Comprehensive Physiology Wiley Online Library

Brain Monoamines, Homeostasis, and Adaptive Behavior

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Homeostasis: Physiological and Behavioral Contributions
1.1 Specific and Nonspecific Components of Homeostatic Responses
2 General Characteristics of Central Monoaminergic Systems
2.1 Anatomical Characteristics
2.2 Physiological Characteristics
2.3 Synaptic Homeostasis
2.4 Constancy of Transmitter Stores
2.5 Summary
3 Dopamine‐Depleting Brain Lesions and Behavior
3.1 Initial Behavioral Deficits
3.2 Recovery of Function
4 Dopamine‐Depleting Brain Lesions and Behavior: A Biological Appraisal
4.1 Why Are Large Lesions Required Before Deficits Occur?
4.2 Why Do Animals Recover From Initial Effects of These Lesions?
4.3 What Is Significance of Residual Behavioral Deficits?
5 Concluding Comments
5.1 Effects of Peripheral Sympathectomy
5.2 Arousal and Motivation
Figure 1. Figure 1.

Distribution of main central neuronal pathways containing norepinephrine (A), dopamine (B), and serotonin (C). A: DB, dorsal bundle; VB, ventral bundle; and dst, descending spinal tract. B: SNC, substantia nigra. C: DR, dorsal raphe nucleus; VT, ventral tegmentum; and MR, median raphe nucleus. Cell groups are named according to nomenclature of Dahlström and Fuxe .

From Cotman and McGaugh
Figure 2. Figure 2.

A: drug‐response histograms (8 sweeps) of response of cerebellar Purkinje cell to microiontophoretic pulses of γ‐aminobutyric acid (GABA; bar) applied before, in conjunction with, and long after preconditioning stimulation of locus coeruleus (LC; dotted line). Stimulation of LC for 3.5 s at 10 Hz, initiated 6.0 s before onset of drug iontophoresis, greatly enhanced inhibitory response to GABA. Numbers beneath bars in histograms indicate percent inhibition of background firing GABA produced. B: poststimulus‐time histograms (100 sweeps) of effects of LC‐preconditioning stimulation on climbing fiber excitation of Purkinje cell evoked by sensorimotor cortex (Ctx) stimulation (3 vertical bars). Stimulation of LC (3 shocks at 100 Hz) at currents subthreshold for directly affecting spontaneous discharge of this cell enhanced activity evoked by climbing fiber input (horizontal bar).

From Woodward et al.
Figure 3. Figure 3.

A: ionotropic neurotransmission, exemplified by acetylcholine (▾) acting at neuromuscular junction, involves binding of transmitter molecules to receptor (R) coupled directly to an ion channel, resulting in momentary change in channel opening. B: metabotropic neurotransmission, exemplified by norepinephrine (▿) acting on β‐adrenergic receptors, involves binding of transmitter molecules to R, followed by activation of catalytic subunit (C) via intermediate regulatory protein (N). Once activated, C catalyzes formation of intracellular second messenger, cAMP, thereby initiating cascade of reactions often involving activation of protein kinase (PK) and protein phosphorylation (protein‐PO4), as well as additional steps (dotted lines) ultimately leading to change in characteristics of target cell.

Adapted from Eccles and McGeer , Kanof et al. , and Rodbell
Figure 4. Figure 4.

Pathways of synaptic homeostasis. Influence of monoaminergic neuron (shaded) on its target can be regulated both by modulation of transmitter release and by amplification of signal provided by that release . This involves a large variety of cell surface receptors, including receptors that respond to monoamine itself (▪), as well as receptors responding to other chemical signals (•, □, ▵, ▴). Principal pathways for regulating transmitter release: 1, direct action of recurrent collaterals onto soma; 2, indirect action of recurrent collaterals, mediated via influence on presynaptic afferents; 3, direct action of transmitter (T) on presynaptic terminal; 4, alterations in rate of transmitter reuptake; 5, humoral signals generated by target; 6, neural signals providing short‐loop negative feedback from target; and 7, neural signals providing long‐loop negative feedback from target. In addition extent to which signal is amplified can be modulated by short‐term modification of the sensitivity of the target, by long‐term changes in number of receptors, and by other means.

