Electrical self-stimulation in the central amygdaloid nucleus after ibotenic acid lesion of the lateral hypothalamus

This experiment was carried out in order to investigate the involvement of lateral hypothalamus (LH) in electrical self-stimulation of the central amygdaloid nucleus (CeA). Adult male Sprague-Dawley rats were bilaterally implanted with a guide cannula situated above each LH and with two electrodes in the CeA. Self-stimulation was subsequently obtained separately from both right and left electrodes. The LH was then lesioned unilaterally by ibotenic acid (IBO) injection. Eight days later, the effect of this unilateral lesion on self-stimulation of the ipsilateral and contralateral CeA was tested. Then the neurons of the remaining non-lesioned LH side were lesioned with IBO and self-stimulation was tested 15 days after the second lesion. Both unilateral as well as bilateral lesions of LH produced a significant decrease in CeA self-stimulation rates but had no significant effect on the reward effectiveness. The unilateral lesions did not produce any modification of the rate-intensity function in the contralateral CeA. This lesion-induced depression in performance was reversed by treatment with phenobarbital. These results provide clear evidence that the rewarding effects of CeA electrical stimulation do not result from the activation of the LH outputs and that the apparent decrease in CeA self-stimulation may result from the LH lesion-induced increase in the frequency of epileptiform manifestations that occur following amygdaloid stimulation.     

Differential effects produced by an anticholinergic on the neuroleptic inhibition of motor behaviour and self-stimulation of the prefrontal cortex in the rat

A specific dopamine receptor blocker, spiroperidol (0.016, 0.032, 0.064 and 0.128 mg/kg) alone or in combined treatment with the centrally acting anticholinergic, dexetimide (0.5, 1.0 mg/kg) was given intraperitoneally to rats pressing a lever for brain self-stimulation through electrodes implanted in the medial prefrontal cortex. The same treatment was also given to rats in which the spontaneous motor behaviour was measured. Spiroperidol produced a dose-related inhibition of both self-stimulation and spontaneous motor activity. Dexetimide, given to spiroperidol treated rats, was able to antagonize the motor impairment produced by spiroperidol, but prefrontal cortex self-stimulation remained decreased. These data support the suggested role for dopamine in self-stimulation of the prefrontal cortex in the rat.     

Comparison of deficits in electrical self-stimulation after ibotenic acid lesion of the lateral hypothalamus and the medial prefrontal cortex

The aim of the present study was to compare the self-stimulation deficit produced by a unilateral injection of the neurotoxin, ibotenic acid, in the lateral hypothalamus (LH) to the deficit produced by the same unilateral injection in the medial prefrontal cortex (MPC). Four groups of adult male Sprague-Dawley rats were used: in two control groups, electrodes were bilaterally implanted in the LH (5 rats) or in the MPC (6 rats) and self-stimulation (ICSS) was obtained separately with the right and left electrodes. In the two experimental groups the intrinsic neurons of the LH (8 rats) or of the MPC (10 rats) were destroyed unilaterally by local injection of ibotenic acid (4 micrograms in 0.5 microliter); the other side served as the sham-lesioned control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral region. As in the case of the control rats, ICSS was determined separately for each electrode, first by a rate dependent test (nose-poke) then by a 'rate-free' test (shuttle-box). In the LH and MPC control rats, ICSS responses were the same with stimulation on either side. In the LH-lesioned rats, the ICSS rates measured with the nose-poke test were significantly decreased with stimulation on the lesioned side, whereas rates with stimulation of the non-lesioned LH were normal. Likewise, while shuttle responses with stimulation of the non-lesioned LH were normal, the OFF-time was increased and the ON-time was decreased with stimulation of the lesioned LH. In the MPC-lesioned rats, ICSS (nose-poke) was totally suppressed and the shuttle responses were disorganized since neither the ON- nor the OFF-times changed in response to increasing current intensities. Nose-poke responses with stimulation of the non-lesioned MPC were just about normal. These results show that in the two brain regions studied local neurons are involved in ICSS. The difference in the magnitude of the deficit observed suggests, that the neuronal circuits involved in MPC self-stimulation are poorly represented whereas in the LH many neuronal circuits involved in these mechanisms overlap.     

Effects of D-amphetamine on concurrent self-stimulation of forebrain and brain stem loci.

