Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex.

Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin-2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness.

Stimulation of glutamate receptors in the ventral tegmental area is necessary for serotonin-2 receptor-induced increases in mesocortical dopamine release.

Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a "long-loop" feedback system from the PFC to the ventral tegmental area (VTA) and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA.

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission.

The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

Sampling glutamate and GABA with microdialysis: suggestions on how to get the dialysis membrane closer to the synapse.

Microdialysis is currently optimized to sample the extrasynaptic pool. As such, the technique has facilitated discovery of ischemia-induced excitotoxic glutamate overflow (Benveniste H, Drejer J, Schousboe A, Diemer NH, 1987, Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fiber through the dorsal hippocampus in the rat. J. Neurochem., 49, 729-734) and adenosinergic sleep drive (Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, Greene RW, McCarley RW, 1997, Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science, 276 (5316), 1265-1268); and is proving essential for clinical monitoring of glutamate and cellular metabolites in stroke and head trauma (Sarrafzadeh AS, Sakowitz OW, Kiening KL, Benndorf G, Lanksch WR, Unterberg AW. Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients? Crit. Care Med. 2002, 30 (5): 1062-1070). Study of the origin of extrasynaptic glutamate sampled with microdialysis has advanced understanding of extrasynaptic signal processing (Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 2002, 22 (20): 9134-9141; Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW, 2003, Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat. Neurosci., 6, 743-749) in the CNS. Microdialysis studies furthermore demonstrate that synaptic pools of some neurotransmitters spill into the extrasynaptic space. For this reason, microdialysis has provided a window into the synaptic pool that has significantly advanced understanding of neurotransmitter control of behavior (Tanda G, Pontieri FE, Di Chiara G, 1997, Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science, 276, 2048-2050). Nonetheless, ability to sample synaptic pools of neurotransmitters is limited. Here we summarize evidence that microdialysis often fails to sample synaptic pools of neurotransmitters, such as glutamate and GABA because of rapid clearance and limited diffusion of these neurotransmitters from the synapse. Moreover, we consider means to move the dialysis membrane closer to the synapse to facilitate sampling of the synaptic pool of these neurotransmitters by minimizing tissue trauma, decreasing probe size and increasing temporal resolution.

Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.

Altered dopamine regulation in the medial prefrontal cortex has been linked to drug abuse and disorders such as schizophrenia. Heterogeneous expression of the dopamine transporter, as well as the ability of the norepinephrine transporter to clear dopamine in the prefrontal cortex, delineates two potential sites for the regulation of synaptic dopamine within the cortex. The present study used in vivo microdialysis to compare the effects of local infusions of dopamine and norepinephrine uptake blockers in the caudate putamen and two subregions of the prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices. Results revealed that all dopamine uptake blockers produced greater increases in dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In addition, amphetamine administration increased dopamine efflux to a greater degree in the prelimbic, relative to the anterior cingulate, cortex. In contrast, the increase in dopamine efflux was similar in both subregions in the presence of nomifensine and desmethylimipramine. Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion. These data indicate a more prominent role for the dopamine transporter in the clearance of extracellular dopamine in the caudate-putamen relative to the prefrontal cortex and an important role for NET in the clearance of dopamine in both the prelimbic and anterior cingulate subregions of the rat medial prefrontal cortex.

Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group.

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT(2A) receptors. It is currently unknown if 5-HT(2A) receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT(2A) receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT(2A) receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT(2A) receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT(2A) immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT(2A) receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT(2A) receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT(2A) receptor activation may modulate reward-related behavior in rodents. 5-HT(2A) receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT(2A) receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.

Tyrosine augments acute clozapine- but not haloperidol-induced dopamine release in the medial prefrontal cortex of the rat: an in vivo microdialysis study.

Tyrosine availability can influence dopamine (DA) synthesis in highly electrophysiologically active DAergic neurons, such as those innervating the medial prefrontal cortex (MPFC). Whether tyrosine concentrations can also affect MPFC extracellular DA concentrations, measured in vivo, is not known. Since clozapine preferentially activates mesocortical DA neurons, we posited that tyrosine administration to a clozapine-pretreated rat would enhance the clozapine-induced augmentation of MPFC extracellular DA concentrations. Tyrosine alone (25-50mg/kg IP) did not affect mesocortical or striatal extracellular DA concentrations measured by in vivo microdialysis. Given 30 minutes after clozapine (10 mg/kg), tyrosine (50 mg/kg) significantly prolonged the clozapine-induced increase in MPFC extracellular DA concentrations but had no effect in the striatum. In contrast, tyrosine (50 mg/kg) significantly prolonged the haloperidol (1 mg/kg) induced increase in striatal extracellular DA concentrations but had no effect in the MPFC. These data constitute the first in vivo evidence that administration of tyrosine can selectively potentiate the clozapine-evoked increase in mesocortical extracellular DA concentrations.

