Comparison of site specific injections into the basal forebrain on water maze and radial arm maze performance in the male rat after immunolesioning with 192 IgG saporin.

In this study we investigated the effects of 192 IgG saporin injections into the medial septal area (MSA), or nucleus basalis magnocellularis (NBM), and combined injections into the MSA and NBM, on the water maze and radial arm maze performance in the male rat. The results of the present study reveal a dissociation between the effects of 192 IgG saporin injections into the basal forebrain on the performance of two tasks of spatial learning in the rat. Bilateral injections of 192 IgG saporin into the NBM, MSA or combined MSA/NBM failed to disrupt water maze performance when compared to controls. In contrast, injections of 192 IgG saporin into the MSA, NBM or MSA/NBM induced mild impairments on a radial arm maze task. Overall, the disruption of spatial learning observed in this study however was relatively mild compared to deficits in spatial learning reported using less selective lesions of the cholinergic basal forebrain. Consequently, the results of this study suggest that a selective reduction in cholinergic transmission in the basal forebrain is by itself, insufficient to account for the functional impairments observed in spatial learning in the rat. Although our data does support the use of 192 IgG saporin as a selective cholinergic toxin in the basal forebrain, it further suggests that assessment of spatial learning in the rat following 192 IgG saporin lesions of the basal forebrain in combination with lesions to other neurotransmitter systems, may be a more viable approach to the elucidation of the neuropathological mechanisms that are associated with the cognitive deficits seen in Alzheimer's Disease.

Comparison of site-specific injections into the basal forebrain on water maze and radial arm maze performance in the male rat after immunolesioning with 192 IgG saporin.

In this study, we investigated the effects of 192 IgG saporin injections into the medial septal area (MSA), or nucleus basalis magnocellularis (NBM), and combined injections into the MSA and NBM, on water maze and radial arm maze performance in the male rat. The results of the present study reveal a dissociation between the effects of 192 IgG saporin injections into the basal forebrain on the performance of two tasks of spatial learning in the rat. Bilateral injections of 192 IgG saporin into the NBM, MSA or combined MSA/NBM failed to disrupt water maze performance when compared to controls. In contrast, injections of 192 IgG saporin into the MSA, NBM or MSA/NBM induced mild impairments on a radial arm maze task. Overall, the disruption of spatial learning observed in this study was, however, relatively mild compared to deficits in spatial learning reported using less selective lesions of the cholinergic basal forebrain. Consequently, the results of this study suggest that a selective reduction in cholinergic transmission in the basal forebrain is, by itself, insufficient to account for the functional impairments observed in spatial learning in the rat. Although our data do support the use of 192 IgG saporin as a selective cholinergic toxin in the basal forebrain, they further suggests that assessment of spatial learning in the rat following 192 IgG saporin lesions of the basal forebrain in combination with lesions to other neurotransmitter systems, may be a more viable approach to the elucidation of the neuropathological mechanisms that are associated with the cognitive deficits seen in Alzheimer's disease.

Bilateral injections of beta A(25-35) + IBO into the hippocampus disrupts acquisition of spatial learning in the rat.

Focal deposits of beta-amyloid (beta A) in the hippocampus have been implicated in Alzheimer's disease. In this study we assessed the effects of bilateral injections into the hippocampus of beta A(25-35), a combination of beta A(25-35) with ibotenic acid (IBO), and IBO on spatial learning in the rat. Bilateral injections of beta A(25-35) into the hippocampus together with IBO (which by itself has no neurotoxic effects) produced a dramatic disruption in the acquisition of a spatial learning in the rat. Separate injections into the hippocampus of beta A(25-35) or the incubated form of beta A(25-35) alone failed to significantly affect maze acquisition in the rat. Histological examination revealed that only the combination of beta A(25-35) with IBO produced a lesion along with focal deposits in the hippocampus.

Site-specific effects of intracerebral injections of three neurokinins (neurokinin A, neurokinin K, and neurokinin gamma) on the expression of male rat sexual behavior.