Two groups of rats with 3 chronic electrodes were allowed continuous access to self-stimulation on all 3 electrodes in a 3-lever chamber. The rats in Experiment 1 had electrodes aimed at the septal area (SEPT), anterior lateral hypothalamus (ALH) and posterior lateral hypothalamus (PLH). After establishing regular baseline rates of lever-pressing on all 3 electrodes the rats were subjected to a series ofd-amphetamine sulfate injections, 0.62, 2.5 and 5.0 mg/kg. Amphetamine increased response rates predominantly on the PLH electrode in all rats. As the dose of amphetamine increased, the rats self-stimulated at higher rates and for longer duration on the PLH electrode. In Experiment 2 the rats had electrodes aimed at the PLH, ventromedial tegmentum (VMT) and locus coeruleus (LC). After establishing baseline rates of lever-pressing on all 3 electrodes, the rats were subjected to two identical series ofd-amphetamine sulfate injections, 0.5, 1.0, 2.0 and 4.0 mg/kg. Amphetamine increased response rates predominantly on the PLH and VMT electrodes at 1.0 mg/kg and on the VMT electrode at the 2.0 and 4.0 mg/kg doses. As the dose increased, the rats self-stimulated at higher rates and for longer duration on the VMT electrode. The LC electrode was the least active site for lever-pressing after the 1.0, 2.0 and 4.0 mg/kg doses. Results suggest a differential anatomical sensitivity tod-amphetamine as measured by selective increases in responding and supports the hypothesis that the mesolimbic dopamine pathway has a role in the facilitative effects of amphetamine on self-stimulation.     

Dopaminergic substrates of intracranial self-stimulation in the caudate-putamen.

An extensive mapping of the caudate-putamen in rat for intracranial self-stimulation (ICS) site was undertaken to provide addtional support for the role of dopamine in brain-stimulation reward. Eight-seven per cent of the placements in the neostriatum supported ICS, with self-stimulation rates greater than 250/15 min at 56% of these sites. Electrical stimulation also elicited rearing and clonus, and contralateral body turn, both of which varied in magnitude between animals. In a second experiment, animals were prepared with electrodes aimed at the lateral caudateputamen. Those subjects displaying ICS subsequently received 6-hydroxydopamine lesions to the dopamine cell bodies in the substantia nigra pars compacta, either ipsilateral or contralateral to the electrode. The destruction of the dopamine cell bodies attenuated ICS in both groups during the first post-lesion test sessions. However, the rates in the ipsilateral group declined to between 2 and 9% of control scores, whereas the rate in the contralateral group improved over testing to 72% of control values, 28 days after the lesion. On the basis of these data, it was concluded that unilateral destruction of the dopaminergic nigro-neostriatal bundle (NSB) has two effects on ICS behavior. First, unilateral reduction of neostriatal dopamine is accompanied by a loss of brain-stimulation reward at sites normally innervated by the NSB, specifically the caudate-putamen. Secondly, lesions of the NSB produce a general disruption in bar-pressing behavior, as evidenced by the attenuation of ICS following contralateral lesions.     

Prefrontal cortex and neostriatum self-stimulation in the rat: Differential effects produced by apomorphine

In a dose-response experiment, the effects of intraperitoneal injections of the dopamine receptor agonist, apomorphine (0.075, 0.15, 0.3, 0.6 and 1.2 mg/kg) were studied on self-stimulation elicited from electrodes implanted in the medial and sulcal prefrontal cortex and caudate-putamen in the rat. From the medial and sulcal prefrontal cortex electrodes, apomorphine produced a dose-related decrease of self-stimulation rate which was consistent across animals. From the caudate-putamen electrodes, on the contrary, apomorphine produced a facilitatory effect in the majority of the animals at one or more doses, however, at other doses a decreased self-stimulation rate was observed. The clear and consistent effects of apomorphine on self-stimulation of the prefrontal cortex, together with other experimental evidence in the same line, suggest that dopamine is mediating self-stimulation of this cortical area.     

Dynamic changes in dopamine tone during self-stimulation of the ventral tegmental area in rats