M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex.

Previous research has suggested that serotonin 5-HT(2A) receptors modulate the functioning of the mesocortical dopamine (DA) pathway. However, the specific role of 5-HT(2A) receptors localized within the medial prefrontal cortex (mPFC) is not known. The present study employed in vivo microdialysis to examine the role of this receptor in the modulation of basal and K(+)-stimulated (Ca(2+)-dependent) DA release. The selective 5-HT(2A) antagonist M100,907 was infused directly into the mPFC of conscious rats. This resulted in a concentration-dependent blockade of K(+)-stimulated DA release. Intracortical application of M100,907 also blocked increases in DA release produced by the systemic administration of the 5-HT(2A/2C) agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These findings demonstrate that local 5-HT(2A) antagonism has an inhibitory effect on stimulated, Ca(2+)-dependent DA release. They suggest that cortical 5-HT(2A) receptors potentiate the phasic release of mesocortical DA.

Comparison of effects of haloperidol administration on amphetamine-stimulated dopamine release in the rat medial prefrontal cortex and dorsal striatum.

Research has shown that there are important neurochemical differences between the mesocortical and mesostriatal dopamine systems. The work reported in this paper has sought to compare the regulation of dopamine release in the medial prefrontal cortex and the anterior caudate-putamen. In vivo microdialysis was used to recover dialysate fluid for subsequent assay for dopamine concentrations. The responses to D2 antagonist (haloperidol) administration, which has been shown to increase impulse-dependent dopamine release, were compared. Results demonstrated a diminished effect of systemic haloperidol administration on dopamine efflux in the prefrontal cortex. The responses to systemic administration of a nonimpulse-dependent, transporter-mediated, dopamine releaser (d-amphetamine) were also contrasted. Results again demonstrated a diminished pharmacological effect in the cortex. The potential interaction of stimulation of these two types of dopamine release was examined by coadministration of these compounds. Haloperidol pretreatment dramatically potentiated the dopamine-releasing effect of amphetamine administration. This effect was observed in both the cortex and the striatum. Subsequent work demonstrated that this effect of haloperidol was mediated by D2-like receptors in the prefrontal cortex. These results are discussed in relation to other neurochemical and neuroanatomical studies demonstrating sparse densities of dopamine transporter sites and dopamine D2 receptors in the cortex compared with the striatum. They demonstrate a functional correlate to the recently reported, largely extrasynaptic localization of dopamine transporter sites in the prefrontal cortex. Furthermore, they demonstrate the existence of cortical D2-like autoreceptors that may normally be "silent" under basal conditions.

Ritanserin administration potentiates amphetamine-stimulated dopamine release in the rat prefrontal cortex.

1. Administration of serotonin 5-HT2 receptor antagonists increases the basal release of dopamine in the mesocorticolimbic pathway. 2. Treatment with dopamine D2 receptor antagonists increases impulse-dependent basal dopamine release in the nigrostriatal pathway. D2 antagonists also potentiate carrier-mediated increases in DA efflux from this pathway. 3. The present study compared the effects of a 5-HT2A/C antagonist (ritanserin) and a D2 antagonist (haloperidol) on carrier-mediated (amphetamine-induced) DA release in the mesocortical system. 4. In vivo microdialysis was used to recover extracellular fluid from the medial prefrontal cortex of conscious rats. Samples were then assayed for dopamine content by HPLC with electrochemical detection. Haloperidol or ritanserin were administered systemically (i.p.) 30 min before d-amphetamine (5.0 mg/kg i.p.). 5. Results demonstrated that 5.0 mg/kg ritanserin, but not 1.0 mg/kg, potentiated amphetamine-induced DA release in the prefrontal cortex. Similar to previous findings in the striatum, haloperidol (1.0 mg/kg) also augmented amphetamine-stimulated DA efflux in the cortex. 6. These results suggest that 5-HT2 and D2 receptor antagonists increase impulse-mediated dopamine release in the rat prefrontal cortex which in turn potentiates carrier-mediated release.

Local infusion of the serotonin antagonists ritanserin or ICS 205,930 increases in vivo dopamine release in the rat medial prefrontal cortex.