Figure 5. Figure 5.

Increases in receptor number after chronic disruption of synaptic transmission. A: [3H]‐dihydroalprenolol binding by cortical membrane after chronic reserpine treatment. Rats received reserpine (0.25–0.50 mg/kg, ip) each day for 4 days and were killed 48 h after last injection. Dissociation constants (Kd are shown. Concentrations of binding sites (Bmax) were 191 and 281 fmol/mg protein in cortices of control and reserpine‐treated animals, respectively. B: [3H] spiperone binding by striatal membranes after chronic haloperidol (Haldol) treatment. Rats received haloperidol (1 mg/kg, sc) for 54 days and were killed 72 h after last injection.

A from Dolphin et al. ; B from R. G. MacKenzie, unpublished observations
Figure 6. Figure 6.

Activation of tyrosine hydroxylase in striatum during increased impulse flow, measured in presence of various concentrations of cofactor 6,7–dimethyl‐5,6,7,8‐tetrahydropterin (DMPH4), or 6‐methyl‐5,6,7,8‐tetrahydropterin. A: effect of reserpine (8 μmol/kg, ip, given 2 h prior to killing rats), which is believed to increase impulse flow via interruption of negative‐feedback loop. B: effect of direct stimulation on nigrostriatal bundle (20 min at 15 Hz).

A from Zivkovic and Guidotti ; B from Murrin et al.
Figure 7. Figure 7.

Short‐ and long‐term activation of adrenal tyrosine hydroxylase (TH). Rats received subcutaneous injections of insulin (20 U/kg) either once or on 4 consecutive days and TH was then assayed 1 h later in presence of subsaturating or saturating concentrations of synthetic cofactor, 6‐methyl‐5,6,7,8‐tetrahydropterin (6MPH4). Increases in enzyme activity detected under both conditions reflect increase in apparent maximal velocity, whereas increases detected only under subsaturating conditions reflect increase in affinity for cofactor.

From Fluharty et al.
Figure 8. Figure 8.

Gradual appearance of TH in terminal regions after 5 mg/kg reserpine administration. A: stellate ganglia and heart. B: locus coeruleus, cerebellum, and hippocampus.

A from Thoenen et al. ; B from Zigmond
Figure 9. Figure 9.

Frontal section of rat brain through hypothalamus. Dots, axons containing norepinephrine in left hemisphere and axons containing dopamine on contralateral side. Vertical lines, major nerve terminal areas. CAI, capsula interna; F, columna fornicis; FMT, fasciculus mamillothalamicus; HD, nucleus dorsomedialis hypothalami; and HV, nucleus ventromedialis hypothalami.

Adapted from Ungerstedt
Figure 10. Figure 10.

Presumed reaction sequence for production of cytotoxic compounds from 6‐hydroxydopamine (6‐OHDA), which is structurally similar to norepinephrine and dopamine and is believed to gain preferential access into neurons containing these catecholamines through amine‐specific uptake mechanisms in their axon terminals. Once concentrated within these neurons, the formed peroxides and quinones destroy nerve terminals.

From Heikkila and Cohen
Figure 11. Figure 11.

Rat with unilateral (right hemisphere) lateral hypothalamic damage shows precise head orientation and biting to various kinds of stimuli on ipsilateral side, while neglecting same stimuli presented contralaterally.

From Marshall et al. . Copyright 1971 by the American Association for the Advancement of Science
Figure 12. Figure 12.

