Tyrosine improves behavioral and neurochemical deficits caused by cold exposure.

The effects of acute cold stress were assessed behaviorally and neurochemically. The norepinephrine (NE) precursor, tyrosine (TYR), the catecholamine-releasing compound, amphetamine (AMPH), and the adrenoceptor agonist, phenylpropanolamine (PPA), were administered systemically either alone or in conjunction with TYR 30 min prior to cold exposure. All three sympathomimetic treatments dose-dependently improved performance in a forced swim test following hypothermia (T(c)=30 degrees C). AMPH/TYR or PPA/TYR combinations further improved performance vs. either agent given alone. Microdialysis showed elevated hippocampal NE concentrations in response to hypothermia. TYR further elevated NE concentration in cold/restrained rats vs. saline (SAL)-treated controls. These results suggest that sympathomimetic agents, including the nutrient TYR, which enhance noradrenergic function, improve performance in animals acutely stressed by hypothermia.

Localization of ionotropic glutamate receptors in caudate-putamen and nucleus accumbens septi of rat brain: comparison of NMDA, AMPA, and kainate receptors.

Changes in binding of selective radioligands at NMDA ([3H]MK-801), AMPA ([3H]CNQX), and kainate ([3H]kainic acid) glutamate (GLU) ionotropic receptors in rat caudate-putamen (CPu) and nucleus accumbens (NAc) were examined by quantitative autoradiography following: 1) unilateral surgical ablation of frontal cerebral cortex to remove descending corticostriatal GLU projections, 2) unilateral injection of kainic acid (KA) into CPu or NAc to degenerate local intrinsic neurons, or 3) unilateral injections of 6-hydroxydopamine (6-OH-DA) into substantia nigra to degenerate ascending nigrostriatal dopamine (DA) projections. Cortical ablation significantly decreased NMDA receptor binding in ipsilateral medial CPu (20%), and NAc (16%), similar to previously reported losses of DA D4 receptors. KA lesions produced large losses of NMDA receptor labeling in CPu and NAc (both by 52%), AMPA (41% and 45%, respectively), and kainate receptors (40% and 45%, respectively) that were similar to the loss of D2 receptors in CPu and NAc after KA injections. Nigral 6-OH-DA lesions yielded smaller but significant losses in NMDA (17%), AMPA (12%), and kainate (11%) receptor binding in CPu. The results indicate that most NMDA, AMPA, and kainate receptors in rat CPu and NAc occur on intrinsic postsynaptic neurons. Also, some NMDA, but not AMPA or kainate, receptors are also found on corticostriatal projections in association with D4 receptors; these may, respectively, represent excitatory presynaptic NMDA autoreceptors and inhibitory D4 heteroceptors that regulate GLU release from corticostriatal axons in medial CPu and NAc. Conversely, the loss of all three GLU receptor subtypes after lesioning DA neurons supports their role as excitatory heteroceptors promoting DA release from nigrostriatal neurons.

Medial prefrontal cortical D2 and striatolimbic D4 dopamine receptors: common targets for typical and atypical antipsychotic drugs.

1. In vitro receptor autoradiography was used to examine the long-term effects of a typical (fluphenazine), atypical (clozapine), or potential atypical antipsychotic (S[+]-N-n-propylnorapomorphine; [+]-NPA) on different dopamine (DA) receptor subtypes. 2. D1-Like and D3 receptor levels were not changed with any treatment in any brain region examined. 3. D2 Receptors in caudate-putamen (CPu), nucleus accumbens (NAc) and olfactory tubercle (OT) were significantly increased by long-term treatment with fluphenazine, but not with clozapine or S[+]-NPA. 4. D2 Receptor levels in medial prefrontal cortex (MPC), but not dorsolateral frontal cortex (DFC), were elevated after repeated daily administration of fluphenazine, clozapine, and S[+]-NPA. 5. D4-Like receptors, assayed under D4-selective conditions, were increased by fluphenazine, clozapine and S(+)-NPA in both NAc and CPu, but by none of these treatments in OT, DFC or MPC. 6. These results support a common role for medial prefrontal cortical D2 and striatolimbic D4 receptors in mediating the clinical actions of typical and atypical antipsychotic drugs.

Local injection of alkylating and nonalkylating dopamine receptor antagonists into rat basal forebrain: autoradiographic assessment of D2-like and D3 sites.

N-chloroethyl derivatives of 7-hydroxy-1,2,3,4-tetrahydronaphthalene (7-OH-DPAT), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), or fluphenazine were microinjected into rat nucleus accumbens (Acc), and receptor binding quantified autoradiographically after 24 h. EEDQ reduced [3H]nemonapride (D2-like receptors) binding in Acc (by 84%) and islands of Calleja (IC; 44%), without affecting [3H](+)-7-OH-DPAT (D3); N-chloroethyl-7-OH-DPATs blocked both radioligands in Acc and IC (30%-70%); fluphenazine had no effect.

