title: Ventral Tegmental Area Dopamine Cell Activation during Male Rat Sexual Behavior Regulates Neuroplasticity and d-Amphetamine Cross-Sensitization following Sex Abstinence.
abstract: Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience.
  
  
  
  Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward.
authors.affiliation: Department of Neurobiology and Anatomical Sciences, Graduate Program in Neuroscience, and.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Beloate
authors.affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
authors.forename: Azar
authors.identifier: 0000-0002-5984-0966
authors.initials: A
authors.lastname: Omrani
authors.affiliation: Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Adan
authors.affiliation: Department of Neurobiology and Anatomical Sciences.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Webb
authors.affiliation: Department of Neurobiology and Anatomical Sciences, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, and lcoolen@umc.edu.
authors.forename: Lique M
authors.identifier: 0000-0003-2920-1116
authors.initials: LM
authors.lastname: Coolen
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D015198:Designer Drugs / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012201:Reward; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D014161:Transduction, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000187:drug effects; D000097573:Red Fluorescent Protein
chemical_list: D000661:Amphetamine; D000697:Central Nervous System Stimulants; D003024:Clozapine; D015198:Designer Drugs; D008164:Luminescent Proteins; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D014446:Tyrosine 3-Monooxygenase; D000097573:Red Fluorescent Protein; C079149:clozapine N-oxide
keywords: FosB; mesolimbic; nucleus accumbens; prefrontal cortex; psychostimulant; reward