Response of monoaminergic cells to sensory stimuli. A: locus coeruleus cells responding to sensory stimuli. Interspike interval histogram shows 162 total counts from sampling period of 253 s. In peristimulus time histogram (PSTH) displays, stimuli were delivered at time 0. Inset: analog record of this neuron's response to 1st stimulus (arrow). Calibration marks: 50 μU, 400 ms. B: substantia nigra cells responding to tail pressure (TP), cervical probing (CP), and light flash (LF). Top and bottom traces are believed to represent 2 classes of dopaminergic cells. C: raphe nucleus cells responding to tone; PSTH from 64 trials. Above PSTH is trace of representative unit response to repetitive stimulus; arrows mark stimulus presentation.

A from Foote et al. ; B from Chiodo et al. ; and C from Heym et al.
Figure 13. Figure 13.

Electrochemical responses to tail shock [1 mA for 1 s, delivered every 10 s for 1 min, administered at 30 min (arrow)] in a rat with large 6‐OHDA‐induced brain lesions (•) and in an intact rat (•). Electrode was implanted in striatum of animals and presumably detects dopamine, its metabolite dihydroxyphenylacetic acid, and ascorbic acid.

From Zigmond and Stricker , © 1984, with permission from Pergamon Press, Ltd
Figure 14. Figure 14.

Conceptualized gating function by which dopaminergic neurons in nigrostriatal bundle mediate sensorimotor integration necessary for behavior. Each exteroceptive sensory stimulus has 2 effects: 1) a specific effect activating neurons involved in mediating that particular sensation; and 2) a nonspecific effect removing inhibitory influence and thereby promoting behavioral response to such stimuli. Stimulus would not evoke behavioral response if either specific or nonspecific pathways were interrupted. Given multiplicity of stimuli impinging on animal at any given time, we presume that overt behavioral response [e.g., feeding (R)] is associated with prepotent stimulus [e.g., hunger (S1)]. Additional stimuli of relevance to motivation [e.g., gustatory and olfactory cues associated with food (S2 and S3)] would tend to augment nonspecific arousal component, owing to multisensory convergence onto single reticular neurons, and thereby facilitate responding. Thus a weak stimulus for hunger still might elicit feeding when combined with incentive arousal from highly palatable food. From this perspective, critical consequence of large dopamine‐depleting brain lesions is to reduce normal activating properties of exteroceptive sensory stimuli and thereby diminish behavioral activity.

Adapted from Stricker and Zigmond
Figure 15. Figure 15.

Changes in behavior of rat given 2 injections of 6‐OHDA (200 μg, iv), each 30 min after pargyline (50 mg/kg, ip). Intragastric (IG) feedings are shown. Bar at bottom indicates access to highly palatable foods. Animal had 98% depletion of striatal dopamine.

From Zigmond and Stricker . Copyright 1973 by the American Association for the Advancement of Science
Figure 16. Figure 16.

Effects of 8 daily injections of protamine‐zinc insulin (PZI) on food intakes of sham‐lesioned control rats (n = 9) and rats that had received intraventricular injections of 6‐OHDA (n = 16). Each point represents mean value; SE (not shown) ranged from 1.3 to 2.2. Brain‐damaged rats had striatal dopamine depletions of 79%‐93% and would not have increased food intake in response to acute glucoprivation .

From Rowland and Stricker , © 1982, with permission from Pergamon Press, Ltd
Figure 17. Figure 17.

Cumulative mean water intakes of 5 rats “recovered” from initial effects of lateral hypothalamic damage after intraperitoneal injection of hypertonic NaCl solution at 4 different times of day. Lights were on between 0800 and 1600 h. Animals did not drink much during light period but drank promptly once it was dark. No food was present during tests. No animal drank, > 1.5 ml in 24 h if not treated with saline.

From Rowland . Copyright 1976 by the American Psychological Association
Figure 18. Figure 18.