Localization of dopamine receptor subtypes in corpus striatum and nucleus accumbens septi of rat brain: comparison of D1-, D2-, and D4-like receptors.

Changes in D1-, D2- and D4-like dopamine receptor binding in rat brain were examined by quantitative autoradiography following: (i) unilateral surgical ablation of frontal cerebral cortex to remove descending projections to corpus striatum and nucleus accumbens, (ii) unilateral injections of kainic acid into corpus striatum or nucleus accumbens to degenerate local intrinsic neurons, (iii) unilateral injections of 6-hydroxydopamine into substantia nigra to degenerate ascending dopamine projections. Rats were killed one week after lesioning, with contralateral tissue controls. Radioligands were: [3H]SCH-23390 for D1-like (D1/D5) receptors, [3H]nemonapride alone for D2-like (D2/D3/D4) receptors, and [3H]nemonapride with 300 nM S[-]-raclopride and other masking agents for D4-like receptors (identified by blockade with D4 selective L-745,870). Frontal cerebral cortex ablation did not alter D1- or D2-like receptor density, but D4-like binding decreased significantly in both corpus striatum (18%) and nucleus accumbens (23%). Kainic acid markedly reduced D1-like (75% and 84%) and D2-like binding (44% and 52%), with smaller D4-like losses (28% and 27%) in corpus striatum and nucleus accumbens, respectively. Nigral 6-hydroxydopamine lesions (verified by autoradiographic loss of dopamine transporters labelled with [3H]GBR-12935) did not significantly change D1-, D2-, or D4-like binding in the corpus striatum. These results suggest that the majority of D1-, and D2-like, and a smaller portion of D4-like receptors in corpus striatum and nucleus accumbens arise on intrinsic postsynaptic neurons, and that some D4-like, but neither D1- nor D2-like, receptors are found on presynaptic corticostriatal afferents.

Lack of effect of chronic clorgyline or selegiline on dopamine and serotonin transporters in rat caudate-putamen or nucleus accumbens septi.

Rats were injected intraperitoneally thrice weekly for 4 weeks with doses of selective inhibitors of monoamine oxidase type A (clorgyline, 1 mg/kg) or B ((-)-selegiline, 10 mg/kg), or saline. Both treatments produced sustained elevations of concentrations of dopamine and serotonin, and decreased their deaminated metabolites in forebrain tissue. Nevertheless, no change in binding of [3H]GBR-12935 to the dopamine transporter or of [3H]paroxetine to the serotonin transporter in caudate-putamen or nucleus accumbens septi was found with quantitative autoradiography. These results support the impression that transporter proteins for these monoamines are not regulated by increased ligand abundance.

Long-term effects of S(+)N-n-propylnorapomorphine compared with typical and atypical antipsychotics: differential increases of cerebrocortical D2-like and striatolimbic D4-like dopamine receptors.

Changes in D2-like dopamine (DA) receptor binding in rat brain regions were compared by quantitative in vitro receptor autoradiography after 21-d treatment with a typical (fluphenazine), atypical (clozapine), or candidate atypical antipsychotic (S[+]-N-n-propylnorapomorphine, [+]-NPA). Fluphenazine treatment significantly increased binding of the D2,3,4 radioligands [3H]nemonapride and [3H]spiperone in caudate-putamen (CPu: 22%, 32%), nucleus accumbens (ACC: 67%, 52%), olfactory tubercle (OT: 53%, 43%), and medial prefrontal cerebral cortex (MPC: 46%, 47%) but not dorsolateral frontal cortex (DFC). D2-like binding in MPC was also increased by (+)-NPA (49%, 39%) and clozapine (60%, 40%), but not in DFC, CPu, ACC, or OT. Binding of D2,3-selective [3H]raclopride increased less after fluphenazine in ACC (27%) and CPu (16%) than with the nonselective radioligands, and not after clozapine or (+)-NPA. D3-selective binding of [3H]R (+)-7-OH-DPAT was not changed with any treatment or region including islands of Calleja. Binding of [3H]nemonapride or [3H]spiperone under D4-selective conditions (with 300 nM S[-]-raclopride and other masking agents, at sites occluded by D4 ligand L-745,870), was increased by fluphenazine, (+)-NPA, clozapine in ACC (120%, 76%, 70%, respectively), and CPu (54%, 37%, 35%), but not in OT, DFC or MPC. These results support the hypothesis that cerebrocortical D2-like and striatolimbic D4-like receptors contribute to antipsychotic actions of both typical and atypical drugs and encourage further consideration of S(+)aporphines as potential atypical antipsychotics.

