Expression of Testosterone Conditioned Place Preference Is Blocked by Peripheral or Intra-accumbens Injection of α-Flupenthixol

Previous evidence indicates that peripheral and intranucleus accumbens injections of testosterone have rewarding effects in male rats as measured in a conditioned place preference (CPP) paradigm. The present study investigated the neurochemical bases of the rewarding properties of testosterone by examining the effect of peripheral and intranucleus accumbens injection of the dopamine receptor antagonist alpha-flupenthixol on expression of testosterone-induced CPP. On alternating days, adult male Long-Evans rats received peripheral injections of testosterone in a water-soluble hydroxypropyl-beta-cyclodextrin (HBC) inclusion complex (0.8 mg/kg) or saline-HBC immediately prior to being confined for 30 min to one of two compartments of a place preference apparatus. All rats received 8 days of pairings (four hormone pairings, four saline pairings). On day 9 the rats were given a 20-min test session during which they had access to all compartments of the apparatus. No hormone was injected prior to the test session; however, rats received a peripheral (20 min prior; 0.2, 0.3 mg/kg) or intra-accumbens (2 min prior, 5.0 micrograms) injection of alpha-flupenthixol or saline. On the test day, rats receiving saline injections spent significantly more time in the compartment previously paired with injections of testosterone than in the compartment previously paired with vehicle injections. In contrast, rats receiving peripheral or intra-accumbens alpha-flupenthixol injections did not spend significantly more time in the compartment previously paired with testosterone. The blockade of testosterone CPP was not due to an effect of alpha-flupenthixol on motor behavior. The findings provide further evidence of the rewarding affective properties of testosterone and indicate that peripheral administration and intra-accumbens administration of alpha-flupenthixol block expression of testosterone CPP. The rewarding affective properties of testosterone are mediated, at least in part, via an interaction with the mesolimbic dopamine system.

[1]  S. Tischkau,et al.  A specific membrane binding protein for progesterone in rat brain: sex differences and induction by estrogen. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Bancroft,et al.  Changes in erectile responsiveness during androgen replacement therapy , 1983, Archives of sexual behavior.

[3]  M. Sar,et al.  Autoradiographic localization of radioactivity in the rat brain after the injection of 1,2-3H-testosterone. , 1973, Endocrinology.

[4]  A. Phillips,et al.  Sexual behavior increases dopamine transmission in the nucleus accumbens and striatum of male rats: comparison with novelty and locomotion. , 1992 .

[5]  K. Pirke,et al.  Psychosexual stimulation and plasma testosterone in man , 1974, Archives of sexual behavior.

[6]  J. Stewart,et al.  Effects of castration, steroid replacement, and sexual experience on mesolimbic dopamine and sexual behaviors in the male rat , 1989, Brain Research.

[7]  R. Miller,et al.  Naloxone inhibits mating and conditioned place preference for an estrous female in male rats soon after castration , 1987, Pharmacology Biochemistry and Behavior.

[8]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[9]  L. Matuszewich,et al.  Dopaminergic drugs in the medial preoptic area and nucleus accumbens: Effects on motor activity, sexual motivation, and sexual performance , 1995, Pharmacology Biochemistry and Behavior.

[10]  A. Phillips,et al.  Dopaminergic substrates of amphetamine-induced place preference conditioning , 1982, Brain Research.

[11]  R. J. Barfield,et al.  Correlation of dopamine release in the nucleus accumbens with masculine sexual behavior in rats , 1990, Brain Research.

[12]  M. J. Baum,et al.  Differential effects of gonadal steroids on dopamine metabolism in mesolimbic and nigro-striatal pathways of male rat brain , 1981, Brain Research.

[13]  Y. Oomura,et al.  Mechanism of the rapid effect of 17 beta-estradiol on medial amygdala neurons. , 1986, Science.

[14]  T. Teyler,et al.  Gonadal steroids: effects on excitability of hippocampal pyramidal cells. , 1980, Science.

[15]  J. Engel,et al.  Brain Reward Systems and Abuse , 1987 .

[16]  F. Macrides,et al.  Strange females increase plasma testosterone levels in male mice. , 1975, Science.

[17]  S. Stoléru,et al.  LH pulsatile secretion and testosterone blood levels are influenced by sexual arousal in human males , 1993, Psychoneuroendocrinology.