Scheme for recovery of function after subtotal damage to central neurons containing monoamine. A: intact animal. B: animal with relatively small lesions; there is increased release of transmitter (T) from residual neurons, increased synthesis of transmitter from precursor (P), and decreased inactivation of transmitter owing to loss of uptake sites, which maintain synaptic levels of transmitter at near‐normal levels (as in A). C: animal with relatively large lesions; these changes cannot maintain synaptic levels of transmitter but may maintain synaptic function together with increases in number of postsynaptic receptors (▪).

Adapted from Zigmond and Stricker
Figure 19. Figure 19.

Increased dopaminergic activity after injury to nigrostriatal bundle. A: electrolytic lesion of nigrostriatal bundle in monkeys, leading to apparent increase in dopamine turnover in residual striatal terminals as determined 1–4 mo later. B: intraventricular 6‐OHDA levels in rats, leading to apparent increase in TH in residual striatal terminals.

A adapted from Sharman et al. ; B adapted from Zigmond et al.
Figure 20. Figure 20.

Evidence for presynaptic supersensitivity after 6‐OHDA treatment. A: loss of specific high‐affinity catecholamine uptake sites, as measured by accumulation of [3H]norepinephrine (3H‐NA) into slices of normal tissue and tissue from animals treated with 6‐OHDA 22–30 days previously. In some experiments slices were incubated in presence of 5 μM desmethylimipramine (DMI), an inhibitor of 3H‐NA uptake. Means ± SE of 4–8 experiments are indicated. B: increased responsiveness to L‐dopa. Groups of 3–4 animals received L‐dopa (100 mg/kg) or saline 30 min after receiving RO 4–4602 (50 mg/kg) to inhibit peripheral dopa decarboxylase. Motor activity (counts) was determined from 30 to 60 min after administering L‐dopa. Means ± SE shown are determined 1–15 days after 2nd of 2 6‐OHDA injections (250 μg, 48 h apart).

A from Uretsky and Iversen ; B from Schoenfeld and Uretsky
Figure 21. Figure 21.

Long‐term increase in TH activity after 6‐OHDA treatment (compare with Fig. ).

Adapted from Acheson and Zigmond
Figure 22. Figure 22.

Evidence for increased dopamine receptor density in striatum after 6‐OHDA lesion. A: time course of changes in [3H]spiroperidol binding to striatal membranes. B: striatal dopamine receptor binding 4‐mo postlesion. Only when lesions are almost complete, with TH activity < 7% of control, does 3H‐ligand binding increase. However, with less‐complete lesions there is no evidence of increased binding of either agonist (apomorphine) or antagonist (spiroperidol).

A from Staunton et al. ; B from Creese


Figure 1.

Distribution of main central neuronal pathways containing norepinephrine (A), dopamine (B), and serotonin (C). A: DB, dorsal bundle; VB, ventral bundle; and dst, descending spinal tract. B: SNC, substantia nigra. C: DR, dorsal raphe nucleus; VT, ventral tegmentum; and MR, median raphe nucleus. Cell groups are named according to nomenclature of Dahlström and Fuxe .

From Cotman and McGaugh


Figure 2.

A: drug‐response histograms (8 sweeps) of response of cerebellar Purkinje cell to microiontophoretic pulses of γ‐aminobutyric acid (GABA; bar) applied before, in conjunction with, and long after preconditioning stimulation of locus coeruleus (LC; dotted line). Stimulation of LC for 3.5 s at 10 Hz, initiated 6.0 s before onset of drug iontophoresis, greatly enhanced inhibitory response to GABA. Numbers beneath bars in histograms indicate percent inhibition of background firing GABA produced. B: poststimulus‐time histograms (100 sweeps) of effects of LC‐preconditioning stimulation on climbing fiber excitation of Purkinje cell evoked by sensorimotor cortex (Ctx) stimulation (3 vertical bars). Stimulation of LC (3 shocks at 100 Hz) at currents subthreshold for directly affecting spontaneous discharge of this cell enhanced activity evoked by climbing fiber input (horizontal bar).

From Woodward et al.


Figure 3.

