Genaro A. Coria-Avila

Who, What, Where, When (and Maybe Even Why)? How the Experience of Sexual Reward Connects Sexual Desire, Preference, and Performance

Although sexual behavior is controlled by hormonal and neurochemical actions in the brain, sexual experience induces a degree of plasticity that allows animals to form instrumental and Pavlovian associations that predict sexual outcomes, thereby directing the strength of sexual responding. This review describes how experience with sexual reward strengthens the development of sexual behavior and induces sexually-conditioned place and partner preferences in rats. In both male and female rats, early sexual experience with partners scented with a neutral or even noxious odor induces a preference for scented partners in subsequent choice tests. Those preferences can also be induced by injections of morphine or oxytocin paired with a male rat’s first exposure to scented females, indicating that pharmacological activation of opioid or oxytocin receptors can “stand in” for the sexual reward-related neurochemical processes normally activated by sexual stimulation. Conversely, conditioned place or partner preferences can be blocked by the opioid receptor antagonist naloxone. A somatosensory cue (a rodent jacket) paired with sexual reward comes to elicit sexual arousal in male rats, such that paired rats with the jacket off show dramatic copulatory deficits. We propose that endogenous opioid activation forms the basis of sexual reward, which also sensitizes hypothalamic and mesolimbic dopamine systems in the presence of cues that predict sexual reward. Those systems act to focus attention on, and activate goal-directed behavior toward, reward-related stimuli. Thus, a critical period exists during an individual’s early sexual experience that creates a “love map” or Gestalt of features, movements, feelings, and interpersonal interactions associated with sexual reward.

Olfactory conditioned partner preference in the female rat.

Paced copulation induces conditioned place preference in female rats. The authors examined whether associating almond-scented males with paced copulation induces conditioned partner preference. The paired group received 4 paced copulations with almond-scented males and 4 nonpaced copulations with unscented males sequentially at 4-day intervals. The unpaired group received the opposite order of association, whereas the randomly paired group received random associations. A 4th group received a single pairing. On the final test, females were placed into an open field with 2 males, 1 scented and 1 unscented. Females in the paired group solicited the scented male more frequently, and most chose the scented male for their 1st ejaculation. Thus, an odor paired with paced copulation elicits conditioned partner preference in female rats.

Conditioned partner preference in female rats for strain of male

Female rats show conditioned place preference following paced copulation, and we have recently demonstrated that pairing almond odor with paced copulation induces a conditioned partner preference for almond-scented males. The present study examined whether cues of two different strains of male (albino and pigmented) induce a conditioned partner preference for the strain of male associated with paced copulation. Ovariectomized, hormone-primed Wistar (W) or Long-Evans (LE) female rats received 10 conditioning trials at 4-day intervals. In the Wistar-pacing group females copulated with W males in a chamber bisected by a 4-hole partition that only the female could pass through. Four days later, they copulated with LE males without the partition. The Long-Evans-pacing group received the opposite association. In the final preference test all females chose freely between two males tethered in opposite corners of an open field, one W and one LE. Regardless the strain of male, females displayed more solicitations toward the pacing-related male, and most of the females received their first ejaculation from that male. The preference was facilitated if the pacing-related male was of the same strain as the female. These results suggest that female rats have an unconditioned preference for males of the same strain, but this preference can be switched towards males of a different strain if that male is associated with the sexual reward induced by paced copulation.

Clitoral stimulation induces conditioned place preference and Fos activation in the rat

The present study examined the ability of clitoral stimulation (CLS) to induce conditioned place preference (CPP) and Fos protein in the brain. Ovariectomized, hormone-primed Long-Evans rats were randomly assigned to receive either distributed CLS (1 stimulation every 5 s for 1 min prior to being placed in one distinctive side of a nonbiased CPP box for 2 min, after which the cycle of stimulation and CPP exposure were repeated for 4 more cycles, totaling 60 stimulations) or continuous CLS (1 stimulation per second for 1 min with 2 min in one side of the CPP box, repeated for 4 more cycles, totaling 300 stimulations). Two days later, females were placed into the other side of the CPP box without prior stimulation. CPP was tested after 5 sequential exposures each of CLS and no stimulation. Females given distributed stimulation developed a significant CPP whereas females given continuous stimulation did not. CLS induced Fos in hypothalamic and limbic structures, including the nucleus accumbens, piriform cortex, arcuate nucleus, and dorsomedial portion of the ventromedial hypothalamus, compared to no stimulation. However, distributed CLS induced more Fos in the medial preoptic area than continuous CLS or no stimulation. In contrast, continuous CLS induced more Fos in the posteroventral medial amygdala compared to no stimulation. These data indicate that CLS induces a reward state in the rat and a pattern of Fos activation in regions of the brain that process genitosensory input, incentive salience, and reward.

Why should we keep the cerebellum in mind when thinking about addiction

Increasing evidence has involved the cerebellum in functions beyond the sphere of motor control. In the present article, we review evidence that involves the cerebellum in addictive behaviour. We aimed on molecular and cellular targets in the cerebellum where addictive drugs can act and induce mechanisms of neuroplasticity that may contribute to the development of an addictive pattern of behaviour. Also, we analyzed the behavioural consequences of repetitive drug administration that result from activity-dependent changes in the efficacy of cerebellar synapses. Revised research involves the cerebellum in drug-induced long-term memory, drug-induced sensitization and the perseverative behavioural phenotype. Results agree to relevant participation of the cerebellum in the functional systems underlying drug addiction. The molecular and cellular actions of addictive drugs in the cerebellum involve long-term adaptative changes in receptors, neurotransmitters and intracellular signalling transduction pathways that may lead to the re-organization of cerebellar microzones and in turn to functional networks where the cerebellum is an important nodal structure. We propose that drug induced activity-dependent synaptic changes in the cerebellum are crucial to the transition from a pattern of recreational drug taking to the compulsive behavioural phenotype. Functional and structural modifications produced by drugs in the cerebellum may enhance the susceptibility of fronto-cerebellar circuitry to be changed by repeated drug exposure. As a part of this functional reorganization, drug-induced cerebellar hyper-responsiveness appears to be central to reducing the influence of executive control of the prefrontal cortex on behaviour and aiding the transition to an automatic mode of control.