Accumulating evidence indicates that neurokinins play a role in the neural regulation of male rat copulatory behavior. We have previously reported that injections of the neurokinin substance P into the medial preoptic nucleus facilitated male rat copulatory behavior. Recently, a number of other neurokinins, neurokinin K (neuropeptide K), neurokinin A (substance K), and neurokinin gamma (derived from the same gene as substance P), have been identified in the mammalian CNS. Therefore, in a series of experiments we examined the effects on male copulatory behavior following bilateral injections of different doses of neurokinin K (NkK), neurokinin A (NkA), or neurokinin gamma (Nk gamma) into the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BnST), or the caudate/putamen. Bilateral injections of NkK into the MPOA or BnST inhibited the expression of male copulatory behavior. The most marked effect was seen following bilateral injections of 0.25 and 0.52 nmol of NkK into the MPOA and the BnST. These injections produced a dramatic suppression of copulatory behavior in previously sexually vigorous male rats when compared to control injections. In contrast, bilateral injections of three different doses of NkA into the MPOA failed to affect any parameter of male copulatory behavior. Bilateral injections of 0.431 nmol of Nk gamma into the MPOA failed to affect the expression of copulatory behavior, but significantly delayed its initiation when compared to controls. Bilateral injections of 0.251 nmol of NkK into the caudate/putamen had no significant effect on copulatory behavior in sexually vigorous male rats when compared to control injections. The results of the present study provide further support for a role of neurokinins in the regulation of copulatory behavior in male rat. Taken together, these results suggest that the effects of neurokinins upon the expression of male copulatory behavior are site specific for brain regions in the sexually dimorphic vomeronasal pathway which includes the MeA, BnST, and MPOA.

Bilateral injections of a selective mu-receptor agonist (morphiceptin) into the medial preoptic nucleus produces a marked delay in the initiation of sexual behavior in the male rat.

We examined the putative functional role of the medial preoptic nucleus mu-receptor population in the expression of male copulatory behavior in sexually vigorous Long-Evans rats. In the first experiment, three doses of morphiceptin (10, 500, and 1000 ng) a selective mu-receptor agonist injected bilaterally into the medial preoptic nucleus, produced a marked delay in the initiation of male copulatory behavior compared to saline injected controls. These injections significantly lengthened intromission and mount latencies while having no appreciable effect on any other parameter of male copulatory behavior. In a separate experiment, the transient inhibition of the expression of male copulatory behavior was completely abolished following pretreatment of naloxone 20 minutes prior to bilateral injections of morphiceptin (1000 ng) into the medial preoptic nucleus. Collectively, these results suggest that the delay in the initiation of copulation that is commonly observed following peripheral or central injections of opioids is mediated at least in part by mu receptors located within the medial preoptic nucleus.

The effects of repeated administration of MDMA on the expression of sexual behavior in the male rat.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a potent neurotoxin which preferentially produces 5-HT nerve terminal degeneration in the CNS in both rodents and primates. Timely research on the behavioral effects of acute and long term treatment of MDMA is critical due to the neuropathological effects of MDMA and its abuse liability. Presently, there are no published reports that have systematically examined the effects of acute or chronic treatment of MDMA on animal sexual behavior. Accordingly, the effects of repeated systemic administration of MDMA on a variety of parameters of male sexual behavior in sexually vigorous male rats were studied. Treatment consisted of subcutaneous injections of MDMA (40 mg/kg) or saline (1 ml/kg) every 12 hours for 4 consecutive days. In addition, neurochemical assessments of brain 5-HT and 5-HIAA depletion following repeated MDMA treatment were also conducted using reverse phase liquid chromatography. The results of this study revealed that repeated systemic administration of MDMA to sexually vigorous male rats produced a transient disruption of the expression of male copulatory behavior. In addition, in MDMA-treated males that did display copulatory behavior, both the ejaculation latency and postejaculatory interval were dramatically lengthened when compared to saline injected controls. Surprisingly, one week after the first behavioral test, copulatory behavior in MDMA treated rats appeared unaffected despite a marked depletion of 5-HT and 5-HIAA content in the striatum, and hippocampus.

Ibotenic acid-induced lesions of the medial zona incerta decrease lordosis behavior in the female rat.