A: ionotropic neurotransmission, exemplified by acetylcholine (▾) acting at neuromuscular junction, involves binding of transmitter molecules to receptor (R) coupled directly to an ion channel, resulting in momentary change in channel opening. B: metabotropic neurotransmission, exemplified by norepinephrine (▿) acting on β‐adrenergic receptors, involves binding of transmitter molecules to R, followed by activation of catalytic subunit (C) via intermediate regulatory protein (N). Once activated, C catalyzes formation of intracellular second messenger, cAMP, thereby initiating cascade of reactions often involving activation of protein kinase (PK) and protein phosphorylation (protein‐PO4), as well as additional steps (dotted lines) ultimately leading to change in characteristics of target cell.

Adapted from Eccles and McGeer , Kanof et al. , and Rodbell


Figure 4.

Pathways of synaptic homeostasis. Influence of monoaminergic neuron (shaded) on its target can be regulated both by modulation of transmitter release and by amplification of signal provided by that release . This involves a large variety of cell surface receptors, including receptors that respond to monoamine itself (▪), as well as receptors responding to other chemical signals (•, □, ▵, ▴). Principal pathways for regulating transmitter release: 1, direct action of recurrent collaterals onto soma; 2, indirect action of recurrent collaterals, mediated via influence on presynaptic afferents; 3, direct action of transmitter (T) on presynaptic terminal; 4, alterations in rate of transmitter reuptake; 5, humoral signals generated by target; 6, neural signals providing short‐loop negative feedback from target; and 7, neural signals providing long‐loop negative feedback from target. In addition extent to which signal is amplified can be modulated by short‐term modification of the sensitivity of the target, by long‐term changes in number of receptors, and by other means.



Figure 5.

Increases in receptor number after chronic disruption of synaptic transmission. A: [3H]‐dihydroalprenolol binding by cortical membrane after chronic reserpine treatment. Rats received reserpine (0.25–0.50 mg/kg, ip) each day for 4 days and were killed 48 h after last injection. Dissociation constants (Kd are shown. Concentrations of binding sites (Bmax) were 191 and 281 fmol/mg protein in cortices of control and reserpine‐treated animals, respectively. B: [3H] spiperone binding by striatal membranes after chronic haloperidol (Haldol) treatment. Rats received haloperidol (1 mg/kg, sc) for 54 days and were killed 72 h after last injection.

A from Dolphin et al. ; B from R. G. MacKenzie, unpublished observations


Figure 6.

Activation of tyrosine hydroxylase in striatum during increased impulse flow, measured in presence of various concentrations of cofactor 6,7–dimethyl‐5,6,7,8‐tetrahydropterin (DMPH4), or 6‐methyl‐5,6,7,8‐tetrahydropterin. A: effect of reserpine (8 μmol/kg, ip, given 2 h prior to killing rats), which is believed to increase impulse flow via interruption of negative‐feedback loop. B: effect of direct stimulation on nigrostriatal bundle (20 min at 15 Hz).

A from Zivkovic and Guidotti ; B from Murrin et al.


Figure 7.

Short‐ and long‐term activation of adrenal tyrosine hydroxylase (TH). Rats received subcutaneous injections of insulin (20 U/kg) either once or on 4 consecutive days and TH was then assayed 1 h later in presence of subsaturating or saturating concentrations of synthetic cofactor, 6‐methyl‐5,6,7,8‐tetrahydropterin (6MPH4). Increases in enzyme activity detected under both conditions reflect increase in apparent maximal velocity, whereas increases detected only under subsaturating conditions reflect increase in affinity for cofactor.

From Fluharty et al.


Figure 8.

Gradual appearance of TH in terminal regions after 5 mg/kg reserpine administration. A: stellate ganglia and heart. B: locus coeruleus, cerebellum, and hippocampus.

A from Thoenen et al. ; B from Zigmond


Figure 9.