Previous research has indicated that atypical antipsychotic drugs like clozapine preferentially increase dopamine (DA) release from the mesocortical, relative to the nigrostriatal, system, While these drugs generally have weak affinity for the D2 receptor subtype, they are potent antagonists of the 5-hydroxytryptamine2 (5-HT2) receptor. Research into neurotransmitter interactions indicates that 5-HT modulates DA release, but the nature of this interaction may depend upon the specific 5-HT receptor subtype and the neuronal location of that subtype. The present research tested the hypothesis that 5-HT2 receptors localized near mesocortical DA nerve terminals regulate DA release. This was accomplished by infusing the specific 5-HT2 antagonist ritanserin directly into the medial prefrontal cortex through reverse dialysis in vivo in the rat. Cortical extracellular fluid was then extracted by microdialysis and DA was subsequently assayed by HPLC with electrochemical detection. These results were compared to the systemic administration of ritanserin (1.0-5.0 mg/kg i.p.) and the local application of ICS 205,930, an antagonist at the 5-HT3/4 receptor subtypes. Both 5-HT antagonists increased cortical DA levels when infused locally at concentrations of 100 microM (12 nmoles/60 min), and these results were concentration-dependent. Systemically administered ritanserin also dose-dependently increased cortical DA efflux. These results indicate that atypical antipsychotic drugs may increase mesocortical DA release by antagonizing 5-HT receptors located in the prefrontal cortex. Furthermore, 5-HT may normally inhibit cortical DA release by actions at the 5-HT2 receptor subtype.

Differential effects of locally administered clozapine and haloperidol on dopamine efflux in the rat prefrontal cortex and caudate-putamen.

Previous research has shown that systemically administered antipsychotic drugs enhance dopamine release from the nigrostriatal and mesocortical dopamine pathways. However, the degree of enhancement differs as a function of the drug used (atypical versus typical antipsychotic) and the dopamine pathway examined. The present studies examined whether these differences result from differential actions of these drugs on dopamine terminal regions. Clozapine or haloperidol was infused locally into the caudate-putamen or prefrontal cortex through reverse microdialysis. Although both drugs increased extracellular dopamine levels, clozapine produced greater effects than haloperidol in the prefrontal cortex, whereas haloperidol produced greater effects in the caudate-putamen. These results suggest that neurochemical differences within dopamine terminal regions may explain the differential actions of antipsychotic drugs on striatal and cortical dopamine release.

Brain region effects of clozapine on amino acid and monoamine transmission.

The purpose of the study was to compare the effects of clozapine and haloperidol on monoamine and amino acid transmission in limbic and extrapyramidal brain regions of the rat. In vivo microdialysis was used to measure the concentrations of neurotransmitters after acute and chronic drug administration. The acute administration of clozapine increased dopamine and glutamate in the medial prefrontal cortex and produced a greater increase, compared with haloperidol, in GABA (gamma-aminobutyric acid) efflux within the ventral pallidum. Chronic treatment with clozapine increased dopamine and serotonin in the medial prefrontal cortex. Chronic haloperidol administration increased glutamate in the striatum by fivefold whereas chronic clozapine treatment had no effect on striatal glutamate. Furthermore, chronic haloperidol administration transiently increased, then decreased, GABA efflux in the substantia nigra. Overall, clozapine has a preferential effect on mesocorticolimbic neurotransmission whereas haloperidol alters glutamate and GABA efflux within the extrapyramidal motor system.

The atypical antipsychotic drug amperozide enhances rat cortical and striatal dopamine efflux.

Previous behavioral, biochemical, and electrophysiological studies have indicated that amperozide, a putative atypical antipsychotic drug with potent 5-HT2 receptor antagonist potency, preferentially affects mesocorticolimbic, as compared to mesostriatal dopamine neurons. The present experiment utilized in vivo microdialysis to compare the effects of amperozide on dopamine efflux in medial prefrontal cortex versus caudate-putamen in the freely moving rat. The results demonstrated that amperozide produced a greater elevation of cortical dopamine. These results were similar to those observed with clozapine but not haloperidol.

Selective subregional dopamine depletions in the rat caudate-putamen following nigrostriatal lesions.

Previous work has demonstrated a complex neurochemical and neuroanatomical heterogeneity of the striatum in normal brains. The present research investigated whether the heterogeneous distribution of dopamine would be altered following unilateral injections of the neurotoxin 6-hydroxydopamine into the substantia nigra of the rat. Four weeks following injection, the nucleus accumbens and subregions of the caudate-putamen and substantia nigra were dissected and analyzed by HPLC with electrochemical detection for dopamine, 5-hydroxytryptamine, and their respective metabolites. Levels of dopamine and its metabolites in the anterodorsolateral caudate-putamen were depleted more than medial, posterior, and ventral, striatal areas in partially lesioned animals (less than 90% dopamine depletion). This resulted in an alteration of striatal heterogeneity such that a mediolateral gradient of dopamine tissue content was now superimposed on the normal rostrocaudal gradient observed in controls. Paralleling these findings, dopamine was more depleted in the lateral, as opposed to the medial, substantia nigra. These results indicate that the nigrostriatal dopamine system degenerates in a heterogeneous fashion following 6-hydroxydopamine administration. It is speculated that the differential loss of dopamine neurons observed in the nigra of Parkinson's patients may be due to a differential sensitivity to toxins within the nigra.

