Elsevier

Neuropharmacology

Volume 109, October 2016, Pages 205-215
Neuropharmacology

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice

https://doi.org/10.1016/j.neuropharm.2016.06.011Get rights and content

Highlights

  • TAT protein expression in the brain produced an anhedonia-like phenotype.

  • TAT protein expression altered mesolimbic dopamine and serotonin levels.

  • Prior TAT expression increases the rewarding effects of methamphetamine.

  • TAT expression may contribute to comorbid depression in HIV+ subjects.

  • TAT expression may exacerbate methamphetamine dependence in HIV+ subjects.

Abstract

Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT- control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT- mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT- mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT- mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT- mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT- mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals.

Introduction

Compromised reward and cognitive function after human immunodeficiency virus (HIV) infection may contribute to comorbid drug dependence and depressive symptoms. Impairments in the response to pleasure (i.e., reward deficits or anhedonia) represent a key feature of depression (Pizzagalli et al., 2005, Der-Avakian et al., 2014), and may explain increased rates of major depression/mood disorders after HIV infection and methamphetamine dependence (Kesby et al., 2015, Panee et al., 2015). In HIV-infected subjects, depressed moods, methamphetamine and nicotine dependence have all been associated with decreased likelihood to initiate highly active antiretroviral therapy (HAART) (Tegger et al., 2008, King et al., 2012). Moreover, depressive symptoms predict greater functional decline and cognitive complaints in patients (Sadek et al., 2007). Understanding the relationship between depressive and cognitive symptoms, drug dependence and HIV infection is critical to implementing effective therapeutic strategies.

Both HIV infection and drugs of abuse, including methamphetamine, target subcortical brain structures (Volkow et al., 2001, Gorry et al., 2003, Wang et al., 2012) and dopaminergic systems in particular, which are critically involved in reward processes (Koob and Volkow, 2010). Therefore, impairments in dopaminergic transmission may be one of the mechanisms underlying reward deficits in people with HIV (Kaul and Lipton, 2006, Ferris et al., 2008). Moreover, damage to corticolimbic brain regions such as the basal ganglia, hippocampus, and cerebral cortex (Gorry et al., 2003) are also implicated in HIV-associated cognitive deficits (Heaton et al., 1995, Heaton et al., 2011). The substantial overlap between the associated damage to these brain regions and neurotransmitter systems after HIV infection suggests that reward dysfunction may be central to depressive symptoms, drug dependence and cognitive function.

In HIV-infected subjects on antiretroviral treatment, cognitive and depressive symptoms are still prevalent (Heaton et al., 2011), suggesting factors other than viral load may be involved. For example, we have previously shown that expression of HIV-associated gp120 protein increases the sensitivity to methamphetamine and exacerbates cognitive impairments in mice (Kesby et al., 2014, Kesby et al., 2015). The viral TAT protein has also been implicated in HIV-induced neuropathology given its central role in the pathogenesis of HIV infection (for review (Li et al., 2009),). Inducible transgenic mice that express the viral TAT protein in the brain, under the glial fibrillary acidic protein (GFAP) promoter, provide a useful in vivo model to study the temporal impact of TAT protein in brain function. TAT-expressing mice show neuropathology similar to that observed in HIV-infected humans including apoptosis, astrocytosis, neurodegeneration of the cortex, degeneration of dendrites and inflammation (Kim et al., 2003). Recent imaging studies have revealed reduced gray matter density and cerebral fractional anisotropy abnormalities in multiple brain areas in TAT-expressing mice (Carey et al., 2013, Carey et al., 2015). TAT protein induces dysfunction of dopaminergic neurotransmission in corticolimbic brain circuits (Ferris et al., 2009b, Zhu et al., 2009, Midde et al., 2012, Theodore et al., 2012) that are involved in reward function (Koob and Volkow, 2010). However, it is not known if TAT-induced alterations in dopaminergic function in corticolimbic circuits result in changes in reward processes.