In a prior study, phasic release of dopamine (DA) in the nucleus accumbens (NAc) was only transiently and rarely detected by means of fast-scan cyclic voltammetry (FCSV) in rats already trained to work for electrical stimulation of the ventral tegmental area (VTA) on a continuous reinforcement schedule. However, in rats receiving rewarding electrical stimulation via lateral hypothalamic (LH) electrodes, elevated DA tone in the NAc terminal field was detected via microdialysis for up to 2h, even when short (1.5s) inter-train intervals were employed. To better characterize the similarities and differences between the FSCV and microdialysis measurements, we trained rats to self-administer VTA stimulation under conditions similar to those employed in the initial FSCV study. The results resemble those obtained by means of microdialysis in rats receiving LH stimulation but differed from the prior FSCV data. Although the concentration of DA in dialysate obtained from NAc probes did fall after having peaked at the 30 min mark, this decline set in much later than in the FSCV studies, and elevated DA tone could still be detected after 110 min of self-stimulation. The stimulation-induced peak in DA tone could be restored by a 30 min rest period, a manipulation that was ineffective previously in restoring the FSCV measure of phasic release. These findings are discussed in terms of the differential sensitivity of the FSCV and microdialysis methods to phasic and tonic signaling by DA neurons and to different transitions between their activity states.     

Inhibition of the release of LH and ovulation by activation of the noradrenergic system. Effect of interrupting the ascending pathways

The effect of stimulation of the central noradrenergic system on the release of LH and ovulation was studied in the female rat. Electrochemical stimulation (ECS) (anodic DC) was applied through monopolar stainless-steel electrodes chronically implanted in animals bearing a plastic cannula inserted into the jugular vein for blood sampling.In ovariectomized, estrogen-primed rats, ECS applied in the nucleus locus coeruleus (LC) blocked the release of LH triggered by electrical stimulation of the medial preoptic area. A similar result was observed when the stimulus was applied in the A5 cell grouping but not when it was applied outside the nuclei but near them or when a cathodic current was passed through the electrode implanted into the LC. The degree of inhibition of LH release was proportional to the amount of current applied.Electrochemical stimulation of the LC, the A5 or the A1 cell grouping in non-anesthetized freely-behaving rats on the day of proestrus also blocked ovulation and the spontaneous surge of LH.Unilateral transection of the dorsal noradrenergic bundle at the level of the mesencephalon completely suppressed the inhibitory effect on LH release resulting from ECS applied to the ipsilateral LC nucleus of A5 cell grouping. On the contrary unilateral transection of the ventral noradrenergic bundle did not interfere with the inhibition elicited from the LC and only partially affected that elicited from the A5 neuronal group.These results provide evidence that endogenous release of norepinephrine elicited by activation of the central noradrenergic system can inhibit LH secretion, suggesting that the noradrenergic system may be envolved inhibitory mechanisms controlling LH release.     

The role of intrinsic neurons in lateral hypothalamic self-stimulation

In this brief review, we summarize some of our recent work concerning the effect of a specific lesion of the intrinsic neurons located in the middle part of the lateral hypothalamus on electrical self-stimulation of this structure by electrodes implanted along the medial forebrain bundle. In a first experiment the neurons of the lateral hypothalamus were destroyed unilaterally by local injection of ibotenic acid (4 micrograms in 0.5 microliter). The contralateral side served as the sham-lesion control. Between 10 and 20 days later, electrodes were bilaterally implanted, one in the lesioned area, the other in the contralateral hypothalamus. Intracranial self-stimulation (ICSS) was obtained separately for each electrode, at various current intensities, using a nose-poke response. ICSS from electrodes implanted in the lesioned area was decreased in all cases, whereas ICSS of the sham-lesioned side was normal. In a second experiment, two groups of rats lesioned and implanted as above, received two additional electrodes either in the anterior hypothalamus or in the posterior hypothalamus. In rats with electrodes in the anterior hypothalamus, the lesion produced a large deficit in self-stimulation when stimulation was applied to the anterior electrode ipsilateral to the lesion. Only 3 of 6 rats showed a decrease in ICSS with stimulation of the posterior hypothalamic electrode ipsilateral to the lesion. These results suggest that ICSS in the anterior part of the medial forebrain bundle is sustained by long fibers originating in the middle part of the lateral hypothalamus, while ICSS in the posterior part of the lateral hypothalamus may not depend on the neurons located in the lesioned area.     