Role of dopamine in behavioral effects of serotonin microinjected into rat striatum.

Bilateral local microinfusion of serotonin (5-hydroxytryptamine; 5-HT) into the ventrolateral striatum (VLS) of the rat forebrain induces quantifiable stereotyped orofacial behaviors. The role of presynaptic dopamine (DA) and structural requirements of indoles for expression of this behavioral effect and for inhibition of neuronal transport of [3H]DA were examined. Bilateral local injection of 6-OHDA (8 micrograms/side) into VLS depleted DA and markedly diminished the behavioral effects of 5-HT. Intracerebral pretreatment with the potent DA transport inhibitors GBR-12909 (6 micrograms/side) or nomifensine (4 micrograms/side) also markedly decreased behavioral responses to 5-HT. A series of indoles and tyramine were examined for ability to induce stereotypy following infusion into the VLS. Of compounds tested, only p-tyramine, 5-HT, tryptamine and L-5-hydroxytryptophan (5-HTP) elicited strong orofacial behaviors; indoles lacking a free amino group or containing other substituents were virtually inactive in vivo, and the effect of 5-HTP was prevented by systemic pretreatment with the decarboxylase inhibitor NSD-1015, indicating its required conversion to 5-HT. Uptake of [3H]DA (0.1 microM) into rat striatal synaptosomes was inhibited in a concentration-dependent manner in the following apparent rank-order: p-tyramine, N-methyl-5-HT, tryptamine, 5-HT, N-methyltryptamine (IC50 = 44-718 nM), other indoles (IC50 = 10-100 microM). These results support the conclusion that oral stereotypy induced by microinjection of 5-HT or other aromatic amines into rat VLS is mediated by local release of endogenous DA. These results extend previous findings indicating that this effect of 5-HT was not blocked by 5-HT receptor antagonists, and suggest mediation by a neuronal transport process involved in the uptake or storage of DA.

Mapping of locomotor behavioral arousal induced by microinjections of dopamine within nucleus accumbens septi of rat forebrain.

Dopamine (DA) at ca. ED50 (16 microg) or saline was stereotaxically microinjected unilaterally 2 h after pretreatment with an MAO inhibitor into left or right nucleus accumbens septi of 697 freely moving rats (1394 injections) to define subregions involved in DA-induced behavioral arousal throughout the anatomical extent of the accumbens. Locomotion was quantified electronically and behavioral responses were assigned to histologically verified injection sites; postural or stereotyped behaviors characteristic of DA injections in caudate-putamen did not occur. Screening with 60 injections across mid-accumbens (2.2-3.2 mm rostral to bregma) indicated that locomotion was elicited non-homogeneously, and was particularly intense dorsomedially. Sites yielding intense arousal and their inactive surround were mapped along the rostrocaudal axis (1.4-4.2 mm anterior to bregma) in coronal sections. Responses to DA showed lateral symmetry and were similar across rostrocaudal levels, with intense responses in dorsomedial accumbens along its border with the caudate-putamen. This functional localization does not coincide closely with reported distributions of DA or its receptors, nor with histologically or histochemically defined core-shell regions of this limbic structure. Nucleus accumbens in rat brain thus appears to be organized functionally into distinct subregions differing markedly in ability to produce locomotor hyperactivity in response to exogenous DA.

Serotonergic stimulation of the ventrolateral striatum induces orofacial stereotypy.

Dopaminergic (DA) stimulation of the ventrolateral striatum produces a syndrome of intense orofacial stereotypies. In addition to dopaminergic projections from the substantia nigra, the striatum receives serotonergic (5-HT) inputs arising from the raphe nuclei. To assess the putative role of striatal 5-HT in orofacial movements, serotonin (0, 0.2, 2, 10, 20 micrograms/1.0 microliters) was infused into the ventrolateral striatum and behaviors were recorded using a time-sampling procedure. Serotonin produced a dose-dependent, site-specific increase in stereotyped orofacial behaviors. Infusion of selective 5-HT receptor agonists or uptake inhibitors did not produce the orofacial syndrome and pretreatment with either selective or nonselective 5-HT receptor antagonists did not block the 5-HT induced stereotypy. In contrast, pretreatment with DA receptor antagonists completely abolished the 5-HT induced repetitive orofacial movements, providing evidence for a 5-HT/DA interaction at this site. Moreover, depletion of DA with a combination of reserpine and alpha-methyl-p-tyrosine markedly decreased the stereotyped behaviors induced by 5-HT microinfusion. These data provide evidence for an interaction between 5-HT and DA in the striatum at presynaptic DA terminals. It is hypothesized that 5-HT may cause release of DA via reversal of the DA transporter. This syndrome may provide an animal model for some aspects of obsessive-compulsive disorder, because current theories of this disorder implicate 5-HT dysfunction in the basal ganglia.