To examine the role of the medial zona incerta (mZI) in female sexual behavior, ovariectomized estrogen- and progesterone-treated female rats were tested for sexual receptivity after bilateral injections of the selective neurotoxin ibotenic acid (3 micrograms/0.3 microliter) directly into the mZI. These injections produced a significant attenuation of lordosis behavior in highly receptive females when compared with saline-injected controls. This decrease in sexual receptivity was also reflected in a significant increase of rejections of male mount attempts. However, these lesions did not abolish the display of lordosis behavior. In addition, the frequency of hopping and darting was decreased in ibotenic acid-injected females when compared with controls. Consistent with previous studies, these lesions also produced a transient impairment of drinking behavior (hypodipsia) typical of rats with large electrolytic lesions of the mZI. This study demonstrates that mZI neurons play a role in mediating sexual receptivity in the female rat. Collectively, these results suggest that in addition to the projection from the ventromedial nucleus of the hypothalamus to the midbrain central gray, the functional integrity of the mZI is of crucial importance for the expression of sexual receptivity in the female rat.

A substance P projection from the VMH to the dorsal midbrain central gray: implication for lordosis.

Substance P has been implicated in the modulation of lordosis behavior at the level of the dorsal midbrain central gray (dMCG). Bilateral injections of substance P into the dMCG facilitate estrogen-induced lordosis behavior in ovariectomized female rats. Input from the ventromedial nucleus of the hypothalamus (VMH) to the dMCG is a vital link in the central nervous system control that mediates the expression of lordosis behavior. Substance P-containing cells have been localized in the VMH and substance P binding sites are localized in the dMCG; this suggested to us that substance P neurons originating in the VMH may terminate in the dMCG. The present study examined the projection of substance P-immunoreactive neurons (SP-IR) in the VMH to the dMCG. The present study examined the projection of substance P-immunoreactive neurons (SP-IR) in the VMH to the dMCG. The retrograde tract tracer fluorogold revealed cell bodies throughout the extent of the VMH and sP immunofluorescence labelled a subpopulation of these cells particularly in the ventrolateral part of the VMH. The majority of sP-projection cells was localized in the caudal two-thirds of the VMH. Thirteen percent of the sP-IR cells were observed to project to the dMCG, while approximately 17% of the sP-IR cells of the ventrolateral part of the VMH projected to the dMCG. These results provide morphological evidence for a substance P projection from the VMH to an area where substance P has been demonstrated to facilitate lordosis behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of site-specific CNS microinjection of cholecystokinin on lordosis behavior in the male rat.

We have previously demonstrated that intracerebroventricular injections of sulphated cholecystokinin octapeptide (sCCK-8) had a dramatic facilitatory effect on lordosis behavior in the gonadectomized, estrogen-primed male rat. In the female, sCCK-8 facilitates or inhibits lordosis when microinjected into the medial preoptic nucleus (MPN) or ventromedial nucleus of the hypothalamus (VMH), respectively. In order to identify sCCK-8 responsive sites that modulate lordosis behavior in gonadectomized males, sCCK-8 was microinjected into the MPN or VMH. Sulphated CCK-8 significantly increased lordosis behavior when microinjected into the MPN of estrogen-primed males, but had no significant effects when microinjected into the VMH. These results imply that CCK-sensitive neural substrates within the MPN may act to disinhibit lordosis in the gonadectomized, estrogen-primed male rat. The lack of an effect of VMH injection of sCCK-8 on lordosis in males is discussed in terms of possible sex differences in sCCK-8-sensitive lordosis-modulating circuits.

Peptidergic control of male rat sexual behavior: the effects of intracerebral injections of substance P and cholecystokinin.

Behavioral experiments examined the roles of substance P (SP) and cholecystokinin (CCK) in male rat copulatory behavior. Male copulatory behavior was recorded subsequent to injections of different doses of CCK and SP into the medial preoptic-anterior-hypothalamic area (MPOA-AH), caudate/putamen (CP), or the lateral ventricles (LV) in sexually experienced male rats. In the first experiment, three different doses of SP (10, 100, and 200 ng/cannula) injected bilaterally into the MPOA-AH produced marked changes in several components of male copulatory behavior. Latencies were most affected. All three doses significantly shortened the interval to initiate copulation, and the 10 and 100 ng, but not 200 ng dose also significantly reduced ejaculation latencies. Injections of 10 ng of SP into the CP did not affect sexual behavior, while injections into the LV produced changes different from those of MPOA-AH injections. These data argue for some degree of site specificity of the effects of the MPOA-AH injections. Bilateral injections of 10 ng of SP into the MPOA-AH, were incapable of inducing copulatory behavior in castrated rats deprived of testosterone. Injections of an undiluted SP antiserum (2 microliters/cannula) into the MPOA-AH produced a dramatic impairment of male copulatory behavior. These injections significantly lengthened amount, intromission, and ejaculation latencies, while having no effect on the number of mounts or intromissions prior to ejaculation. In contrast, bilateral injections of CCK-8 (10, 100, and 200 ng/cannula) into the MPOA-AH failed to affect any parameter of male copulatory behavior.(ABSTRACT TRUNCATED AT 250 WORDS)

Microinjection of cholecystokinin into the medial preoptic nucleus facilitates lordosis behavior in the female rat.