Intrinsic neurons are involved in lateral hypothalamic self-stimulation

The recent technique of using ibotenic acid to lesion selectively local neurons while sparing fibers of passage permitted us to answer a long-standing question: is lateral hypothalamic self-stimulation supported by fibers of passage or are the intrinsic hypothalamic neurons involved? Three groups of adult male Sprague-Dawley rats were used. In a normal group, electrodes were bilaterally implanted in the lateral hypothalamus and self-stimulation (ICSS) was obtained separately with the right and left electrodes, at various current intensities, using a nose-poke response. In the experimental group, the intrinsic neurons of the lateral hypothalamus were destroyed unilaterally by local injection of ibotenic acid (4 or 6 μg in 0.5 μl); the other side served as the sham-lesion control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral hypothalamus. As in the case of the normal animals, the rate of nose-poking (ICSS) was then determined separately for each electrode. In the normal rats, ICSS rates were the same with stimulation on either side and the increase in ICSS rate as a function of the increase in current intensity was the same on each side. In the experimental rats, ICSS of the lesioned side was decreased in all cases; moreover, after lesion with the 6 μg dose, ICSS was totally suppressed. Self-stimulation of the sham-lesioned side was not significantly different from that observed in the normal rats. In 6 rats sampled from the lesioned groups as well as in 3 additional unimplanted animals, biochemical assays compared dopamine and serotonin contents of the two striata and noradrenaline and serotonin contents of the two hippocampi. No difference was observed for these two structures between the side ipsilateral to the lesion and the contralateral side. Moreover, none of these monoamine levels differed from those seen in the unimplanted rats. These results, taken together, suggest that intrinsic lateral hypothalamic neurons are involved in ICSS.     

Lateralized decrease in self-stimulation induced by haloperidol in rats with unilateral 6-hydroxydopamine lesions

Rats with bilateral hypothalamic electrode placements which generated similar self-stimulation rate-intensity functions were subjected to unilateral injections of 6-hydroxydopamine (6-OHDA) into A9 and A10 areas. Following 12 weeks of postoperative recovery which was bilaterally symmetrical the rats were administered 0.1 mg/kg haloperidol. In sham- and vehicle-injected control rats the haloperidol produced bilaterally symmetrical decreases in self-stimulation. In the rats with 6-OHDA lesions the haloperidol effect was asymmetric with a much greater decrease in self-stimulation evident for electrode placements in the dopamine deficient hemisphere than for electrodes in the non-lesion hemisphere. Biochemical evaluation of the lesions indicated that dopamine was severely depleted in limbic and striatal forebrain areas. The combined use of a lesion with a pharmacological blockade of a neurotransmitter system appears to be an effective technique to distinguish reward versus performance effects of the transmitter on self-stimulation.     

Self-stimulation in the mesencephalic trajectory of the ventral noradrenergic bundle

The ventral noradrenergic bundle (VB) was mapped for self-stimulation throughout the region of its separation from the dorsal noradrenergic bundle in the mesencephalon of the rat. Eleven positive electrodes were located in the VB at sites clearly caudal to all known dopamine cell groups. Since the activation of dopamine neurons or other noradrenergic systems by current spread could be ruled out, the self-stimulation behavior was attributed to the activation of noradrenergic fibers in the VB itself. The cells of origin of these fibers were not determined, but it is probable from other evidence that noradrenergic cells from groups A6 and A7 were mainly involved. Twenty-nine electrodes in rostral VB sites yielded significantly higher maximum self-stimulation rates than the 11 caudal VB electrodes. The higher rates observed at rostral VB sites were attributed to: (a) the simultaneous activation of dorsal bundle and periventricular noradrenergic reward components that join the VB via the tegmental radiations, (b) the simultaneous activation of dopaminergic systems in the region of the substantia nigra, and (c) reduction of caudal VB rates by the simultaneous activation of directly-demonstrated escape systems.     

Chronic food restriction and weight loss produce opioid facilitation of perifornical hypothalamic self-stimulation

Electrical stimulation frequency thresholds for lateral hypothalamic (LH) self-stimulation were monitored throughout a 3 week period of food restriction and a subsequent 3 week period of re-feeding. Rats with electrodes placed in the perifornical LH were sensitive to this dietary manipulation as evidenced by a high positive correlation between body weight and self-stimulation threshold. Rats with electrodes in the zona incerta/subincertal region or ventral hypothalamus displayed little or no change in threshold. Lateral ventricular injection of naltrexone (200.0 nM) reversed the decline in threshold that was otherwise present during food restriction in rats with perifornical placements. Naltrexone had no effect on thresholds of rats with placements outside the perifornical region. These findings suggest that food restriction and weight loss activate an opioid mechanism that facilitates perifornical LH self-stimulation. The documented association of perifornical LH with the phenomenon of stimulation-induced feeding, and the reciprocal connections between this region and gustatory structures, supports the hypothesis that facilitation of self-stimulation by food restriction is related to the natural phenomenon of positive alliesthesia (i.e. the hunger-dependency of food reward).     