Neurochemical basis of conditioned partner preference in the female rat: I. Disruption by naloxone.

The effects of the opioid antagonist naloxone were examined on the development of conditioned partner preference induced by paced copulation in female rats. In Experiment 1, ovariectomized, hormone-primed rats were conditioned to associate scented and unscented male rats with paced and nonpaced copulation, respectively. Female rats in Experiment 2 associated albino or pigmented male rats with paced or nonpaced copulation. Naloxone or saline was administered before each conditioning trial. During a final drug-free preference test, female rats could choose to copulate with either a pacing related or unrelated male. Saline-trained female rats in the paired group copulated preferentially with the pacing-related male rat, whereas naloxone-trained female rats did not show a preference. The authors concluded that opioids mediated the conditioned partner preference induced by paced copulation.

Neurobiology of social attachments

Many types of social attachments can be observed in nature. We discuss the neurobiology of two types (1) intraspecific (with a partner) and (2) parental (with the offspring). Stimuli related to copulation facilitate the first, whereas pregnancy, parturition and lactation facilitate the second. Both types develop as consequence of cohabitation. These events seem to stimulate similar neural pathways that increase (1) social recognition, (2) motivation, reward; and (3) decrease fear/anxiety. Subregions of the amygdala and cortex facilitate social recognition and also disinhibition to decrease rejection responses. The interrelationship between MeA, BNST, LS may mediate the activation of NAcc via the mPOA to increase motivation and reward. Cortical areas such as the ACC discriminate between stimuli. The interaction between OT and D2-type receptors in NAcc shell facilitates intraspecific attachment, but D1-type appears to facilitate parental attachment. This difference may be important for maternal females to direct their attention, motivation and expression of attachment toward the appropriate target.

Neuronal activation by stimuli that predict sexual reward in female rats

Conditioned stimuli (CSs) associated with paced copulation induce a conditioned partner preference for males bearing the CS. Here we examined the activation of Fos immunoreactivity (Fos-IR) following exposure to a CS previously paired with either paced or nonpaced copulation. Ovariectomized, hormone-primed rats received 10 sequential conditioning trials at 4-day intervals. In experiment 1, females in the odor-paired group learned to associate an almond odor on a male with paced copulation and an unscented male with nonpaced copulation. In the odor-unpaired group, females received the opposite association. In experiment 2, females associated two different strains of male, Long-Evans or Wistar, with paced or nonpaced copulation, respectively. A preference test indicated that females in both experiments developed a conditioned preference for the pacing-related males, as indicated by significantly more solicitations toward the male and a preference to copulate with the pacing-related male. Subsequently, females were exposed to the CS (odor or strain) alone for 1 h prior to kill and preparation of their brains for immunocytochemistry. In both experiments, the CS associated with paced copulation produced significantly more Fos-IR in the piriform cortex, medial preoptic area, and ventral tegmental area, relative to the same odor or strain cues associated with nonpaced copulation. These findings provide evidence that the state associated with paced copulation can be conditioned to environmental stimuli such as neutral odors or strain cues, which earn an incentive value via classical conditioning. The significance of the brain areas activated is discussed with regard to their role in sexual and other motivated behaviors.

Neurochemical basis of conditioned partner preference in the female rat: II. Disruption by flupenthixol.

The effects of the dopamine receptor antagonist flupenthixol were examined on the development of conditioned partner preference induced by paced copulation in female rats. In Experiment 1, ovariectomized, hormone-primed rats were conditioned to associate scented and unscented males with paced and nonpaced copulation, respectively. Females in Experiment 2 associated albino or pigmented males with paced or nonpaced copulation. Flupenthixol or saline was administered before each conditioning trial. During a final drug-free preference test, females could choose to copulate with either a pacing-related or nonpacing-related male. Saline-trained females copulated preferentially with the pacing-related male, whereas flupenthixol disrupted odor but not strain conditioning. The role of dopamine in conditioned partner preference depends on the type of stimuli to be learned.

Have we been ignoring the elephant in the room? Seven arguments for considering the cerebellum as part of addiction circuitry.

Addiction involves alterations in multiple brain regions that are associated with functions such as memory, motivation and executive control. Indeed, it is now well accepted that addictive drugs produce long-lasting molecular and structural plasticity changes in corticostriatal-limbic loops. However, there are brain regions that might be relevant to addiction other than the prefrontal cortex, amygdala, hippocampus and basal ganglia. In addition to these circuits, a growing amount of data suggests the involvement of the cerebellum in many of the brain functions affected in addicts, though this region has been overlooked, traditionally, in the addiction field. Therefore, in the present review we provide seven arguments as to why we should consider the cerebellum in drug addiction. We present and discuss compelling evidence about the effects of drugs of abuse on cerebellar plasticity, the involvement of the cerebellum in drug-induced cue-related memories, and several findings showing that the instrumental memory and executive functions also recruit the cerebellar circuitry. In addition, a hypothetical model of the cerebellums role relative to other areas within corticostriatal-limbic networks is also provided. Our goal is not to review animal and human studies exhaustively but to support the inclusion of cerebellar alterations as a part of the physiopathology of addiction disorder.