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In the fifty years since the organizational hypothesis was proposed, many sex differences have been found in behavior as well as structure of the brain that depend on the organizational effects of gonadal hormones early in development. Remarkably, in most cases we do not understand how the two are related. This paper makes the case that overstating the magnitude or constancy of sex differences in behavior and too narrowly interpreting the functional consequences of structural differences are significant roadblocks in resolving this issue.

Anorexia, nausea, and vomiting are common symptoms of uremic intoxication. Fractions in the middle molecule weight range, isolated from normal urine and uremic plasma ultrafiltrate, inhibit ingestive behavior in the rat. To investigate their site of action and specificity, male rats were injected intraperitoneally, intravenously, or intracerebroventricularly with concentrated fractions of uremic plasma ultrafiltrate or normal urine (molecular weight range: 1.0 to 5.0 kD) and tested for ingestive and sexual behavior. An intraperitoneal injection of 0.5 ml of urine fraction (10:1) or 2.0 ml of uremic plasma ultrafiltrate fraction (25:1) inhibited carbohydrate intake by 76.3 and 45.9%, respectively, but an intravenous injection had no effect. However, intravenous injection of higher doses inhibited carbohydrate ingestion. An intracerebroventricular injection of 5 or 10 microl of urine (20:1) middle molecule fraction inhibited carbohydrate intake by 13.4 and 41.6%, respectively. An injection of 5 or 10 microl of uremic plasma ultrafiltrate (125:1) middle molecule fraction inhibited carbohydrate intake by 22.6 and 49.5%, respectively. Injections of the corresponding fraction from normal plasma ultrafiltrate had no effect. Injection of urine or uremic plasma ultrafiltrate middle molecule fractions did not affect the display of sexual behavior. These results suggest that middle molecule fractions from uremic plasma ultrafiltrate or normal urine act in the splanchnic region and/or brain to inhibit food intake and that the effect is specific for ingestive behavior.

Injection of Met-enkephalin, either subcutaneously (10 or 100 microgram, s.c.), intracerebroventricularly (100 ng or 1 microgram, i.c.v.) or into the mesencephalic central gray (100 ng), had no inhibitory effect on sexual behavior in female rats. If combined with [(R)-3-(N-hydroxy)-carboxamido-2-benzylpropanoyl]-L-alanine (kelatorphan, 5 micrograms i.c.v.; 1.5 micrograms in the central gray; 200 micrograms s.c.), an inhibitor of enkephalin degrading enzymes, however, i.c.v. or central gray (100 ng), but not s.c. (100 micrograms), injection of Met-enkephalin suppressed the behavior. Injection of Leu-enkephalin, s.c. or i.c.v. alone or in combination with kelatorphan, had no inhibitory effect. Peptidases may rapidly inactivate Met-enkephalin after intracerebral injection and prevent the behavioral effect. Inhibition of sexual behavior by Met-enkephalin may occur during lactation, a physiological state when the behavior is suppressed by an opioid peptide.

Subcutaneous (s.c.) administration of Arg-vasopressin (AVP) prolongs retention of a learned behaviour and elevates arterial blood pressure. Intracerebroventricular (i.c.v.) injection of a thousandfold lower dose of AVP than needed with s.c. injection produces the same behavioural effect, suggesting that AVP acts on the brain to control behaviour. However, as i.c.v. injection of AVP also elevates arterial blood pressure, it was suggested that AVP, and perhaps other peptides as well, influences behaviour indirectly by eliciting a peripheral response, for example blood pressure changes, rather than by acting directly on the brain. The suprachiasmatic nuclei (SCN) of the hypothalamus, a source of vasopressin production, inhibit sexual receptivity in oestradiol-17 beta-treated ovariectomized rats during the light phase of the daily lighting cycle, leading to speculation that vasopressin might inhibit sexual behaviour. Here we report that i.c.v. injections of AVP (1, 4 or 10 ng) inhibit sexual behaviour in receptive rats. This behavioural response is prevented by i.c.v. injection of an antiserum to AVP 30 min before AVP injection. Subcutaneous injection of a high dose of AVP (1 microgram) has no behavioural effect but elevates arterial blood pressure within 30 min of administration. Intracerebroventricular injection of a behaviourally effective dose of AVP (1 ng) has no effect on blood pressure. The results provide direct evidence that AVP can alter behaviour by an action on the brain and independently of its effect on blood pressure.

The synthesis of catecholamines and serotonin in the brains of castrated male rats was analyzed at either various times after castration or at various ages. It was found that (a) castration of rats at 50 days or later causes an increase in brain monoamine synthesis, and (b) this phenomenon was not observed until 20 days after castration. The increase in brain monoamine synthesis following castration was counteracted by treatment with testosterone, thus relating the biochemical consequences of castration with changed hormonal conditions of the animal. It is suggested that testosterone exerts an inhibitory influence on monoamine synthesis.

Ejaculation by male rats caused an abrupt and marked increase in the concentration of GABA in the cerebrospinal fluid and an equally abrupt and marked inhibition of sexual behaviour in female rats. The increase in the concentration of GABA in the cerebrospinal fluid and the inhibition of the behaviour was specifically mediated by the ejaculation of the male; sexual stimulation unaccompanied by ejaculation had no effect. The post-ejaculatory suppression of sexual receptivity in female rats was partially reversed by intracerebroventricular injection of the GABA antagonist bicuculline and the behaviour of receptive rats was inhibited by intracerebroventricular injection of the GABA agonist muscimol. Increasing the concentration of GABA in the cerebrospinal fluid by i.p. injection of the GABA transminase inhibitor gamma-vinyl GABA caused an increase of the concentration of GABA in the cerebrospinal fluid and inhibited the display of sexual receptivity. It is suggested that GABA mediates physiologically relevant inhibition of sexual behaviour in female rats.