[18]  M. Papp.  Different effects of short- and long-term treatment with imipramine on the apomorphine- and food-induced place preference conditioning in rats , 1988, Pharmacology Biochemistry and Behavior.

[19]  G. Alexander,et al.  Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate--a clinical research center study. , 1995, The Journal of clinical endocrinology and metabolism.

[20]  M. Packard,et al.  Testosterone has rewarding affective properties in male rats: implications for the biological basis of sexual motivation. , 1994, Behavioral neuroscience.

[21]  Y. Yamada,et al.  Effects of estrogen and adrenal androgen on unit activity of the rat brain , 1978, Brain Research.

[22]  E. Melamed,et al.  Dissociation of the effects of castration and testosterone replacement on sexual behavior and neural metabolism of dopamine in the male rat , 1986, Brain Research Bulletin.

[23]  J. Fallon,et al.  Catecholamine innervation of the basal forebrain IV. Topography of the dopamine projection to the basal forebrain and neostriatum , 1978, The Journal of comparative neurology.

[24]  R. L. Moss,et al.  Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[25]  C. Harding.  Social Modulation of Circulating Hormone Levels in the Male , 1981 .

[26]  N. Hiroi,et al.  The amphetamine conditioned place preference: differential involvement of dopamine receptor subtypes and two dopaminergic terminal areas , 1991, Brain Research.

[27]  Michael A. Bozarth.  Methods of assessing the reinforcing properties of abused drugs , 1987 .

[28]  R. Swerdloff,et al.  Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. , 1996, The Journal of clinical endocrinology and metabolism.

[29]  M. Packard,et al.  Rewarding affective properties of intra-nucleus accumbens injections of testosterone. , 1997, Behavioral neuroscience.

[30]  N. Skakkebaek,et al.  ANDROGEN REPLACEMENT WITH ORAL TESTOSTERONE UNDECANOATE IN HYPOGONADAL MEN: A DOUBLE BLIND CONTROLLED STUDY , 1981, Clinical endocrinology.

[31]  B. McEwen,et al.  Non-genomic and genomic effects of steroids on neural activity. , 1991, Trends in pharmacological sciences.

[32]  N. Hiroi,et al.  The reserpine-sensitive dopamine pool mediates (+)-amphetamine-conditioned reward in the place preference paradigm , 1990, Brain Research.

[33]  B. Everitt.  Sexual motivation: A neural and behavioural analysis of the mechanisms underlying appetitive and copulatory responses of male rats , 1990, Neuroscience & Biobehavioral Reviews.

[34]  C. Frye,et al.  P-3-BSA, but not P-11-BSA, implants in the VTA rapidly facilitate receptivity in hamsters after progesterone priming to the VMH , 1993, Behavioural Brain Research.

[35]  F E Bloom,et al.  Central catecholamine neuron systems: anatomy and physiology of the dopamine systems. , 1978, Annual review of neuroscience.

[36]  E. Smith,et al.  Effects of androgen on sexual behavior in hypogonadal men. , 1979, The Journal of clinical endocrinology and metabolism.

[37]  N. White,et al.  Operationalizing and Measuring the Organizing Influence of Drugs on Behavior , 1987 .

[38]  J. Slangen,et al.  Testosterone as appetitive and discriminative stimulus in rats: Sex- and dose-dependent effects , 1992, Physiology & Behavior.

[39]  I. Bernstein,et al.  Plasma Testosterone Levels in the Male Rhesus: Influences of Sexual and Social Stimuli , 1972, Science.

[40]  A. Phillips,et al.  Conditioned place preference as a measure of drug reward. , 1989 .

[41]  A. Phillips,et al.  Role of dopamine in anticipatory and consummatory aspects of sexual behavior in the male rat. , 1991, Behavioral neuroscience.

[42]  B. Hoebel,et al.  Food reward and cocaine increase extracellular dopamine in the nucleus accumbens as measured by microdialysis. , 1988, Life sciences.

[43]  C. Desjardins,et al.  Classical conditioning: induction of luteinizing hormone and testosterone secretion in anticipation of sexual activity. , 1980, Science.

[44]  D. Surmeier,et al.  Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  J. Pitha.  Amorphous water-soluble derivatives of cyclodextrins: nontoxic dissolution enhancing excipients. , 1985, Journal of pharmaceutical sciences.

[46]  Diane C. Huffman.  The use of place conditioning in studying the neuropharmacology of drug reinforcement , 1989, Brain Research Bulletin.