Effects of cathinone and amphetamine on the neurochemistry of dopamine in vivo.

The effects of (-)cathinone, the primary psychoactive alkaloid of the Khat plant, were compared to those of (+)amphetamine in the anterior caudate-putamen and the nucleus accumbens. In vivo microdialysis was used to measure extracellular levels of dopamine and metabolites in both regions of the brain simultaneously, after intraperitoneal administration of 0.8, 1.6 or 3.2 mg/kg of either drug (doses expressed as the salts). Both drugs increased levels of dopamine but decreased levels of metabolites in a dose-dependent manner. However, the relative magnitude of these effects depended upon the specific drug, the dose and area of the brain examined. At the largest dose used, amphetamine had a relatively greater effect than cathinone on dopamine in both caudate and accumbens. However, among smaller doses, this difference was only observed in the nucleus accumbens after administration of 1.6 mg/kg. The results also demonstrated a differential regional effect of both drugs at 3.2 mg/kg, in that both had a greater effect on dopamine in the caudate, as opposed to the accumbens. These findings demonstrate a functional heterogeneity of the striatum of the rat, that may be relevant to the understanding of both normal brain function and the neural responses to psychoactive drugs.

Discriminative stimulus properties of (+)cathine, an alkaloid of the khat plant.

The effects of the psychostimulant (+)cathine (norpseudoephedrine) were examined in a two-choice, food-motivated, drug-discrimination paradigm. Rats were able to discriminate cathine from vehicle and this effect was dose- and time-dependent. Prior administration of cathine resulted in a diminished response (tolerance) to subsequent cathine and this effect developed and dissipated rapidly. Thus, different dose-response curves were generated depending upon whether cathine or vehicle was administered the day before testing. The development of tolerance also shortened cathine's time course of action and enhanced the ability of haloperidol to antagonize the cathine cue. These results suggest caution in interpreting effects produced by intermittent drug injection schedules.

A neurochemical heterogeneity of the rat striatum as measured by in vivo electrochemistry and microdialysis.

The neurochemical heterogeneity of the rat striatum was assessed in vivo by measuring subregional changes in extracellular dopamine and DOPAC by in vivo electrochemistry and microdialysis in response to amphetamine and the D2 antagonist, (-)-sulpiride. Both in vivo electrochemical and microdialysis experiments indicated a significant rostrocaudal gradient in dopamine release following amphetamine. The increase in dopamine release was highest in the rostral areas (over 800% of baseline values) and lowest in the most caudal subregion (425% of baseline). No lateromedial differences in dopamine release were observed. DOPAC levels decreased in dialysates but were similar for all 6 subregions examined. In contrast, D2 blockade with (-)-sulpiride revealed a lateromedial gradient in the increases seen for dopamine and DOPAC such that greater increases were observed in the lateral subregions. (-)-Sulpiride did not produce any differential effects along the rostrocaudal axis. The regional gradients detected in extracellular fluid changes of dopamine and DOPAC indicate that dopamine release is locally regulated by an interaction between the density of dopaminergic innervation to a particular subregion and the D2 receptor density.

The effects of intracranial administration of the dopamine agonist apomorphine on penile reflexes and seminal emission in the rat.

Previous studies employing systemic administration of the dopamine agonist apomorphine have shown that the dose response curves for apomorphine's effects on penile reflexes and seminal emission differ, suggesting that experimentally separable populations of dopamine receptors regulate these two responses. The present experiments examined the locations of central nervous system DA receptors mediating genital responses in the restrained, supine rate by injecting apomorphine into the medial preoptic area and the paraventricular nucleus through chronic, indwelling cannulae. Medial preoptic area injections facilitated penile reflexes, but not seminal emission, while paraventricular injections facilitated seminal emission. These results suggest that systemically administered apomorphine may facilitate penile reflexes by acting on the medial preoptic area and may enhance seminal emission by acting on the paraventricular nucleus.

The effects of intrathecal administration of the dopamine agonist apomorphine on penile reflexes and copulation in the male rat.

Relatively high doses of systemically administered apomorphine inhibit penile reflexes. It is possible that these inhibitory effects are due, at least in part, to actions of apomorphine on the lumbosacral spinal cord. The present experiments examined this possibility by injecting apomorphine (10 and 50 micrograms/5.0 microliters vehicle) into the lumbosacral subarachnoid space through chronic, indwelling cannulae. Such injections impaired ex copula penile reflexes, slowed the rate of copulation, and decreased the number of intromissions preceding ejaculation. These results suggest that lumbosacral cord dopamine receptors may normally regulate male sexual performance.