We examined the effect of cholecystokinin (CCK) on lordosis behavior when administered into the medial preoptic area or the nucleus accumbens (NAcc) of ovariectomized estrogen-primed female rats. The frequency of lordotic responses was measured subsequent to unilateral microinjections of sulphated octapeptide CCK (sCCK-8) into the medial preoptic nucleus (MPN) or the NAcc. In the first experiment, three doses of sCCK-8 (1, 5, and 50 ng) microinjected into the MPN, and 50 ng injected into the NAcc produced a marked facilitation of lordosis. In a separate experiment, unilateral injections of an undiluted sCCK-8 antiserum into the MPN produced significant reduction in lordosis behavior in highly receptive females when compared with a normal rabbit serum injected control group. The results of the present study indicate that the CCK innervation of the MPN is involved in the neural regulation of lordosis behavior in the female rat.

Neuropeptides and male sexual behavior.

Evidence is rapidly accumulating that a number of neuropeptides are involved in the central control of male sexual behavior. This is consistent with their neuroanatomical distribution, i.e., in CNS loci previously implicated in the control of this behavior such as the medial preoptic area, and with recent findings that the peptide content of some of these regions is regulated by testosterone or its metabolites. Most of the work has been done using rats, but relevant human studies have been included whenever such material has been available. At this point there are relatively few studies which directly demonstrate the involvement of peptides in this behavior. Inhibitory and facilitatory actions, however, have been demonstrated following injections of peptides, peptide antisera, or antagonists into the CNS of male rats. Significant new developments include demonstrations that injections of substance P and A-MSH directly into the medial preoptic area can facilitate this behavior, while ventricular injection of an oxytocin antagonist can produce a powerful inhibition. The emerging picture is that GnRH, oxytocin, A-MSH and substance P stimulate, while CRF, beta-endorphin, prolactin, and neuropeptide Y are inhibitory. The inhibitory peptides CRF, beta-endorphin and prolactin are related, as they are released in response to stress. This may be relevant to the low level of sexual motivation in some depressed men. Questions concerning sites of action and mechanisms of action which mediate the behavioral effects which have been demonstrated remain largely unanswered.

Facilitation of lordosis by injection of substance P into the midbrain central gray.

Behavioral experiments tested the idea that the substance P (SP) innervation of the midbrain central gray (MCG) may be involved in the hormonal induction of sexual receptivity in female rats. SP, a SP antiserum or a reported SP antagonist were injected bilaterally into the MCG in ovariectomized, estrogen-treated females, and the lordosis response was recorded at repeated intervals. In the first experiment, three doses of SP (50,500 and 1,000 ng/cannula), a single dose of LHRH (50 ng/cannula) or vehicle were given to separate groups of females. All three doses of SP produced a rapid and long-lasting (3 h) increase in lordosis scores in moderately receptive females in tests with either manual stimulation or male rats. This facilitation was similar in latency, magnitude and duration to that produced by LHRH. In the second experiment, the basic findings of experiment 1 were replicated using blind testing. As no dose-response relation was established in experiment 1, a lower dose of SP (10 ng/cannula) was used in addition to doses of 50 and 500 ng/cannula also used in experiment 1. All three doses produced similar long-lasting increases in lordosis scores as in experiment 1. MCG injections of SP also increased lordosis scores in a second series of tests using manual stimulation alone. This demonstrates that the SP-induced facilitation does not depend on an interaction between the injections and stimuli delivered only by the male rat, eg., vaginal stimuli or ultrasonic calls. The question of the importance of endogenous SP for receptivity was examined in experiment 2 using MCG injections of a SP antiserum or the SP analogue, (D-Pro2, D-Trp7,9)-SP, which has been reported to block the excitation of locus coeruleus neurons by SP.(ABSTRACT TRUNCATED AT 250 WORDS)