Frontal section of rat brain through hypothalamus. Dots, axons containing norepinephrine in left hemisphere and axons containing dopamine on contralateral side. Vertical lines, major nerve terminal areas. CAI, capsula interna; F, columna fornicis; FMT, fasciculus mamillothalamicus; HD, nucleus dorsomedialis hypothalami; and HV, nucleus ventromedialis hypothalami.

Adapted from Ungerstedt


Figure 10.

Presumed reaction sequence for production of cytotoxic compounds from 6‐hydroxydopamine (6‐OHDA), which is structurally similar to norepinephrine and dopamine and is believed to gain preferential access into neurons containing these catecholamines through amine‐specific uptake mechanisms in their axon terminals. Once concentrated within these neurons, the formed peroxides and quinones destroy nerve terminals.

From Heikkila and Cohen


Figure 11.

Rat with unilateral (right hemisphere) lateral hypothalamic damage shows precise head orientation and biting to various kinds of stimuli on ipsilateral side, while neglecting same stimuli presented contralaterally.

From Marshall et al. . Copyright 1971 by the American Association for the Advancement of Science


Figure 12.

Response of monoaminergic cells to sensory stimuli. A: locus coeruleus cells responding to sensory stimuli. Interspike interval histogram shows 162 total counts from sampling period of 253 s. In peristimulus time histogram (PSTH) displays, stimuli were delivered at time 0. Inset: analog record of this neuron's response to 1st stimulus (arrow). Calibration marks: 50 μU, 400 ms. B: substantia nigra cells responding to tail pressure (TP), cervical probing (CP), and light flash (LF). Top and bottom traces are believed to represent 2 classes of dopaminergic cells. C: raphe nucleus cells responding to tone; PSTH from 64 trials. Above PSTH is trace of representative unit response to repetitive stimulus; arrows mark stimulus presentation.

A from Foote et al. ; B from Chiodo et al. ; and C from Heym et al.


Figure 13.

Electrochemical responses to tail shock [1 mA for 1 s, delivered every 10 s for 1 min, administered at 30 min (arrow)] in a rat with large 6‐OHDA‐induced brain lesions (•) and in an intact rat (•). Electrode was implanted in striatum of animals and presumably detects dopamine, its metabolite dihydroxyphenylacetic acid, and ascorbic acid.

From Zigmond and Stricker , © 1984, with permission from Pergamon Press, Ltd


Figure 14.

Conceptualized gating function by which dopaminergic neurons in nigrostriatal bundle mediate sensorimotor integration necessary for behavior. Each exteroceptive sensory stimulus has 2 effects: 1) a specific effect activating neurons involved in mediating that particular sensation; and 2) a nonspecific effect removing inhibitory influence and thereby promoting behavioral response to such stimuli. Stimulus would not evoke behavioral response if either specific or nonspecific pathways were interrupted. Given multiplicity of stimuli impinging on animal at any given time, we presume that overt behavioral response [e.g., feeding (R)] is associated with prepotent stimulus [e.g., hunger (S1)]. Additional stimuli of relevance to motivation [e.g., gustatory and olfactory cues associated with food (S2 and S3)] would tend to augment nonspecific arousal component, owing to multisensory convergence onto single reticular neurons, and thereby facilitate responding. Thus a weak stimulus for hunger still might elicit feeding when combined with incentive arousal from highly palatable food. From this perspective, critical consequence of large dopamine‐depleting brain lesions is to reduce normal activating properties of exteroceptive sensory stimuli and thereby diminish behavioral activity.

Adapted from Stricker and Zigmond


Figure 15.

Changes in behavior of rat given 2 injections of 6‐OHDA (200 μg, iv), each 30 min after pargyline (50 mg/kg, ip). Intragastric (IG) feedings are shown. Bar at bottom indicates access to highly palatable foods. Animal had 98% depletion of striatal dopamine.

From Zigmond and Stricker . Copyright 1973 by the American Association for the Advancement of Science


Figure 16.

