDAR antagonist MK-801, a pharmacological model of schizophrenia. An operant-based cognitive set-shifting task was utilized to assess cognitive flexibility, in vivo microdialysis procedures to measure extracellular glutamate levels in the mPFC, and diolistic labeling to assess the effects on dendritic spine density and morphology in the mPFC. Results revealed that chronic administration of the mGluR5 PAM CDPPB was able to significantly reduce the effects of chronically administered MK-801 on both behavioral perseveration and glutamate neurotransmission. Results also showed that CDPPB had no evidence of an effect on dendritic spine density or morphology, but the mGluR5 negative allosteric modulator fenobam caused significant increases in spine density and the frequency of occurrence of spines with smaller head diameters. Conclusions include that CDPPB is able to reverse MK-801 induced cognitive deficits as well as alterations in mPFC glutamate neurochemistry. The culmination of these studies add further support for targeting mGluR5 with PAMs as a novel mechanism to alleviate cognitive impairments in patients with schizophrenia.