Application of in vivo electrochemistry to the measurement of changes in dopamine release during intracranial self-stimulation

Stearate-modified graphite paste recording electrodes were acutely or chronically implanted into the nucleus accumbens along with bipolar stimulating electrodes in the ipsilateral ventral tegmental area (VTA). Chronoamperometry was used to monitor changes in electrochemical signals that may correspond to the oxidation of dopamine (DA) during experimenter-administered stimulation (EAS) and intracranial self-stimulation (ICS). Application of EAS to stimulating electrodes in the VTA produced increases in the electrochemical signal in both the anesthetized and conscious preparation. The magnitude of both effects increased as a function of current intensity. Initiation of ICS was also accompanied by an immediate increase in the electrochemical signal. Rate-intensity experiments revealed a corresponding increase in both the ICS rates and the electrochemical signal with successive increases or decreases in current intensity. In subsequent experiments, intraperitoneal injections of DA uptake blockers nomifensine and GBR-12909 produced significant increases in the amplitude of the chronoamperometric signal which corresponded to drug-induced increases in bar press rates. The noradrenergic uptake blocker desipramine had no significant effect on either ICS rates or oxidation current. These data indicate that ICS of the VTA may produce concurrent increases in DA neurotransmission in the nucleus accumbens. The pharmacological studies are consistent with a dopaminergic substrate of brain stimulation reward at electrode sites in the VTA.     

Effect of number of tailshocks on learned helplessness and activation of serotonergic and noradrenergic neurons in the rat

Adult male albino rats were exposed to varying numbers of tailshocks (0, 10, 50 or 100). The following day, their escape latencies in a shuttlebox were measured in order to estimate the degree of learned helplessness (LH) produced by the varying number of shocks. Only the groups exposed to 50 or 100 shocks displayed evidence of LH. In a parallel experiment, c-fos activation was used to determine the degree of activation of raphe serotonergic neurons (FosIR+5-HT) and locus coeruleus (LC) noradrenergic neurons (FosIR+TH) produced by the same shock conditions. Compared to unhandled cage controls, all shock groups (0 shocks was a restrained group) significantly activated both raphe and LC neurons. The 50 and 100 shock groups had significantly higher degrees of activation of serotonergic neurons in the rostral raphe groups and the LC than the 0 and 10 shock groups. These data are consistent with the hypothesis that activation of rostral raphe serotonergic neurons and LC noradrenergic neurons beyond a certain threshold may be critical for the development of LH. The relevance of these results for elucidating the neural bases of psychopathology is discussed.     

Enhancement of self-stimulation behavior in rats and monkeys after chronic neuroleptic treatment: Evidence for mesolimbic supersensitivity

The effect of chronic neuroleptic drug treatment on self-stimulation of the mesolimbic dopamine system was tested. Rats with electrodes implanted into the ventral tegmental nucleus (A10 cell body area) were treated with haloperidol for three weeks. Afterwards, the rats showed a 35% increase in self-stimulation rate, as compared to pre-drug control rates. This increase persisted for three weeks after drug withdrawal before returning to baseline rates. Rats treated for three weeks with the atypical neuroleptic, clozapine, also showed an increase, the duration and magnitude of which was similar to that seen in the haloperidol group. In addition, four rhesus monkeys with electrodes in the nucleus accumbens (one of the terminal projection areas of the A10 mesolimbic dopamine system) were given a three week treatment with haloperidol, after which all animals showed a significant, long-lasting decrease in self-stimulation threshold, as measured by a rate-independent reward paradigm. Taken together, these results suggest the induction of receptor supersensitivity in the mesolimbic dopamine system by long-term treatment with neuroleptic drugs.     

Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation

The ability of chronic treatment with the atypical neuroleptic clozapine to induce functional dopaminergic hypersensitivity in laboratory rats was assessed. The intracranial electrical self-stimulation paradigm, known to be sensitive to changes in functional dopaminergic sensitivity, was used. Animals with electrodes in the ventral tegmental nucleus (mesolimbic dopamine cell body area) showed a marked increase in self-stimulation rate following 3 weeks of chronic clozapine. This increase was similar in magnitude and duration to that shown by animals given 3 weeks of chronic haloperidol. In contrast, animals with electrodes in the substantia nigra (nigrostriatal dopamine cell body area) showed no change in self-stimulation rate following 3 weeks of chronic clozapine. These data are interpreted in the light of previous suggestions that clozapine and other atypical neuroleptics may possess functional selectivity for the mesolimbic dopamine system.     