Effects of 8 daily injections of protamine‐zinc insulin (PZI) on food intakes of sham‐lesioned control rats (n = 9) and rats that had received intraventricular injections of 6‐OHDA (n = 16). Each point represents mean value; SE (not shown) ranged from 1.3 to 2.2. Brain‐damaged rats had striatal dopamine depletions of 79%‐93% and would not have increased food intake in response to acute glucoprivation .

From Rowland and Stricker , © 1982, with permission from Pergamon Press, Ltd


Figure 17.

Cumulative mean water intakes of 5 rats “recovered” from initial effects of lateral hypothalamic damage after intraperitoneal injection of hypertonic NaCl solution at 4 different times of day. Lights were on between 0800 and 1600 h. Animals did not drink much during light period but drank promptly once it was dark. No food was present during tests. No animal drank, > 1.5 ml in 24 h if not treated with saline.

From Rowland . Copyright 1976 by the American Psychological Association


Figure 18.

Scheme for recovery of function after subtotal damage to central neurons containing monoamine. A: intact animal. B: animal with relatively small lesions; there is increased release of transmitter (T) from residual neurons, increased synthesis of transmitter from precursor (P), and decreased inactivation of transmitter owing to loss of uptake sites, which maintain synaptic levels of transmitter at near‐normal levels (as in A). C: animal with relatively large lesions; these changes cannot maintain synaptic levels of transmitter but may maintain synaptic function together with increases in number of postsynaptic receptors (▪).

Adapted from Zigmond and Stricker


Figure 19.

Increased dopaminergic activity after injury to nigrostriatal bundle. A: electrolytic lesion of nigrostriatal bundle in monkeys, leading to apparent increase in dopamine turnover in residual striatal terminals as determined 1–4 mo later. B: intraventricular 6‐OHDA levels in rats, leading to apparent increase in TH in residual striatal terminals.

A adapted from Sharman et al. ; B adapted from Zigmond et al.


Figure 20.

Evidence for presynaptic supersensitivity after 6‐OHDA treatment. A: loss of specific high‐affinity catecholamine uptake sites, as measured by accumulation of [3H]norepinephrine (3H‐NA) into slices of normal tissue and tissue from animals treated with 6‐OHDA 22–30 days previously. In some experiments slices were incubated in presence of 5 μM desmethylimipramine (DMI), an inhibitor of 3H‐NA uptake. Means ± SE of 4–8 experiments are indicated. B: increased responsiveness to L‐dopa. Groups of 3–4 animals received L‐dopa (100 mg/kg) or saline 30 min after receiving RO 4–4602 (50 mg/kg) to inhibit peripheral dopa decarboxylase. Motor activity (counts) was determined from 30 to 60 min after administering L‐dopa. Means ± SE shown are determined 1–15 days after 2nd of 2 6‐OHDA injections (250 μg, 48 h apart).

A from Uretsky and Iversen ; B from Schoenfeld and Uretsky


Figure 21.

Long‐term increase in TH activity after 6‐OHDA treatment (compare with Fig. ).

Adapted from Acheson and Zigmond


Figure 22.

Evidence for increased dopamine receptor density in striatum after 6‐OHDA lesion. A: time course of changes in [3H]spiroperidol binding to striatal membranes. B: striatal dopamine receptor binding 4‐mo postlesion. Only when lesions are almost complete, with TH activity < 7% of control, does 3H‐ligand binding increase. However, with less‐complete lesions there is no evidence of increased binding of either agonist (apomorphine) or antagonist (spiroperidol).

A from Staunton et al. ; B from Creese
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Edward M. Stricker, Michael J. Zigmond. Brain Monoamines, Homeostasis, and Adaptive Behavior. Compr Physiol 2011, Supplement 4: Handbook of Physiology, The Nervous System, Intrinsic Regulatory Systems of the Brain: 677-700. First published in print 1986. doi: 10.1002/cphy.cp010413