The goal of the present study was to determine the acute and persistent impact of TAT expression on brain reward function (specifically, reward deficits or anhedonia) and neurochemistry. Furthermore, whether TAT-induced impairments in reward function can predict impairments in working memory, a commonly observed deficit in HIV-infected patients (Heaton et al., 2004), was also determined. The use of a doxycycline-inducible transgenic mouse allowed for the assessment of both acute and prolonged effects of TAT expression in the adult mice. Brain reward function in response to TAT expression and acute psychostimulant administration (nicotine and methamphetamine), was assessed in the intracranial self-stimulation (ICSS) procedure (Barnes et al., 2014, Amitai et al., 2009, Stoker et al., 2008). The ICSS procedure is particularly sensitive to alterations in limbic dopaminergic projections critical to the motivational aspects of anhedonia (Der-Avakian and Markou, 2012). In addition, dopaminergic and serotonergic function was assessed in the striatum at two time points after the doxycycline regimen by high-performance liquid chromatography (HPLC). Considering that subjects with HIV exhibit deficits in working memory (Heaton et al., 2011), delay-dependent working memory was assessed in TAT-expressing mice using a spatial delayed nonmatch-to-position task (Woolley and Ballard, 2005).

Section snippets

Animals

For the ICSS study, a total of 30 male mice, with 16 mice containing either the GFAP-null alleles or the TAT protein transgene (TAT-) and 14 mice containing both the GFAP-null alleles and TAT protein transgene (TAT+) were used. An additional cohort of mice (n = 6 TAT- and n = 6 TAT+ mice) were used to assess neurotransmitter function 3 days after completion of the doxycycline regimen. This time point ensured that TAT protein expression was still evident (Paris et al., 2014c) and differences in

ICSS testing during doxycycline-induced TAT expression

ICSS data were analyzed as four blocks of 7 days, consisting of the baseline, DOX (days immediately after DOX injections) and two post-DOX weeks (Fig. 1). For reward thresholds (Fig. 1A), there was a significant main effect of Block (F3,81 = 8.0, p < 0.001) with reward thresholds significantly higher during DOX compared with thresholds during the baseline or post-DOX periods (p < 0.01). There was also significant main effect of TAT (F1,27 = 9.1, p < 0.01) and a significant interaction of Block

Discussion

The present study demonstrated that acute TAT protein expression led to reward deficits or anhedonia as demonstrated by elevated reward thresholds in the ICSS task. Furthermore, increased serotonergic function and decreased dopaminergic function were observed in the Acb of TAT+ mice at a time point associated with TAT-induced anhedonia. In addition, prior TAT exposure led to an increased sensitivity to methamphetamine-induced reward enhancement but did not affect nicotine-induced alterations in

Conclusions

Our findings in mice suggest that TAT protein expression is sufficient to induce anhedonia and lead to a long-lasting increase in sensitivity to the rewarding effects of methamphetamine. However, TAT-mediated effects on reward function do not predict impairments in delay-dependent working memory and, therefore, do not represent an impairment in general brain function. Our findings suggest that TAT expression may contribute to comorbid depression in treated HIV-infected subjects, even those with

Author contributions

JPK, AM and SS were responsible for the study concept and design. JPK was responsible for the acquisition of the animal data, data analysis and manuscript drafting. SS and AM provided critical revision of the manuscript for important intellectual content. All of the authors critically reviewed the content and approved the final version for publication.

Conflict of interest statement

AM has received contract research support from Forest Laboratories and Astra-Zeneca and consulting fees from AbbVie during the past 2 years. AM and SS have a patent on metabotropic glutamate compound use for the treatment of nicotine dependence, unrelated to the present research. JPK, AM and SS have no competing financial interests in relation to the work described.

Acknowledgments

This work was supported by an NIH/NIDA grant (DA033849 to SS), the Translational Methamphetamine AIDS Research Center (P50DA026306) and the Interdisciplinary Research Fellowship in NeuroAIDS (R25MH081482 to JPK).

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