Intracranial self-stimulation in the parafascicular nucleus of the rat

A behavioral analysis of intracranial self-stimulation was provided for parafascicular nucleus. To evaluate whether intracranial self-stimulation in this nucleus could be site-specific and to determine if the positive sites are the same parafascicular areas that facilitate learning when stimulated, rats were tested via monopolar electrodes situated throughout the parafascicular nucleus. Animals were trained to self-stimulate by pressing a lever in a conventional Skinner box (1-5 sessions). Twenty-two of the 42 animals included in the study, had the electrode at the parafascicular nucleus. Only two of them showed intracranial self-stimulation. Histological analyses indicated that the latter rats had the electrode implanted at the anterior area of the medial parafascicular. Other two animals also showed intracranial self-stimulation but they had the electrode in a more posterior brain region, between the Dark-schewitsch nucleus and the red nucleus. The animals implanted at the parafascicular showed higher response rates than the other two rats. These results confirm that: (a) the anterior region of the medial parafascicular is a positive site for stable and regular intracranial self-stimulation behavior, and (b) these positive sites do not coincide with the parafascicular regions related to learning improvement.     

Ascending monoamine-containing fiber pathways related to intracranial self-stimulation: histochemical fluorescence study

Lesions made via self-stimulation electrodes in the medial forebrain bundle (MFB) of rats always resulted in monoamine accumulation, as studied with the histochemical fluorescence method. Build-up was often in the monoamine systems of the MFB itself, those systems being the ventral norepinephrine bundle, the nigro-neostriate bundle, and the mesolimbic fibers. In other cases, build-up was restricted to a bundle of fibers dorsomedial to the MFB, probably originating in the locus coeruleus or the subcoeruleus area. In still other instances, build-up was seen in both this dorsal bundle of fibers and the catecholamine systems of the MFB. Electrodes in rats with sites of implantation in the region of the A1, A2 and A5 cell groups of origin of the ventral norepinephrine system, as identified with combined Nissl and histochemical examination, were never positive with respect to self-stimulation; nor were placements in this ventral system caudal to the origin of the dorsal bundle positive with respect to that behavior. These results argued against the association of the ventral system with self-stimulation. By implication, the catecholamine fibers of the MFB which are capable of supporting self-stimulation might be the two ascending dopamine systems of the ventral mesencephalic tegmentum. Lesions made via positive electrodes in the vicinity of the brachium conjuctivum always resulted in monoamine build-up in the dorsal norepinephrine fiber system. In sum, our results implicate the A9 and A10 dopamine ventral midbrain systems and the A6 norepinephrine dorsal bundle in intracranial self-stimulation.     

Reversible Unilateral Nigrostriatal Pathway Inhibition Induced Through Expression of Adenovirus-mediated Clostridial Light Chain Gene in the Substantia Nigra

Clostridial light chain (LC) inhibits synaptic transmission by digesting a vesicle-docking protein, synaptobrevin, without killing neurons. We here report the feasibility of creating a rat hemiparkinsonism model through LC gene expression in the substantia nigra (SN), inhibiting nigrostriatal transmission. 40 adult Sprague Dawley rats were divided into four groups for SN injections of PBS, 6-hydroxydopamine (6-OHDA), or adenoviral vectors for the expression of LC (AdLC), or GFP (AdGFP). Amphetamine and apomorphine induced rotations were assessed before and after SN injection, revealing significant rotational alterations at 8 or 10 days after injection in both AdLC and 6-OHDA but not PBS and AdGFP groups. Induced rotation recovered by one month in AdLC rats but persisted in 6-OHDA rats. Histological analysis of the SN revealed LC and GFP expression with corresponding synaptobrevin depletion in the LC, but not the GFP groups. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry (IHC) showed markedly decreased staining in ipsilateral SN and striatum in 6-OHDA but not AdLC or AdGFP rats. Similarly, compared with contralateral, ipsilateral striatal dopamine level only decreased in 6-OHDA but not AdLC, AdGFP, or PBS treated rats. Thus, LC expression induces nigral synaptobrevin depletion with resulting inhibition of nigrostriatal synaptic transmission. Unlike 6-OHDA, LC expression inhibits synaptic activity without killing neurons. This approach, therefore, represents a potentially reversible means of nigrostriatal pathway inhibition as a model for Parkinson’s disease. Such a model might facilitate transient and controlled nigral inhibition for studying striatal recovery, dopaminergic re-innervation, and normalization of striatal receptors following the recovery of nigrostriatal transmission.